Clinical trial NCT03611582
Conditions: Overweight Obesity
Sponsor: Novo Nordisk A/S
Start date: 2018-08-01; Completion date: 2020-04-28
Enrollment: 611 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. Together with the medicine, the participant will also be part of an intensive lifestyle program where the participant will have talks with study staff about healthy food choices, what the participant can do to lose weight and be more physically active. The participant will either get semaglutide or "dummy" medicine - which treatment the participant gets is decided by chance. The participant 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. For the first 2 months the participant will be on a low calorie diet. The diet is made up of bars, shakes and 1 low calorie pre-prepared meal for each day. The study will last for about 1.5 years. The participant will have 32 clinic visits with the study doctor.

Detailed description:

Arms: arm 1: Participants will receive semaglutide 2.4 mg during 68-week treatment period in addition to intensive behavioural therapy. arm 2: Participants will receive semaglutide placebo during 68-week treatment period in addition to intensive behavioural therapy.
Interventions: intervention 1: Semaglutide intervention 2: Placebo (semaglutide)
Intervention descriptions: intervention 1: Subcutaneous (s.c., under the skin) injections of semaglutide once weekly at escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks. intervention 2: S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03611582 
Sponsor trial ID: 
NN9536-4375 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly as 
adjunct to intensive behavioural therapy in subjects with 
overweight or obesity 
Document date: 
03 August 2020 
 


Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Amendment 1 - Global.......................................................................................................................
Amendment  2 - Global......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4375 (STEP 3)
Clinical Trial Report
Appendix 16.1.1
03 August 2020
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
17 January 2018
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
Status:
Final
Page:
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Protocol
Protocol title:
Effect and safety of semaglutide 2.4 mg once-weekly as adjunct to intensive 
behavioural therapy in subjects with overweight or obesity
Substance name: semaglutide
Universal Trial Number: U1111-1200-8199 
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.


Protocol
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Date:
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Trial ID: NN9536-4375
Version:
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Synopsis................................................................................................................................................5
2
Flowchart .............................................................................................................................................8
3
Introduction .......................................................................................................................................13
3.1
Trial rationale..........................................................................................................................13
3.2
Background.............................................................................................................................13
3.2.1
Semaglutide...........................................................................................................13
3.2.2
Trial population .....................................................................................................14
3.3
Benefit-risk assessment ...........................................................................................................14
3.3.1
Benefits .................................................................................................................14
3.3.2
Risks and precautions.............................................................................................15
3.3.3
Conclusion on benefit-risk profile ..........................................................................16
4
Objectives and endpoints...................................................................................................................17
4.1
Primary, secondary and exploratory objectives ........................................................................17
4.1.1
Primary objective...................................................................................................17
4.1.2
Secondary objectives .............................................................................................17
4.1.3
Exploratory objectives ...........................................................................................17
4.2
Primary, secondary and exploratory endpoints.........................................................................18
4.2.1
Primary endpoints..................................................................................................18
4.2.2
Secondary endpoint................................................................................................18
4.2.2.1
Confirmatory secondary endpoints ...................................................18
4.2.2.2
Supportive secondary endpoints .......................................................18
4.2.3
Exploratory endpoints............................................................................................20
5
Trial design ........................................................................................................................................20
5.1
Overall design.........................................................................................................................20
5.2
Subject and trial completion....................................................................................................21
5.3
End of trial definition..............................................................................................................22
5.4
Scientific rationale for trial design...........................................................................................22
5.5
Justification for dose ...............................................................................................................22
6
Trial population .................................................................................................................................23
6.1
Inclusion criteria .....................................................................................................................23
6.2
Exclusion criteria ....................................................................................................................23
6.3
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
7.1.2
Intensive Behavioural Therapy...............................................................................28
7.2
Dose modification...................................................................................................................29
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7.3
Method of treatment assignment..............................................................................................30
7.4
Blinding..................................................................................................................................30
7.5
Preparation/Handling/Storage/Accountability..........................................................................30
7.6
Treatment compliance.............................................................................................................32
7.7
Concomitant medication..........................................................................................................32
7.8
Treatment after the end of the trial...........................................................................................32
8
Discontinuation/Withdrawal criteria ................................................................................................32
8.1
Discontinuation of trial treatment ............................................................................................33
8.1.1
Temporary discontinuation of trial treatment..........................................................34
8.2
Withdrawal from the trial ........................................................................................................34
8.2.1
Replacement of subjects.........................................................................................34
8.3
Lost to follow-up.....................................................................................................................34
9
Trial assessments and procedures .....................................................................................................35
9.1
Efficacy assessments...............................................................................................................36
9.1.1
Body measurements...............................................................................................36
9.1.2
Clinical outcome assessments ................................................................................37
9.1.3
Clinical efficacy laboratory assessments.................................................................37
9.2
Adverse events........................................................................................................................38
9.2.1
Time period and frequency for collecting AE and SAE information........................38
9.2.1.1
Events for adjudication.....................................................................39
9.2.2
Method of detecting AEs and SAEs .......................................................................40
9.2.3
Follow-up on AEs and SAEs..................................................................................40
9.2.4
Regulatory reporting requirements for SAEs ..........................................................41
9.2.5
Hypoglycaemic, cardiovascular and death events ...................................................41
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE...................................................................................................................41
9.2.7
Pregnancies and associated adverse events .............................................................41
9.2.8
Medical device incidents (including malfunctions).................................................42
9.2.9
Technical complaints .............................................................................................42
9.3
Treatment of overdose.............................................................................................................43
9.4
Safety assessments ..................................................................................................................43
9.4.1
Mental health assessment instruments ....................................................................43
9.4.2
Physical examinations............................................................................................44
9.4.3
Vital signs..............................................................................................................44
9.4.4
Electrocardiograms ................................................................................................45
9.4.5
Clinical safety laboratory assessments....................................................................45
9.5
Pharmacokinetics ....................................................................................................................45
9.6
Pharmacodynamics .................................................................................................................45
9.7
Genetics..................................................................................................................................45
9.8
Biomarkers .............................................................................................................................45
9.9
Severe hypersensitivity............................................................................................................45
10
Statistical considerations ...................................................................................................................46
10.1
Sample size determination.......................................................................................................46
10.2
Definition of analysis sets........................................................................................................49
10.3
Statistical analyses ..................................................................................................................50
10.3.1
Primary endpoint ...................................................................................................50
10.3.2
Secondary endpoints ..............................................................................................55
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Trial ID: NN9536-4375
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10.3.2.1
Confirmatory secondary endpoints ...................................................55
10.3.2.2
Supportive secondary endpoints .......................................................57
10.3.3
Exploratory endpoints............................................................................................60
10.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers.....................60
10.3.5
Other analyses .......................................................................................................60
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................60
Abbreviations and Trademarks.......................................................................................61
Appendix 1
Clinical laboratory tests ...................................................................................................64
Appendix 2
Trial governance considerations......................................................................................67
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting .....................................................................................................................................76
Contraceptive guidance and collection of pregnancy information .................................82
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting ................................................................................................................................85
Monitoring of calcitonin...................................................................................................87
Appendix 7
11
References ..........................................................................................................................................90
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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Date:
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Trial ID: NN9536-4375
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1
Synopsis
Rationale:
The present trial is a 68-week trial designed to provide substantial weight loss and weight loss-
dependent health benefits, and to increase the likelihood of long-term weight maintenance in 
subjects with obesity or overweight by combining semaglutide subcutaneous (s.c.) 2.4 mg once-
weekly and intensive behavioural therapy (IBT) including an initial 8-week low-calorie diet (LCD). 
Short-duration LCDs lead to rapid and significant weight loss1, and the combination of LCD and 
highly structured hypo-caloric diets including meal replacements with increased physical activity 
and frequent behavioural counselling (in combination known as IBT) is the current gold-standard 
for lifestyle interventions which increases the likelihood of achieving and maintaining significant 
weight loss2, 3.
Objectives and endpoints
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity. 
Key secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity:
!
Cardiovascular risk factors 
!
Clinical Outcome Assessments (COAs)
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to IBT including an initial 8-week LCD, 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). The 
estimand will cover all effect-related objectives.
The following expansion of the primary estimand will cover the supportive secondary endpoint 
“Change from baseline at week 0 to week 8 in body weight (%)”. The estimand will quantify the 
average treatment effect of semaglutide relative to semaglutide placebo after 8 weeks, as an adjunct 
to IBT including LCD, in all randomised subjects regardless of adherence to treatment and 
regardless of starting rescue interventions.
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Date:
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Trial ID: NN9536-4375
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Primary endpoints 
Primary endpoints addressing the primary objective:
!
Change from baseline at week 0 to week 68 in body weight (%)
!
Subjects who after 68 weeks achieve (yes/no): 
!
Body weight reduction ≥5% from baseline at week 0
Confirmatory secondary endpoints
!
Subjects who after 68 weeks achieve (yes/no): 
!
Body weight reduction ≥ 10% from baseline at week 0 
!
Body weight reduction ≥ 15% from baseline at week 0
!
Change from baseline at week 0 to week 68 in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36) (range of score is 1-100) 
!
Total score (WRSSM)
Overall design:
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre clinical trial conducted in US, which compare semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo, as an adjunct to IBT, in subjects with overweight or obesity. 
Key inclusion criteria
1. Male or female, age ≥ 18 years at the time of signing informed consent
2. 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
3. History of at least one self-reported unsuccessful dietary effort to lose body weight
Key exclusion criteria
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening
2. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening  
irrespective of medical records
3. End stage renal disease defined as estimated Glomerular Filtration Rate (eGFR) value of < 15 
mL/min/1.73 m2 as defined by KDIGO 20124 by the central laboratory at screening
Number of subjects:
Approximately 706 subjects will be screened to achieve 600 subjects randomly assigned to trial 
product.  
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Protocol
CONFIDENTIAL
Date:
17 January 2018
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Trial ID: NN9536-4375
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1.0
Status:
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Page:
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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 fulfilling all randomisation criteria at 
visit 2 will be randomised in a 2:1 manner to receive either semaglutide s.c. 2.4 mg once-weekly or 
semaglutide placebo, as an adjunct to 68 weeks IBT which comprises of an initial 8-week LCD 
followed by 60 weeks hypo-caloric diet and increased physical activity. Subjects will in the first 16 
weeks be dose escalated from 0.25 mg once-weekly until target dose (please see Figure 5-1). 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 for the duration of the trial:
!
Semaglutide B 1.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
!
Semaglutide B 3.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
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Protocol
     
Date:
17 January 2018
Status:
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Trial ID: NN9536-4375
     
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2
Flowchart
Screening
Randomisation 
Dose escalation period
Maintenance period
End of treatment
End of trial
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Timing of Visit (Weeks)
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
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
±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
Randomisation criteria and 
randomisation (6.3)
X
Medical history/Concomitant illness
(9.4)
X
Weight History ( 9)
X
History of Gallbladder Disease
X
History of Breast  Neoplasmb
X
History of Colon  Neoplasm
X
History of Skin Cancer (9.4)
X
History of Psychiatric disorder
X
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Protocol
     
Date:
17 January 2018
Status:
Final
Novo Nordisk
Trial ID: NN9536-4375
     
Version:
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Screening
Randomisation 
Dose escalation period
Maintenance period
End of treatment
End of trial
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Timing of Visit (Weeks)
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
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
±3
±3
±3
±3
±3
±3
±3
0 to +5
Tobacco usec
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
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
X
X
X
X
X
X
X
Evaluation of lipid-lowering 
treatment (9)
X
X
Evaluation of antihypertensive 
treatment (9) 
X
X
Evaluation of glycaemia status
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
X
X
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
HbA1c (Appendix 2)
X
X
X
X
X
Fasting plasma glucose
(Appendix 2)
X
X
X
X
Fasting serum insulin (Appendix 2)
X
X
Lipids (Appendix 2
X
X
X
Biomarkers (9.8)
X
X
X
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Date:
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Screening
Randomisation 
Dose escalation period
Maintenance period
End of treatment
End of trial
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Timing of Visit (Weeks)
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
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
±3
±3
±3
±3
±3
±3
±3
0 to +5
Vital Signs (9.4.3)
    Systolic Blood Pressure
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
Clinical Outcome Assessments
(9.1.2)
Short Form- 36 (SF-36) 
X
X
X
X
X
X
X
Weight related signs 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
Patient Global Impression of 
Change  (PGI-C) 
X
X
X
X
X
X
X
Work productivity activity 
impairment (WPAI-I- SHP)
X
X
X
SAFETY
Physical examination (9.4.2)
X
X
Pregnancy test (9.4.5, Appendix 5)
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
X
X
X
X
X
X
X
Technical complaint (9.2.9)
X
X
X
X
X
X
X
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
X
X
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Date:
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Status:
Final
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Trial ID: NN9536-4375
     
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Screening
Randomisation 
Dose escalation period
Maintenance period
End of treatment
End of trial
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Timing of Visit (Weeks)
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
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
±3
±3
±3
±3
±3
±3
±3
0 to +5
Colon neoplasms follow-up
X
X
Haematology (Appendix 2)
X
X
X
X
Biochemistry (Appendix 2)
X
X
X
X
Vital signs (9.4.3)
    Pulse
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 Suicidality Sev. Rating 
Scale (C-SSRS) 
X
X
X
X
X
X
X
TRIAL MATERIAL
First date on trial product
X
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
X
X
X
X
X
X
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Screening
Randomisation 
Dose escalation period
Maintenance period
End of treatment
End of trial
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Timing of Visit (Weeks)
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
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
±3
±3
±3
±3
±3
±3
±3
0 to +5
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
X
X
X
X
X
X
X
X
X
X
X
X
Dispense activity tracker (7.1.2)
X
Hand out directions for use (7.1.1)
X
Hand out dose reminder card (7.1.1)
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
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 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 and overweight have reached epidemic proportions in most countries 
around the world and the prevalence is still increasing at an alarming rate5-11. The medical and 
societal impacts are considerable and obesity and overweight are some of the most significant 
public health challenges worldwide5-11. Obesity and overweight are 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 diseases, certain types of cancer, and risk of early death12-
26. Moreover, obesity adversely affects physical and mental health and reduces health related quality 
of life27, 28. Obesity is also associated with decreased cardiorespiratory fitness, which also increases 
the risk of cardiovascular diseases and all-cause mortality29.
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 T2D.30-33 Furthermore, a weight loss of 5−10% improves many other obesity related 
comorbidities as well as physical symptoms and quality of life.34-41 Finally, studies suggest a 
beneficial impact of weight loss on cardiovascular risk and mortality in both people with diabetes 
and obesity.42-44
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity and 
overweight, but most people with obesity and overweight struggle to achieve and maintain their 
weight loss.45-54 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 costly.45-50, 55, 56 Pharmacotherapy may therefore serve as a valuable adjunct to 
lifestyle intervention for individuals with obesity and overweight 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 co-morbidities.45-49, 57, 58
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 dosing59. GLP-1 RA is a physiological regulator of appetite and GLP-1 
receptors are present in several areas of the brain involved in appetite regulation60.
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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 13.84% at the highest dose tested 
(0.4 mg once-daily) compared to the weight loss of 2.3% achieved by diet, exercise and placebo 
alone61
Clinical62-66 and non-clinical data67 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)61 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.68 69
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
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percentage points 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, 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. 
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. 
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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 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. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of semaglutide may be found in the IB61 and any updates hereof. 
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4
Objectives and endpoints
4.1
Primary, secondary and exploratory objectives
4.1.1
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity.
4.1.2
Secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity on:
!
Cardiovascular risk factors 
!
Clinical Outcome Assessments (COAs)
!
Glucose metabolism
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo as an adjunct to IBT in subjects with overweight or obesity. 
4.1.3
Exploratory objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity on:
!
Glycaemic status
!
Use of medication for hypertension and dyslipidaemia
!
Work productivity
!
Treatment discontinuation
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to IBT including an initial 8-week LCD, 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). The 
estimand will cover all effect-related objectives.
The following expansion of the primary estimand will cover the supportive secondary endpoint 
“Change from baseline at week 0 to week 8 in body weight (%)”. The estimand will quantify the 
average treatment effect of semaglutide relative to semaglutide placebo after 8 weeks, as an adjunct 
to IBT including LCD, in all randomised subjects regardless of adherence to treatment and 
regardless of starting rescue interventions.
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Secondary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to IBT including an initial 8-week LCD, in all randomised 
subjects had they remained on their randomised treatment for the entire planned duration of the trial 
and not started any rescue intervention (weight management drugs or bariatric surgery) 
(“efficacy”/“hypothetical” estimand). The estimand will cover the primary objective.
4.2
Primary, secondary and exploratory endpoints
4.2.1
Primary endpoints 
Primary endpoints addressing the primary objective:
!
Change from baseline at week 0 to week 68 in body weight (%)
!
Subjects who after 68 weeks achieve (yes/no): 
!
Body weight reduction ≥5% from baseline at week 0
4.2.2
Secondary endpoint
The confirmatory and supportive secondary endpoints addressing the primary and secondary 
objectives are listed in Section 4.2.2.1 and 4.2.2.2.
4.2.2.1
Confirmatory secondary endpoints
Subjects who after 68 weeks achieve (yes/no): 
!
Body weight reduction ≥10% from baseline at week 0
!
Body weight reduction ≥15% from baseline at week 0
Change from baseline at week 0 to week 68 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
Change from baseline at week 0 to week 68 in:
!
Body weight (kg)
!
BMI (kg/m2)
!
Hemoglobin A1c (HbA1c) (%, mmol/mol)
!
Fasting plasma glucose (mg/dL)
!
Fasting serum insulin (μIU/mL)
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!
Diastolic blood pressure (mmHg)
!
Lipids (mg/mL)
!
Total cholesterol
!
High-density lipoprotein
!
Low-density lipoprotein
!
Very low-density lipoprotein
!
Free fatty acids
!
Triglycerides
!
High sensitivity C-reactive protein (hsCRP) (mg/L)
!
Plasminogen activator inhibitor-1 (PAI-1) Activity (UA/mL)
!
SF-36: (range of score is 1-100) 
!
Role-Physical score
!
Bodily Pain score 
!
General Health score
!
Vitality score
!
Social Functioning score 
!
Role-Emotional score 
!
Mental Health score 
!
Physical component summary
!
Mental component summary
Subjects who after 68 weeks achieve (yes/no):
!
Responder definition value for SF-36 physical function score
!
Responder definition value for WRSSM total score 
Change from baseline at week 0 to week 8 in body weight (%)
Safety endpoints
Number of treatment-emergent adverse events (TEAEs) from baseline at week 0 to week 75
Number of serious adverse events (SAEs) from baseline at week 0 to week 75
Change from baseline at week 0 to week 68 in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L)
!
Calcitonin (ng/L)
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4.2.3
Exploratory endpoints
Exploratory endpoints addressing the exploratory objectives:
Change from baseline at week 0 to week 68 in:
!
Glycaemic category (normo-glycaemia, pre-diabetes, T2D)
!
Antihypertensive medication (decrease, no change, increase)
!
Lipid lowering medication (decrease, no change, increase)
!
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem V2.0 
(WPAI-SHP)
!
Work time missed due to weight (%)
!
Impairment while working due to weight (%)
!
Overall work impairment due to weight (%)
!
Activity impairment due to weight (%)
Subjects who from randomisation to week 68 have permanently discontinued randomised trial 
product (yes/no)
Time to permanent discontinuation of randomised trial product (weeks) 
5
Trial design
5.1
Overall design
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre clinical trial conducted in US, which compare semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo, as an adjunct to IBT, in subjects with overweight or obesity. 
The trial includes a screening visit to assess the subject’s eligibility followed by weekly visits 
during the first 12 weeks. From week 12 to 24, visits will take place every 2nd week. From week 24, 
visits 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.
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Figure 5-1
Trial Design
Figure 5-1 A schematic diagram of the trial design with the duration of the trial periods including 
follow-up period
The follow-up period is 7 weeks. 
5.2
Subject and trial completion
Approximately 706 subjects will be screened to achieve 600 subjects randomly assigned to trial 
product.
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 at 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.
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5.3
End of trial definition
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
5.4
Scientific rationale for trial design
The treatment duration of the trial is 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 (including 52 weeks on target dose) is considered 
sufficient to assess weight loss, safety and tolerability in the phase 3 weight management 
development programme in accordance with regulatory guidelines68 69.
A randomised, double-blinded, placebo-controlled, two-armed, parallel group, multi-centre 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 IBT. 
Short-duration LCDs lead to rapid and significant weight loss1. By transitioning subjects from LCD 
to a highly structured hypo-caloric diet while combining with increased physical activity and 
frequent behavioural counselling the trial follow the current gold-standard for long term lifestyle 
interventions.
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 GI 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.
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6
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1
Inclusion criteria
Subjects are eligible to be included in the trial only if all 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 the 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 TSH > 6.0 mIU/L or < 0.4 mIU/L as measured by the 
central laboratory at screening
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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
General safety:
14. Subject is unable to adhere to low-calorie diet as judged by the investigator
15. Physical activity is considered to be unsafe as judged by the investigator
16. Presence of acute pancreatitis within the past 180 days prior to the day of screening
17. History or presence of chronic pancreatitis 
18. Calcitonin ≥ 100 ng/L as measured by the central laboratory at screening
19. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma
20. End stage renal disease defined as estimated Glomerular Filtration Rate (eGFR) value of < 15 
mL/min/1.73 m2 as defined by KDIGO 20124 by the central laboratory at screening
21. History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous 
cell skin cancer and any carcinoma in-situ are allowed
22. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening
23. Subject presently classified as being in New York Heart Association (NYHA) Class IV
24. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator 
25. Known or suspected abuse of alcohol or recreational drugs
26. Known or suspected hypersensitivity to trial product(s) or related products
27. Previous participation in this trial. Participation is defined as signed informed consent 
28. Participation in another clinical trial within 90 days before screening 
29. Other subject(s) from the same household participating in any semaglutide trial
30. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using highly effective contraceptive methods
31. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, 
which in the investigator’s opinion, might jeopardise the subject’s safety or compliance with the 
protocol
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
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6.3
Randomisation criteria 
Subjects are eligible to be randomised in the trial only if all of the following criteria apply:  
1. Have kept a food diary with at least one entry per day between screening and randomisation.     
However, missed entries for a maximum of two days are allowed. 
2. A Patient health questionnaire-9 (PHQ-9) score of < 15 at randomisation. 
3. No suicidal behaviour in the period between screening and randomisation.  
4. No suicidal ideation corresponding to type 4 or 5 on the Columbia–Suicide Severity Rating  
Scale (C-SSRS) in the period between screening and randomisation.  
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 fasting plasma glucose (FPG), fasting serum insulin and free fatty acids.
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 and/or randomisation 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 serious adverse 
event (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 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
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7
Treatments
7.1
Treatments administered
!
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 or 
Semaglutide placebo* 
Semaglutide B
3.0 mg/mL PDS290 or 
Semaglutide placebo
Dosage form:
Solution for injection
Solution for injection
Route of administration: 
Subcutaneous
Subcutaneous
Dosing instructions:
Once-weekly
Once-weekly
Delivery device
3 mL PDS290 pre-filled pen-injector
3 mL PDS290 pre-filled pen-injector
          * Semaglutide B 1.0 mg/mL PDS290/semaglutide placebo will only be dispensed at the first dispensing visit.
!
Dose escalation of semaglutide/semaglutide placebo should take place during the first 16 weeks 
after randomisation as described in Table 7-2. All subjects should aim at reaching the
recommended target dose of 2.4 mg semaglutide once-weekly or the corresponding volume of 
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 consults Novo Nordisk in case of persistent deviations 
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
Dose escalation period
Semaglutide B 1.0 mg/mL
PDS290/ 
semaglutide placebo
0.25 mg
0.25 mL
25*
4 weeks
Semaglutide B 1.0 mg/mL 
PDS290/ 
semaglutide placebo
0.5 mg
0.50 mL
50*
4 weeks
Semaglutide B 3.0 mg/mL/ 
semaglutide placebo
1.0 mg
0.34 mL
34*
4 weeks
Semaglutide B 3.0 mg/mL/ 
semaglutide placebo
1.7 mg
0.57 mL
57*
4 weeks
Maintenance period
Semaglutide 3.0 mg/mL/ 
semaglutide placebo
2.4 mg
0.80 mL
80*
52 weeks
*Conversion to dose is calculated based on 0.01mL/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. Subjects will be provided with an Activity Tracker (Section 7.1.2)
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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.
Activity Tracker 
The activity tracker will be used for counselling purposes.  Data from the tracker will be 
used for exploratory purposes. 
7.1.1
Medical devices
Information about the PDS290 pre-filled pen-injector may be found in the IB61 and any updates 
hereof.
Information about the use of the pre-filled PDS290 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
Intensive Behavioural Therapy 
The structure and content of each IBT session is specified in an IBT guide, consisting of a dietician 
part and a subject hand-outs. 
Each IBT session will cover a specific topic, for example, advice on diet or physical activity as well 
as lifestyle modification (e.g., challenging negative thoughts, obtaining social support).  Subjects 
will receive weekly intensive behavioural support by a dietician or a similarly qualified healthcare 
professional and discuss progress, review food diary/app and address any compliance or other 
issues and prepare for transition to the next phase with structured diet. Most of the topics will be 
accompanied by a homework assignment from the subject hand-outs to be completed before next 
visit according to the visit schedule. Behavioural support will gradually decrease from weekly to bi-
weekly and finally monthly sessions. 
After randomisation the dietary intervention should start. The first 8 weeks should consist of a 
1000-1200 kcal/day low-calorie diet (LCD), at the discretion of the investigator, provided as meal 
replacements (e.g. liquid shakes and solid bars) and portion controlled meals. 
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Meal replacements will be supplied by Novo Nordisk. 
Physical activity should be initiated from randomization and be prescribed with a target of 100 
minutes physical activity per week. Subjects should be physically active in bouts of >10 minutes in 
duration with moderate intensity (such as brisk walking), and the physical activity should be spread 
equally across 4-5 days each week. Physical activity should progress gradually by 25 minutes every 
4 weeks and up to 200 minutes/week, consistent with targets required for maintenance of lost 
weight70. 
After 8 weeks on LCD, subjects should gradually be transferred to a less strict hypo-caloric diet 
comprised of conventional foods. From week 8 to ‘end of treatment’ daily caloric target should be 
calculated based on body weight at randomisation (Visit 2) according to below algorithm:
!
Subjects weighing less than 200 lbs should be prescribed a diet of 1200 kcal/day
!
Subjects weighing between 200 lbs and 300 lbs should be prescribed a diet calculated as: 
 	
	 (	) = 
 ℎ() ∗6 (	/)
!
Subjects weighing more than 300 lbs should be prescribed 1800 kcal/day
This caloric target should be kept for the remainder of the trial. If a subject achieves a BMI ≤ 22.5 
kg/m2, the recommended energy intake should be re-calculated with no caloric deficit for the 
remainder of the trial. 
Subjects will receive and use an activity tracker and will be instructed to record their food intake in 
order to assist their lifestyle intervention. The activity tracker, food diary/app and content of the 
subject hand out from IBT guide will be used for counselling purposes by the dietician or a 
similarly qualified healthcare professional at all visits. 
Data from the activity tracker collected in this trial will be used for exploratory purposes. Subjects 
will be allowed to keep the activity tracker after approval by the independent ethics committee
(IEC)/institutional review board (IRB). 
Subjects may use a food registry tool of their own choice (paper/app/other tool) for dietary 
recording, ensuring it can be reviewed during the counselling sessions. Subjects must receive 
instructions in how to capture food intake and should be encouraged to keep the diary on a daily 
basis.
7.2
Dose modification
Not applicable for this trial. Please refer to Section 7.1 for description of missed dose(s). 
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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 active drug and placebo are visually identical for the following trial products:
!
Semaglutide B 1.0 mg/mL PDS290/semaglutide placebo
!
Semaglutide B 3.0 mg/mL PDS290 /semaglutide placebo
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 subjects medical records. 
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. 
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Table 7-4
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 placebo
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
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 and randomised. 
!
The investigator must confirm that appropriate temperature conditions have been maintained 
during transit for all trial products received (see Table 7-4) 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.
!
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.
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!
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 
record.
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 treatment is initiated, the subject should be instructed to stop the 
anti-obesity treatment.
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.
7.8
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 to 
receive the IBT and assessments performed. 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.
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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.
!
If the subject does not wish to attend the scheduled clinical 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.
!
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 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
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 criteria71 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 (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 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. 
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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 temporarily 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 been made 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. 
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. 
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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 the ‘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. 
!
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 (Section 9.1.2) and mental health assessment instruments 
(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.
!
Subject must receive instructions in how to capture their daily food intake in the handed out 
food diary from screening to randomisation. Entries must be evaluated in accordance with the 
randomisation criteria.
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!
Only the subject can make entries and corrections in the diaries, unless the section is specified 
for site staff.
!
Subjects should wear the provided activity tracker.
!
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.
!
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.
!
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 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 definitions72. 
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.
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!
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 assessments
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: 
!
.Weight Related Sign and Symptom Measure (WRSSM), version 2.
!
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 sign of signs and symptoms,
version 4b.
!
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-
SHP), version 2.0. The WPAI-SHP is as a patient-reported quantitative assessment of the 
amount of absenteeism, presenteeism and daily activity impairment attributable to a specific 
health problem.73
!
Occupation and income group, version 1.0: Collection of information on occupation and
income.
!
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 scores.74
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 laboratory manual. 
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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 9-1.
Some AEs require additional data collection via a specific event form in the CRF. This includes 
medication errors observed during the trial. The relevant specific events are listed in Table 9-1 and 
the reporting timelines in Figure 9-1.
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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
9.2.1.1
Events for adjudication
Event adjudication will be performed for adverse events in randomised subjects.
These events are reviewed by an independent external event adjudication committee in a blinded 
manner, refer to Appendix 3 for further details.
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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.
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 event adjudication system (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 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.
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.
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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 
(SUSAR) 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 9.2.1.1.
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 9-2 and Appendix 5. 
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
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Maternal form 1b
≤14 calendar days after birth
Maternal form 1a
≤14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤14 calendar days
Paternal form*1 ≤14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy.
9.2.8
Medical device incidents (including malfunctions)
Section 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 9-2.
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.
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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 (Appendix 4) and for reporting timelines 
(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 IB61
9.4
Safety assessments 
Planned time points for all safety assessments are provided in the flowchart.
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 de 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 at week 0 must be reported as an AE (Section 9.2).
9.4.1
Mental health assessment instruments
!
PHQ-975 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.
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!
C-SSRS76is 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 and translated version. 
!
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
!
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 
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 blood pressure) 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.
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9.4.4
Electrocardiograms
!
12-lead ECG will be outlined as specified in the flowchart using a local ECG machine that 
automatically calculates the heart rate and measures PR, QRS, and 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 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.
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
Collection of samples for biomarker research is part of this trial to support the effect objectives. The 
following samples must be conducted in accordance with the laboratory manual and the flowchart.
Biomarkers linked to cardiovascular risk:
!
Plasminogen Activator Inhibitor-1 (PAI-1) Activity will be analysed by activity assay.
!
High sensitive C-reactive protein (hsCRP)
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 
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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 (CTR).
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).
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 
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successively. As the two primary endpoints are included in the statistical testing hierarchy, 
significant superiority of semaglutide 2.4 mg vs. semaglutide placebo must be demonstrated for 
each of the primary endpoints.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) is 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.
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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
!
For binary endpoints the Pearson chi-square test for two independent proportions is used 
!
Based on data from NN9536-4153
!
20% of subjects discontinue permanently and 
!
60% of these are retrieved (AD) at week 68 
!
All subjects in the placebo arm are assumed to have same effect as subjects who complete the 
trial on 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 600 subjects (400 in the semaglutide 2.4 mg once 
weekly and 200 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 86% for the first seven endpoints in the hierarchical testing procedure. 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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Table 10-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number 600 randomised 
subjects
Order
Endpoint
Assumed mean (±SD) or 
proportion for completers
Expected mean 
(±SD) or 
proportion
Expected 
difference 
or 
proportion 
ratio
Marginal 
power 
(%)
Effective 
power 
(%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight loss #
17 (10)
7 (10)
15.6 (11)
8.6 %-
points
> 99
> 99
2
5% responders
88%
58%
85%
1.5
> 99
> 99
3
10% responders
76%
38%
71%
1.9
> 99
> 99
4
15% responders
58%
21%
53%
2.5
> 99
> 99
5
WC change (cm) #
17 (11)
8 (11)
15.7 (12)
7.7 cm
> 99
> 99
6
sBP change (mmHg) 
#
9.1 (13)
4.5 (13)
8.5 (14)
4 mmHg
91
91
7
SF-36 PF score 
change
6 (±10)
2 (±10)
5.4 (±11)
3.4 score-
points
95
86
8
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; # shown as a positive number
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 randomised subjects exposed to at least one dose of 
randomised treatment.
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 
randomisation 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.
!
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.
!
For the evaluation of adverse events the lag time for each on-treatment time interval is 7 
weeks (49 days)
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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 value. 
If no assessments are available, the mean value at randomisation across all subjects is used as the 
baseline value.
10.3.1
Primary endpoint
Definition of primary endpoint: % weight change
Change from baseline (week 0) 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.
Definition of primary endpoint: 5% responders
A body weight reduction of least 5% from baseline (week 0) to week 68 is defined as 
5% responder = 1 if  % weight change ≤ – 5%
0 if  % weight change > – 5%
Analyses addressing the primary estimand
The following statistical analyses 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 
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treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% CI and corresponding p-value.
The analysis model for the 5% responder endpoint is a logistic regression using randomised 
treatment as a factor and baseline body weight (kg) as covariate. The estimated odds ratio (OR) 
between semaglutide 2.4 mg and semaglutide placebo will be reported together with the associated 
two-sided 95% CI and corresponding p-value.
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows 
for the two analysis models.
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
:  !"#$%&'( ≥ !"#$%&'( *$"+ ,- ./
0:  !"#$%&'( <  !"#$%&'( *$"+ ,-.
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Let ORsemaglutide/semaglutide placebo denote the true odds ratio between semaglutide 2.4 mg and
semaglutide placebo. The null and alternative hypotheses tested are
: 34 !"#$%&'( / !"#$%&'( *$"+ ,- ≤1 ./
0: 34 !"#$%&'( / !"#$%&'( *$"+ ,- > 1.
The hypothesis will be rejected and superiority claimed, if the lower limit of the estimated two-
sided 95% CI is above 1.
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 endpoints 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 endpoints is given followed by a description o f 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 77. 
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 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 17 weeks). If timing by quarters is too 
restrictive, halves (intervals of 34 weeks) 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 models 
(ANCOVA and logistic regression) results in 1,000 times 2 estimations.
3. Pooling: Integrates the 1,000 times 2 estimation results into two final results 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 95364375 as seed number.
Sensitivity analysis
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 IBT including an initial 8-week LCD78. The multiple imputation approach is done as 
above with the first step replaced by:
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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 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 Sacks79 (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 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 analyses 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.
Non-retrieved subjects as non-responders: For the 5% responder analysis an analysis using non-
retrieved subjects as non-responders in the logistic regressions will be done.
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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 analyses 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. 
The secondary estimand for 5% responders will be assessed using the same MMRM for efficacy. 
From the MMRM individually predicted values for % weight change at week 68 will be used to 
classify each subject as 5% responder or not. This classification will then be analysed using a 
logistic regression model with treatment as the only factor.
An overview of all analysis and imputation methods to address the effectiveness and efficacy 
estimands for the primary endpoints 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 endpoints and to address the primary estimand. The imputation model is the same as 
for the primary endpoints 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 body weight replaced by the baseline 
assessment of the endpoint to be analysed. The statistical model for body weight responder
endpoints will be logistic regression with factor and covariate as for the primary endpoint 5% 
responders. 
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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 
endpoints.
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. For all binary confirmatory secondary endpoints a 
sensitivity analysis using non-retrieved subjects as non-responders will be carried out.
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.
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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 endpoints
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS
MMRM
-
-
Primary
5% responders
2
Binary
Primary
FAS
LR
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Non-
responder
Secondary
FAS
LR
MMRM
-
Confirmatory secondary endpoints
Primary
10% responders
3
Binary
Primary
FAS
LR
RD-MI
Non-
responders
Secondary
FAS
LR
MMRM
-
Primary
15% responders
4
Binary
Primary
FAS
LR
RD-MI
Non-
responders
Secondary
FAS
LR
MMRM
-
Primary
WC change (cm)
5
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
6
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
7
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
WRSSM total score 
change
8
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; LR = logistic regression; 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 endpoints and to address the primary estimand. The imputation 
model is the same as for the primary endpoints 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 body weight 
replaced by the baseline assessment of the endpoint to be analysed. The statistical model for 
responder endpoints relating to COAs will be logistic regression with randomised treatment as a 
factor and the baseline assessment of the endpoint to be analysed as covariate.
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For lipids and biomarkers a multiplicative model will be used, i.e. the ratio between post 
randomisation measurements and baseline 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 
endpoints.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
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)
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 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
hsCRP change (mg/L)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
PAI-1 change (mg/L)
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
% weight change*
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Supportive secondary endpoints (safety related)
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 
statistic
-
-
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; hsCRP = high sensitivity C-Reactive Protein; 
PAI-1 = Plasminogen Activator Inhibitor-1; 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; * from 
baseline to week 8
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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
Explorative statistical analysis for pharmacogenetics and biomarkers
The statistical analysis of biomarker endpoints is described under section 10.3.2.2. 
10.3.5
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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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
CI
confidence interval 
CLAE
clinical laboratory adverse event
COA
Clinical Outcome Assessments
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTR
clinical trial report 
DFU
direction for use 
DUN
dispensing unit number
EAC
event adjudication committee 
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 lipoprotein 
HRT
hormone replacement therapy
hsCRP
high sensitive C-reactive protein 
IB
investigator’s brochure
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IBT
intensive behavioural therapy 
ICH
International Council for Harmonisation
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
LCD 
low-calorie diet 
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 
OR
odds ratio
PAI-1
plasminogen Activator Inhibitor-1 
PCD
primary completion date
PGI-C
Patient Global Impression of Change 
PGI-S
Patient Global Impression of Severity 
PHQ-9
Patient Health Questionnarie -9
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan 
SAS
safety analysis set 
sBP
systolic blood pressure 
s.c.
subcutaneous
SIF
safety information form
SD
standard deviation 
SF-36
Short Form-36 v2.0 acute
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SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes 
TEAE
treatment emergent adverse event 
TMM
trial materials manual
TSH 
thyroid stimulating hormone 
UNL
upper normal limit 
VLDL
very-low-density lipoprotein 
WC
waist circumference
WOCBP
woman of child bearing potential
WPAI-SHP 
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem
WRSSM
Weight related sign and symptom measure v2.0
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Clinical laboratory tests
Appendix 2
!
The tests detailed in Table 10-5 and Table 10-6 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 10-5
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism 
!
Fasting plasma glucose1
!
HbA1c
!
Fasting serum insulin
Lipids
!
Cholesterol
!
High density lipoprotein (HDL) cholesterol
!
Low density lipoprotein (LDL) cholesterol
!
Triglycerides
!
Very-low-density lipoprotein (VLDL) cholesterol
!
Free fatty acids
Biomarkers
!
Plasma PAI -1 Activity
!
Serum hsCRP
Note: 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 10-6
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
!
Basophils
!
Eosinophils
!
Erythrocytes
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Lymphocytes
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!
Monocytes
!
Neutrophils
!
Thrombocytes
Biochemistry1
!
Alanine Aminotransferase (ALT)2
!
Albumin
!
Albumine corrected calcium
!
Alkaline phosphatase
!
Amylase5
!
Aspartate Aminotransferase (AST)2
!
Calcitonin5
!
Creatine kinase
!
Creatinine
!
Lipase5
!
Potassium
!
Sodium
!
Total Bilirubin
!
Thyroid stimulating hormone (TSH)3
!
Urea
Pregnancy Testing
!
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)4
Other tests
!
eGFR calculated by the central laboratory based on the creatinine value using 
the CKD-EPI equation as defined in KDIGO 20124
!
(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 samples should be taken from subjects to analyse, 
international normalised ratio (INR) by central laboratory (except at screening visit). Repeat testing of the abnormal 
lab assessments should be performed for the subject until abnormalities return to normal or baseline state.
3If 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
4Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
5Not collected at week 52  
Laboratory outlier: If the following laboratory parameters are above/below the cut-off values in 
Table 10-7 they are considered to be laboratory outliers and should be reported by completing a 
laboratory outlier form in the CRF:
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Table 10-7
Criteria for laboratory outliers
Cut-off
Haematology
Leucocytes
< 1 × 109/L
Lymphocytes
< 0,2 × 109/L
Thrombocytes
< 25 × 109/L
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 outliers: If the following hepatic laboratory parameters are above the cut-off
values in Table 10-8, it is considered to be hepatic laboratory outliers and should be reported as a 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 10-8
Criteria for hepatic laboratory outliers 
Cut-off
Alkaline phosphatase
>20 x UNL
ALT
>5 x UNL
AST
>5 x UNL
Total bilirubin
>10 x 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:
!
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki80and applicable ICH Good Clinical Practice (GCP) Guideline81
!
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:
!
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
!
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
!
providing oversight of the conduct of the trial at the site and adherence to requirements of  
ICH guidelines, the IRB/IEC, and all other applicable local regulations
!
ensuring submission of the clinical trial report synopsis to the IRB/IEC.
2) Financial disclosure
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial.
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest.
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. 
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!
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
!
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 guidelines 81, Declaration of Helsinki80 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 tran slated 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, fitness memberships, 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.
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 
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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 obesity82. In addition, events of acute pancreatitis will be adjudicated because Novo Nordisk 
monitors these events closely as treatment with GLP-1 agonists has been associated with acute 
pancreatitis. 
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 
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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 publications83.
Communication of results
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means. 
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication.
Authorship
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications.
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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 83.
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)84, the Food and Drug Administration Amendment 
Act (FDAAA)85, European Commission Requirements23, 86, 87, 88, 89and 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 
completed ‘end of treatment’ visit. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to FDAAA.
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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:
!
Pregnancy forms
!
The following will be provided as paper CRFs to be used when access to the electronic CRF is 
revoked or temporarily unavailable: 
!
AE forms 
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related, 
e.g. discovered at trial site before allocation)
!
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 addition the relevant trial site staff should be available for 
discussions at monitoring visits and between monitoring visits (e.g. by telephone). 
!
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 
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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 outcomes instruments are the data originators. 
Data will be transmitted to a technology service provider database, thus the service provider 
database is the source. 
!
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.
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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 t ime, 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
!
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 
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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. 
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
o
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.
o
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
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Note:

Hospitalisations for administrative, trial related and social purposes do not constitute AEs and should 
therefore not be reported as AEs or SAEs.

Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
!
Results in persistent disability/incapacity
o
The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
o
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:
o
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.
o
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
– 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 >3 x UNL 
and total bilirubin > 2 x UNL, where no alternative aetiology exists (Hy's 
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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.
!
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 
!
Acute pancreatitis
!
Mild
!
Moderately severe
!
Severe 
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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
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.
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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.
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.
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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):
o
AE form within 24 hours.
o
Safety information form within 5 calendar days. 
o
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 10-9
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 b
! oral 
! intravaginal 
! transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
! oral 
! injectable 
Highly effective methods that are user independentb
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 abstinenceb
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
Notes: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
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 10-9 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 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 flowchart.
!
Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period, if required locally.
!
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 9.4. 
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 
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complaint form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID.
All technical complaints are handled by Customer Complaint Center, Novo Nordisk. Technical 
complaints related to adverse events will be included in the CTR. 
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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 10-2 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 10-2
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 (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 disease90 . 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 disease90. 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 disease90. 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.90 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 conclusions91, 92.
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Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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Clinical Trial Report
Appendix 16.1.1
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Protocol Amendment
no 1
to Protocol, version 1
dated 17 Jan 2018
Trial ID:NN9536-4375
Effect and safety of semaglutide 2.4 mg once-weekly as adjunct to intensive behavioural 
therapy in subjects with overweight or obesity
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.
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Protocol Amendment no 1
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Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 1 Synopsis ....................................................................................................................3
2.2
Section 3.2  Background............................................................................................................3
2.3
Section 6.2 Exclusion criteria ....................................................................................................4
2.4
Section 7.1  Treatments administered ........................................................................................5
2.5
Section 7.1.2  Intensive Behavioural Therapy............................................................................5
2.6
Section 8  Discontinuation/Withdrawal criteria..........................................................................5
2.7
Section 9.2.9 Technical complaints............................................................................................5
2.8
Section 10.1 Sample size determination.....................................................................................6
2.9
Section 10.3.1 Primary endpoints ..............................................................................................6
2.10
Appendix 3  Trial governance considerations ............................................................................6
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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
Key exclusion criteria
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening
2. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening  
irrespective of medical records
3. End stage renal disease defined as estimated Glomerular Filtration Rate (eGFR) value of < 15 
mL/min/1.73 m2 as defined by KDIGO 20124 by the central laboratory at screening
2.2
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 regulation60.
Clinical62-667 and non-clinical data 67new 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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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.
2.3
Section 6.2
Exclusion criteria
20. End stage renal disease defined Renal impairment measured as estimated Glomerular Filtration 
Rate (eGFR) value of < 15 mL/min/1.73 m2 as defined by KDIGO 20124 by the central 
laboratory at screening
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2.4
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
2.5
Section 7.1.2 
Intensive Behavioural Therapy
Subjects will receive and use an activity tracker and will be instructed to record their food intake in 
order to assist their lifestyle intervention. The activity tracker, food diary/app and content of the 
subject hand out from IBT guide will be used for counselling purposes by the dietician or a 
similarly qualified healthcare professional at all visits. Data collected from the activity tracker will 
be reported outside the CTR.
2.6
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 randomisation 
criteria
2 1. Safety concern as judged by the investigator
3.2. Calcitonin ≥ 100 ng/L (see Appendix 9)
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 criteria71 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).
2.7
Section 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 2 9-3.
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2.8
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 600 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; # shown as a positive number
All tests in the hierarchy are based on the primary estimand
2.9
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; LR = logistic regression; 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
2.10
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.
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
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Protocol Amendment
no 2
to Protocol, version 2
dated 07 June 2018
Trial ID:
Effect and safety of semaglutide 2.4 mg once-weekly as adjunct to intensive behavioural 
therapy in subjects with overweight or obesity
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.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
2 of 11
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...................................................................................................................4
2.3
Section 4 Objectives and endpoints ...........................................................................................4
2.4
Section 7 Treatments.................................................................................................................5
2.5
Section 7.1.1 Medical devices ...................................................................................................5
2.6
Section 7.4 Blinding..................................................................................................................5
2.7
Section 7.5 Preparation/Handling/Storage/Accountability..........................................................6
2.8
Section 9.2.1 Time period and frequency for collecting AE and SAE information......................6
2.9
Section 10 Statistical considerations..........................................................................................6
2.10
Appendix 4 Adverse events: definitions and procedures for recording, evaluation, follow-
up, and reporting .....................................................................................................................10
2.11
Appendix 5 Contraceptive guidance and collection of pregnancy information..........................10
2.12
Appendix 6 Technical complaints: Definition and procedures for recording evaluation, 
follow-up and reporting...........................................................................................................11
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
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1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons:
!
To fulfil the regulatory requirements for clinical trial testing of the intended to-be-marketed 
drug product (semaglutide B 3.2 mg/mL PDS290). Subjects will switch from semaglutide B 3.0 
mg/mL PDS290/semaglutide placebo to semaglutide B 3.2 mg/mL PDS290/semaglutide 
placebo at week 60 (visit 29).
!
Confirmatory, supportive secondary and exploratory endpoints related to 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 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
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity, on body weight.
Confirmatory secondary endpoints
Change from baseline at week 0 to week 68 in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36) (range of score is 1-100)
!
Total score (WRSSM)
Treatment groups and duration:
The following trial products will be supplied by Novo Nordisk for the duration of the trial:
!
Semaglutide B 1.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
!
Semaglutide B 3.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
!
Semaglutide B 3.2 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
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Status:
Final
     
Page:
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2.2
Section 2
Flowchart
Concomitant medication X added at V32, Hand out directions for use X added at V29, and Hand 
out dose reminder card X added at V29.
2.3
Section 4
Objectives and endpoints
Section 4.1.1
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity, on body weight.
Section 4.2.2.1
Confirmatory secondary endpoints
Change from baseline at week 0 to week 68 in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36)
!
Total score (WRSSM)
Section 4.2.2.2
Supportive secondary endpoints
Effect endpoints
!
SF-36: (range of score is 1-100)
Subjects who after 68 weeks achieve (yes/no):
!
Responder definition value for WRSSM total score
Section 4.2.3 
Exploratory endpoints
Exploratory endpoints addressing the exploratory objectives:
Change from baseline at week 0 to week 68 in:
!
Glycaemic category (normo-glycaemia, pre-diabetes, T2D)
!
Antihypertensive medication (decrease, no change, increase)
!
Lipid lowering medication (decrease, no change, increase)
!
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem V2.0 
(WPAI-SHP)
o
Work time missed due to weight (%)
o
Impairment while working due to weight (%)
o
Overall work impairment due to weight (%)
o
Activity impairment due to weight (%)
!
Total score (WRSSM)
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
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2.4
Section 7
Treatments
Table 7-1
Trial product provided by Novo Nordisk A/S
Trial product name:
Semaglutide B
1.0 mg/mL PDS290 or 
Semaglutide placebo*
Semaglutide B
3.0 mg/mL PDS290 or 
Semaglutide placebo
Semaglutide B
3.2 mg/mL PDS290 or 
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/semaglutide placebo will only be dispensed at the first dispensing visit
**Semaglutide B 3.2 mg/mL PDS290/semaglutide placebo will only be dispensed at the last dispensing visit
Section 7.1 
Treatments administered
!
A dose reminder card will be handed out to the subjects at each site visit during the 
escalation period and at week 60 (last dispensing visit). 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, with exception of week 60 (last 
dispensing visit) the dose reminder card is only handed out as needed. 
Table 7-2
Dose escalation and maintenance of semaglutide/semaglutide placebo
Trial Product name
Dose
Volume
Value shown in 
dose counter
Duration
Maintenance period
Semaglutide B 3.0 mg/mL/
semaglutide placebo
2.4 mg
0.80 mL
80*
44 weeks
Semaglutide B 3.2 mg/mL/
semaglutide placebo
2.4 mg
0.75 mL
75*
8 weeks
*Conversion to dose is calculated based on 0.01 mL/value for both all strengths.
2.5
Section 7.1.1
Medical devices
Information about the use of the pre-filled PDS290 pen-injector for semaglutide 1.0 mg/mL 
semaglutide 3.0 mg/mL, semaglutide 3.2 mg/mL, and semaglutide placebo can be found in the 
DFU.
2.6
Section 7.4
Blinding
The active drug and placebo are visually identical for the following trial products:
!
Semaglutide B 1.0 mg/mL  PDS290/semaglutide placebo
!
Semaglutide B 3.0 mg/mL PDS290 /semaglutide placebo
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
6 of 11
!
Semaglutide B 3.2 mg/mL PDS290 /semaglutide placebo
2.7
Section 7.5
Preparation/Handling/Storage/Accountability
Table 7-4
Trial product storage conditions
Trial product name
Storage conditions
(not-in-use)
In-use conditions
In-use time
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 placebo
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
Semaglutide B 3.2 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
2.8
Section 9.2.1
Time period and frequency for collecting AE and SAE information
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
Misuse or abuse of trial product*
X
*Additional data for misuse or abuse of trial product is reported on the medication error event form.
2.9
Section 10
Statistical considerations
Section 10.1
Sample size determination
Assumptions
Given these assumptions, the sample size of 600 subjects (400 in the semaglutide 2.4 mg once 
weekly and 200 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 86% for the first seven endpoints in the hierarchical testing procedure. 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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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
7 of 11
Table 10-2 
Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 600 randomised subjects
Order
Endpoint
Assumed mean (±SD) or 
proportion for completers
Expected 
mean (±SD) 
or proportion
Expected 
difference or 
proportion 
ratio
Marginal 
power (%)
Effective 
power (%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight loss #
17 (10)
7 (10)
15.6 (11)
8.6 %-points
> 99
> 99
2
5% responders
88%
58%
85%
1.5
> 99
> 99
3
10% responders
76%
38%
71%
1.9
> 99
> 99
4
15% responders
58%
21%
53%
2.5
> 99
> 99
5
WC change (cm) #
17 (11)
8 (11)
15.7 (12)
7.7 cm
> 99
> 99
6
sBP change (mmHg) 
#
9.1 (13)
4.5 (13)
8.5 (14)
4 mmHg
91
91
7
SF-36 PF score 
change
6 (±10)
2 (±10)
5.4 (±11)
3.4 score-
points
95
86
8
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; # shown as a positive number
All tests in the hierarchy are based on the primary estimand
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
8 of 11
Section 10.3.2.1 Confirmatory secondary endpoints
Table 10-3
Analysis and imputation methods to address the effectiveness and efficacy
estimands for the primary and confirmatory secondary endpoint in the statistical testing 
hierarchy
Objective
Endpoint
Test 
order
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Primary endpoints
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS
MMRM
-
-
Primary
5% responders
2
Binary
Primary
FAS
LR
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Non-
responder
Secondary
FAS
LR
MMRM
-
Confirmatory secondary endpoints
Primary
10% responders
3
Binary
Primary
FAS
LR
RD-MI
Non-
responders
Secondary
FAS
LR
MMRM
-
Primary
15% responders
4
Binary
Primary
FAS
LR
RD-MI
Non-
responders
Secondary
FAS
LR
MMRM
-
Primary
WC change (cm)
5
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
6
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
7
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
WRSSM total score 
change
8
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; LR = logistic regression; 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
Section 10.3.2.2 Supportive secondary endpoints
Analyses addressing the secondary estimand
The supportive secondary endpoints evaluated at week 68 which relate to the primary objective will 
be analysed to address the secondary estimand using the same MMRM for efficacy described for 
the primary endpoints.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
9 of 11
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).
An overview of all analysis and imputation methods to address the effectiveness and efficacy
estimands for supportive secondary endpoints is given Table 10-4.
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)
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
-
-
Primary
% weight change*
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FPG change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Fasting 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
hsCRP change (mg/L)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
PAI-1 change (AU/mL ) (mg/L)
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
% weight change*
Continuous
Primary
FAS
ANCOVA
RD-MI
Supportive secondary endpoints (safety related)
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 
statistic
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
10 of 11
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; hsCRP = high sensitivity C-Reactive Protein; 
PAI-1 = Plasminogen Activator Inhibitor-1; 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; * from 
baseline to week 8
2.10
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 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
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.
2.11
Appendix 5
Contraceptive guidance and collection of pregnancy information
Table 10-9 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. 
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
     
Status:
Final
     
Page:
11 of 11
2.12
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. Technical 
complaints related to adverse events will be included in the CTR. 
3URWRFRO$PHQGPHQWJOREY_
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03611582 
Sponsor trial ID: 
NN9536-4375 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly as 
adjunct to intensive behavioural therapy in subjects with 
overweight or obesity 
Document date: 
28 July 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: NN9536-4375 (STEP 3)
Clinical Trial Report
Appendix 16.1.9
28 July 2020
1.0
Final
16.1.9 Documentation of statistical methods
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Statistical Analysis Plan
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Statistical Analysis Plan
Trial ID: NN9536-4375
STEP 3
Effect and safety of semaglutide 2.4 mg once-weekly as
adjunct to intensive behavioural therapy in subjects with 
overweight or obesity
Author
Biostatistics Aalborg 2
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 
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 endpoints .................................................................................6 
1.1.3.2 
Secondary endpoints .............................................................................6 
Confirmatory secondary endpoints..........................................................................6 
Supportive secondary endpoints...............................................................................6 
1.1.3.3 
Exploratory endpoints ...........................................................................7 
1.1.4 
Type of trial................................................................................................................8 
1.2 
Scope of the statistical analysis plan..............................................................................................8 
2 
Statistical considerations ..........................................................................................................................8 
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..................................................................................................18 
x 
Confirmatory secondary endpoints .................................................18 
x 
Supportive secondary endpoints......................................................20 
2.3.3 
Exploratory endpoints................................................................................................23 
2.3.4 
Explorative statistical analysis for pharmacogenetics and biomarkers......................23 
2.3.5 
Other analyses............................................................................................................23 
2.4 
Pharmacokinetic and/or pharmacodynamic modelling................................................................23 
3 
Changes to the statistical analyses planned in the protocol.................................................................23 
3.1 
Trial-specific changes..................................................................................................................23 
3.2 
Changes applied across STEP trials.............................................................................................24 
4 
Change log................................................................................................................................................27 
5 
References................................................................................................................................................28 
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List of abbreviations
AD
available but discontinued
AE
adverse event
AT
available on randomised treatment
ANCOVA
analysis of covariance
BMI
body mass index
BP
bodily pain
CI
confidence interval
COA
clinical outcome assessment
CRF
case report form
CTR
clinical trial report
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
hsCRP
high-sensitivity C-Reactive Protein
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
OR
odds ratio
PAI-1
plasminogen activator inhibitor-1
PCS
physical component summary
PDD
pain/discomfort domain
PF
physical functioning
PFD
physical function domain
PK
pharmacokinetics
PYE
patient years of exposure
PYO
patient years of observation
RE
role-emotional
RP
role-physical
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SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
sBP
systolic blood pressure
SD
standard deviation
SF
social functioning
SF-36
Short Form-36
TEAE
treatment-emergent adverse event
VLDL
very low density lipoprotein
VT
vitality
WC
waist circumference
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1
Introduction
1.1
Trial information
1.1.1
Objective(s)
1.1.1.1
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity on body weight.
1.1.1.2
Secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to IBT in subjects with overweight or obesity on:
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments (COAs)
x
Glucose metabolism
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo as an adjunct to IBT in subjects with overweight or obesity. 
1.1.2
Estimands
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to IBT including an initial 8-week LCD, 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 
estimand will cover all effect-related objectives.
The following expansion of the primary estimand will cover the supportive secondary endpoint 
“Change from baseline at week 0 to week 8 in body weight (%)”. The estimand will quantify the 
average treatment effect of semaglutide relative to semaglutide placebo after 8 weeks, as an adjunct 
to IBT including LCD, in all randomised subjects regardless of adherence to treatment and 
regardless of initiation of other anti-obesity therapies.
Secondary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to IBT including an initial 8-week LCD, in all randomised 
subjects had they remained on their randomised treatment for the entire planned duration of the trial 
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and not initiated any other anti-obesity therapies (i.e. weight management drugs or bariatric 
surgery) (“hypothetical” estimand). The estimand will cover all effect-related objectives.
1.1.3
Endpoints
1.1.3.1
Primary endpoints 
Primary endpoints addressing the primary objective:
x
Change from baseline at week 0 to week 68 in body weight (%)
x
Subjects who after 68 weeks achieve (yes/no): 
x
Body weight reduction ≥5% from baseline at week 0
1.1.3.2
Secondary endpoints
The confirmatory and supportive secondary endpoints addressing the primary and secondary 
objectives are listed below.
Confirmatory secondary endpoints
Subjects who after 68 weeks achieve (yes/no): 
x
Body weight reduction ≥10% from baseline at week 0
x
Body weight reduction ≥15% from baseline at week 0
Change from baseline at week 0 to week 68 in:
x
Waist circumference (cm)
x
Systolic blood pressure (mmHg)
x
Physical functioning score (SF-36)
Supportive secondary endpoints
Effect endpoints
x
Change from baseline at week 0 to week 68 in:
x
Body weight (kg)
x
BMI (kg/m2)
x
Hemoglobin A1c (HbA1c) (%, mmol/mol)
x
Fasting plasma glucose (mg/dL)
x
Fasting serum insulin (μIU/mL)
x
Diastolic blood pressure (mmHg)
x
Lipids (mg/mL)
o
Total cholesterol
o
High-density lipoprotein
o
Low-density lipoprotein
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o
Very low-density lipoprotein
o
Free fatty acids
o
Triglycerides
x
High sensitivity C-reactive protein (hsCRP) (mg/L)
x
Plasminogen activator inhibitor-1 (PAI-1) Activity (UA/mL)
x
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 after 68 weeks achieve (yes/no):
x
Body weight reduction ≥20% from baseline at week 0
x
Increase in SF-36 physical function score ≥4.3 from baseline at week 0
Change from baseline at week 0 to week 8 in body weight (%)
Safety endpoints
Number of treatment-emergent adverse events (TEAEs) from baseline at week 0 to week 75
Number of serious adverse events (SAEs) from baseline at week 0 to week 75
Change from baseline at week 0 to week 68 in:
x
Pulse (bpm)
x
Amylase (U/L)
x
Lipase (U/L)
x
Calcitonin (ng/L)
1.1.3.3
Exploratory endpoints
Exploratory endpoints addressing the exploratory objectives:
Change from baseline at week 0 to week 68 in:
x
Glycaemic category (normo-glycaemia, pre-diabetes, T2D)
x
Antihypertensive medication (decrease, no change, increase)
x
Lipid lowering medication (decrease, no change, increase)
x
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem V2.0 
(WPAI-SHP)
o
Work time missed due to weight (%)
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o
Impairment while working due to weight (%)
o
Overall work impairment due to weight (%)
o
Activity impairment due to weight (%)
x
Total score (WRSSM)
Subjects who from randomisation to week 68 have permanently discontinued randomised trial 
product (yes/no)
Time to permanent discontinuation of randomised trial product (weeks).
1.1.4
Type of trial
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre clinical trial conducted in US, which compare semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo, as an adjunct to IBT, in subjects with overweight or obesity.
The trial includes a screening visit to assess the subject’s eligibility followed by weekly visits 
during the first 12 weeks. From week 12 to 24, visits will take place every 2nd week. From week 24, 
visits 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.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol for trial NN9536-4375 “Effect and 
safety of semaglutide 2.4 mg once-weekly as adjunct to intensive behavioural therapy in subjects 
with overweight or obesity”, version 3.0 (28 May 2019), 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 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).
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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. As the two primary endpoints are included in the statistical testing hierarchy, 
significant superiority of semaglutide 2.4 mg vs. semaglutide placebo must be demonstrated for 
each of the primary endpoints.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) is 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.
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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

For binary endpoints the Pearson chi-square test for two independent proportions is used 

Based on data from NN9536-4153
1. 20% of subjects discontinue permanently and 
2. 60% of these are retrieved (AD) at week 68 

All subjects in the placebo arm are assumed to have same effect as subjects who complete the 
trial on 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 600 subjects (400 in the semaglutide 2.4 mg once 
weekly and 200 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 86% for the seven endpoints in the hierarchical testing procedure. 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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Table 2-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number 600 randomised 
subjects
Order
Endpoint
Assumed mean (±SD) or 
proportion for completers
Expected mean 
(±SD) or 
proportion
Expected 
difference 
or 
proportion 
ratio
Marginal 
power 
(%)
Effective 
power 
(%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight loss #
17 (10)
7 (10)
15.6 (11)
8.6 %-
points
> 99
> 99
2
5% responders
88%
58%
85%
1.5
> 99
> 99
3
10% responders
76%
38%
71%
1.9
> 99
> 99
4
15% responders
58%
21%
53%
2.5
> 99
> 99
5
WC change (cm) #
17 (11)
8 (11)
15.7 (12)
7.7 cm
> 99
> 99
6
sBP change (mmHg) 
#
9.1 (13)
4.5 (13)
8.5 (14)
4 mmHg
91
91
7
SF-36 PF score 
change
6 (±10)
2 (±10)
5.4 (±11)
3.4 score-
points
95
86
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; 
PF = physical functioning; # shown as a positive number
All tests in the hierarchy are based on the primary estimand
2.2
Definition of analysis sets
x
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 randomised subjects exposed to at least one dose of 
randomised treatment. 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:
x
In-trial: The in-trial period is defined as the uninterrupted time interval from date of
randomisation to date of last contact with trial site.
x
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)
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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.
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 value. 
If no assessments are available, the mean of baseline values across all subjects is used as the 
baseline value.
2.3.1
Primary endpoint
x
Definition of primary endpoint: % weight change
x
Change from baseline (week 0) to week 68 in body weight (%) is defined as
x
% weight change= 
(body weight at week 68 – body weight at baseline)
body weight at baseline
 ×100.
x
Definition of primary endpoint: 5% responders
x
A body weight reduction of least 5% from baseline (week 0) to week 68 is defined as 
x
5% responder = ൜1 if  % weight change ≤ Ȃ 5%
0 if  % weight change > Ȃ 5%
Analyses addressing the primary estimand
The following statistical analyses 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 
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treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% CI and corresponding p-value.
The analysis model for the 5% responder endpoint is a logistic regression using randomised 
treatment as a factor and baseline body weight (kg) as covariate. The estimated odds ratio (OR) 
between semaglutide 2.4 mg and semaglutide placebo will be reported together with the associated 
two-sided 95% CI and corresponding p-value.
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows 
for the two analysis models.
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
ܪǣߤ௦௘௠௔௚௟௨௧௜ௗ௘൒ߤ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢ݒݏ
ܪ஺ǣ ߤ௦௘௠௔௚௟௨௧௜ௗ௘൏ߤ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢Ǥ
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Let ORsemaglutide/semaglutide placebo denote the true odds ratio between semaglutide 2.4 mg and 
semaglutide placebo. The null and alternative hypotheses tested are
ܪǣܱܴ௦௘௠௔௚௟௨௧௜ௗ௘Ȁ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢൑ͳݒݏ
ܪ஺ǣ ܱܴ௦௘௠௔௚௟௨௧௜ௗ௘Ȁ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢൐ͳǤ
The hypothesis will be rejected and superiority claimed, if the lower limit of the estimated two-
sided 95% CI is above 1.
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 endpoints 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 endpoints 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.
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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 McEvoy1. 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:
3. 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 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 17 weeks). If timing by quarters is too 
restrictive, halves (intervals of 34 weeks) 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. 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 group. 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.
4. Analysis: Analysis of each of the 1,000 complete data sets, using the analysis models 
(ANCOVA and logistic regression) results in 1,000 times 2 estimations.
5. Pooling: Integrates the 1,000 times 2 estimation results into two final results 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 95364375 as seed number. In addition to the seed 
number, it is specified that the dataset is sorted by subject ID.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
15 of 28
Sensitivity analysis
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 IBT including an initial 8-week LCD4. 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 -<35,35-<40, ≥40) as factors 
and baseline 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 one 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 group. 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 Sacks5 (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 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 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
16 of 28
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 analyses 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. For the 5% responder analysis, the same MMRM will be applied except 
that body weight (kg) will be used as response variable in the model. Individual missing values for 
body weight  at week 68 will be predicted from the MMRM and used to classify each subject as 5% 
responder or not. This classification will then be analysed using the same logistic regression model 
as in the primary analysis of the primary estimand.
Subjects with missing week 68 assessment as non-responders: For the 5% responder analysis an 
analysis using  subjects with missing week 68 assessment as non-responders in the logistic 
regressions will be done.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
17 of 28
Figure 2-1
Illustration of imputation approaches for the primary estimand 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
18 of 28
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 other anti-obesity therapies 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 analyses 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. 
The secondary estimand for 5% 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 5% responder or not. This classification will then be 
analysed using a logistic regression model with randomised treatment as a factor and baseline body 
weight (kg) as covariate.
An overview of all analysis and imputation methods to address the primary and secondary
estimands for the primary endpoints is given in Table 2-3.
2.3.2
Secondary endpoints
x
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in section 4.2.2.1 of the study protocoland 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 endpoints and to address the primary estimand. The imputation model is the same as 
for the primary endpoints 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 body weight replaced by the baseline 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
19 of 28
assessment of the endpoint to be analysed. The statistical model for body weight responder 
endpoints will be logistic regression with factor and covariate as for the primary endpoint 5% 
responders. 
Analyses addressing the secondary estimand
The confirmatory secondary endpoints which relate to the primary objective for week 68 will be 
analysed to address the secondary estimand using the same MMRM for efficacy described for the 
primary endpoints.
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. For all binary confirmatory secondary endpoints a 
sensitivity analysis using non-retrieved subjects as non-responders will be carried out.
An overview of all analysis and imputation methods to address the primary and secondary
estimands for confirmatory secondary endpoints is given Table 2-3.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
20 of 28
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 endpoints
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS 
MMRM
-
-
Primary
5% responders
2
Binary
Primary
FAS 
LR
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Non-
responder
Secondary
FAS 
LR
MMRM
-
Confirmatory secondary endpoints
Primary
10% responders
3
Binary
Primary
FAS 
LR 
RD-MI
Non-
responders
Secondary
FAS 
LR 
MMRM
-
Primary
15% responders
4
Binary
Primary
FAS 
LR 
RD-MI
Non-
responders
Secondary
FAS 
LR 
MMRM
-
Primary
WC change (cm)
5
Continuous
Primary
FAS 
ANCOVA
RD-MI
J2R-MI
Secondary
FAS 
MMRM
-
-
Secondary
sBP change (mmHg)
6
Continuous
Primary
FAS 
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
SF-36 PF score change
7
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; LR = logistic regression; 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.
x
Supportive secondary endpoints
Supportive secondary endpoints are listed in section 4.2.2.2 of the study 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 endpoints and to address the primary estimand. The imputation 
model is the same as for the primary endpoints 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 body weight 
replaced by the baseline assessment of the endpoint to be analysed. The statistical model for 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
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21 of 28
responder endpoints relating to COAs will be logistic regression with randomised treatment as a 
factor and the baseline assessment of the endpoint to be analysed as covariate.
For lipids, fasting serum insulin and biomarkers a multiplicative model will be used, i.e. the ratio 
between post randomisation measurements and baseline 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 evaluated at week 68 will be analysed to address the secondary 
estimand using the same MMRM for efficacy described for the primary endpoints.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
Analysis of safety endpoints
The safety endpoint pulse will be analysed using an MMRM for efficacy as described in section 
2.3.1. 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 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 and secondary
estimands for supportive secondary endpoints is given in Table 2-4.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
22 of 28
Table 2-4
Analysis and imputation methods to address the primary and secondary
estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (effect related)
Primary
20% responders
Binary
Primary 
FAS
LR
RD-MI
- 
Secondary
FAS 
LR
MMRM
-
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
-
-
Primary
% weight change*
Continuous
Primary
FAS
ANCOVA
J2R-MI
-
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 insulin change (mIU/L,
pmol/mol)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
Continuous
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
hsCRP change (mg/L)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
FAS
MMRM
-
-
Secondary
PAI-1 change (AU/mL )
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 PF score change
Continuous
Secondary
FAS
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
- 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
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23 of 28
Secondary
FAS
MMRM
-
-
Supportive secondary endpoints (safety related)
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 
statistic
-
- 
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; hsCRP = high sensitivity C-Reactive Protein; 
PAI-1 = Plasminogen Activator Inhibitor-1; 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; * from baseline 
to week 8 
2.3.3
Exploratory endpoints
Exploratory endpoints are listed in section 4.2.3 of the study protocol. Observed data for 
exploratory endpoints will be summarised by descriptive statistics. 
2.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers
The statistical analysis of biomarker endpoints is described under section 10.3.2.2 of the study 
protocol.
2.3.5
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. 
3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9536-4375. However, 
clarifications and more detailed descriptions of endpoints and analyses are provided in this SAP. 
The changes from the study protocol of NN9536-4375 are summarised below.
3.1
Trial-specific changes
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4375
Version:
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UTN: U1111-1200-8199
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x
The following secondary objective has been added (concerning the supportive secondary
endpoint “Change from baseline at week 0 to week 8 in body weight (%)). “To compare the
effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an adjunct to
IBT including LCD in subjects with overweight or obesity on body weight”. Furthermore it
is specified that the imputation approach for percent change in body weight at week 8 will
be a jump to reference multiple imputation, as it is expected that the multiple imputation
model using retrieved subjects cannot be fit due to inadequate numbers of retrieved subjects
in 1 or more groups.
x
For analyses for the supportive secondary endpoints which relate to the primary objective
and addressing the secondary estimand, it has been specified that this only includes
endpoints evaluated at week 68 analyses (i.e. not week 8). This is in agreement with the
secondary estimand and the text has only been updated in the section describing the
statistical analyses for the supportive secondary endpoints .
3.2
Changes applied across STEP trials
x
The supportive secondary endpoint “Body weight reduction ≥ 20% from baseline at week 0”
has been added.
x
It has been clarified that subjects in the FAS/SAS will be evaluated “as randomised”/“as
treated”.
x
It has been clarified that the on-treatment period will be from date of first trial product
administration to date of last trial product administration ‘(+14 days)’
x
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.
x
Units for PAI-1 corrected to AU/mL (only applies to NN9536-4373, NN9536-4374 and
NN9536-4375)
x
It is specified that all AEs will be coded using the most recent version of the Medical
Dictionary for Regulatory Activities (MedDRA) coding.
x
The BMI-grouping “27-<35” has been changed to “-<35”, since subjects may loose weight
between the screening and the randomisation visit, and therefore have a BMI below 27
kg/m2 at the time of randomisation.
x
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 by McEvoy1.
Furthermore it is clarified that the LAO-OT must be prior to the landmark visit (week 68).
x
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
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
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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.
x
It is clarified that if no post-baseline LAO-OT exist, then the LAO-OT will be the baseline
value and the timing of LAO-OT will be the first interval.
x
In all multiple imputation procedures, in addition to the seed number, it is specified that the
dataset is sorted by subject ID.
x
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
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.
o
The rationale for the change in TP-MI is the following feedback from FDA: “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.”]
x
A description has been included of the sensitivity analysis of the 5% responder endpoint
(primary estimand) using MMRM.
x
It has been clarified that the non-responder analysis includes subjects with missing body
weight assessment at week 68 as non-responders.
x
It has been clarified that the 5% responder analysis using MMRM for the secondary
estimand will be predicting individual values for body weight only when body weight is
missing at week 68. Furthermore, it is clarified that the logistic regression will include both
randomised treatment as a factor and baseline body weight as covariate.
x
For physical functioning score (SF-36) the range of the scale was described as being 1-100.
This has been deleted, since calculations are done on the norm based scores6.
x
It is specified that fasting serum insulin will be log-transformed and analysed using a
multiplicative model.
x
It is specified that lipids, FPG and fasting insulin will also be analysed in SI-units.
x
Text and tables have been updated to reflect that analyses for all non-weight related
endpoints based on the secondary estimand are to be done.
6$367(3_
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
26 of 28
6$367(3_
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
27 of 28
4
Change log
SAP change log
Version
Reason for change
1.0
New
2.0
The BMI grouping “27-<35” has been changed to “-<35” to accommodate the 
fact that subjects may lose weight between the screening and the randomisation 
visit and therefore have a BMI below 27 kg/m2 at the time of randomisation.
Table 2-3 has been updated to also include the secondary estimand for the sBP 
change (mmHg) and SF-36 PF score change. This is a consequence of the update 
in version 1 that stated that the secondary estimand will cover all effect-related 
objectives.
6$367(3_
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4375
Version:
1.0
UTN: U1111-1200-8199
Status:
Final
EudraCT No.:
Page:
28 of 28
5
References
1. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat.
2016;26(1):30-6.
2. 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.
3. 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
4. Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM, et al. National, regional, and
global trends in adult overweight and obesity prevalences. Popul Health Metr. 2012;10(1):22.
5. NCD Risk Factor Collaboration. Trends in adult body-mass index in 200 countries from 1975 to
2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million
participants. Lancet. 2016;387(10026):1377-96.
6. Maruish, M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI:
QualityMetric.
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CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
1 of 7
Clinical Trial Report
Trial ID: NN9536-4375 (STEP 3)
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.
CONFIDENTIAL
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
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
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
3 of 7
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:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
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:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
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:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
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:
04 June 2020
Novo Nordisk
Trial ID: NN9536-4375 (STEP 3)
Version:
2.0
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