Clinical trial NCT03552757
Conditions: Obesity Overweight
Sponsor: Novo Nordisk A/S
Start date: 2018-06-04; Completion date: 2020-05-01
Enrollment: 1210 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at the change in the participant's body weight from the start to the end of the study. This is to compare the effect on body weight in people taking semaglutide (a new medicine) and people taking "dummy" medicine. In addition to taking the study medicine, the participant will have talks with study staff about healthy food choices, how to be more physically active and what else the participant can do to lose weight. Overweight and obesity is associated with an increased risk of type 2 diabetes. Therefore, weight loss has shown to have a beneficial impact on the blood sugar levels. The participant will either get semaglutide or "dummy" medicine - which treatment the participant get is decided by chance. The participant will need to take 2 injections at the same time once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study will last for about 1.5 years

Detailed description:

Arms: arm 1: Participants will receive semaglutide 1.0 mg and semaglutide placebo I during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity. arm 2: Participants will receive semaglutide 2.4 mg and semaglutide placebo II during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity. arm 3: Participants will receive semaglutide placebo I and II during 68-week treatment period in addition to a reduced-calorie diet and increased physical activity.
Interventions: intervention 1: Semaglutide 1.0 mg intervention 2: Semaglutide 2.4 mg intervention 3: Placebo I (Semaglutide) intervention 4: Placebo II (Semaglutide)
Intervention descriptions: intervention 1: Subcutaneous (s.c.) injections of semaglutide once weekly at an escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week). The dose will be escalated to next level every 4 weeks. intervention 2: Subcutaneous injections of semaglutide once weekly at an escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week, 1.7 mg/week and 2.4 mg/week). The dose will be escalated to next level every 4 weeks. intervention 3: S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 2.4 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week, 1.7 mg/week and 2.4 mg/week). The dose will be escalated to next level every 4 weeks. intervention 4: S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide 1.0 mg (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg mg/week). The dose will be escalated to next level every 4 weeks.

Protocol documents:
Prot_002.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03552757 
Sponsor trial ID: 
NN9536-4374 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly in 
subjects with overweight or obesity and type 2 diabetes 
Document date*: 
0 1RYHPEHU 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.


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List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - AR ..............................................................................................................
Protocol amendment 2 - US...............................................................................................................
Protocol amendment 3 - UK..............................................................................................................
Protocol amendment 4 - Global ........................................................................................................
Protocol amendment 5 - UK..............................................................................................................
Protocol amendment 6 - AE ..............................................................................................................
Protocol amendment 7 - DE ..............................................................................................................
Protocol amendment 8 - AE ..............................................................................................................
Protocol amendment 9 - ZA ..............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4374 (STEP 2)
Clinical Trial Report
Appendix 16.1.1
03 Jul\ 2020
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16.1.1 Protocol and protocol amendments
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Protocol
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly in subjects with 
overweight or obesity and type 2 diabetes
Substance name: semaglutide
Universal Trial Number: U1111-1200-8148 
EudraCT Number: 2017-003414-10
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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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Synopsis................................................................................................................................................5
2
Flowchart .............................................................................................................................................9
3
Introduction .......................................................................................................................................14
3.1
Trial rationale..........................................................................................................................14
3.2
Background.............................................................................................................................15
3.2.1
Semaglutide...........................................................................................................15
3.2.2
Trial population .....................................................................................................15
3.3
Benefit-risk assessment ...........................................................................................................16
3.3.1
Benefits .................................................................................................................16
3.3.2
Risks and precautions.............................................................................................16
3.3.3
Conclusion on benefit-risk profile ..........................................................................18
4
Objectives and endpoints...................................................................................................................18
4.1
Primary, secondary and exploratory objective(s)......................................................................18
4.1.1
Primary objective...................................................................................................18
4.1.2
Secondary objectives .............................................................................................18
4.1.3
Exploratory objectives ...........................................................................................19
4.2
Primary, secondary and exploratory endpoints.........................................................................20
4.2.1
Primary endpoint ...................................................................................................20
4.2.2
Secondary endpoints ..............................................................................................20
4.2.2.1
Confirmatory secondary endpoints ...................................................20
4.2.2.2
Supportive secondary endpoints .......................................................20
4.2.3
Exploratory endpoints............................................................................................22
5
Trial design ........................................................................................................................................23
5.1
Overall design.........................................................................................................................23
5.2
Subject and trial completion....................................................................................................24
5.3
End of trial definition..............................................................................................................24
5.4
Scientific rationale for trial design...........................................................................................24
5.5
Justification for dose ...............................................................................................................25
6
Trial population .................................................................................................................................25
6.1
Inclusion criteria .....................................................................................................................25
6.2
Exclusion criteria ....................................................................................................................26
6.3
Randomisation criteria ............................................................................................................27
6.4
Lifestyle restrictions................................................................................................................28
6.4.1
Meals and dietary restrictions.................................................................................28
6.4.2
Caffeine and tobacco..............................................................................................28
6.5
Screen failures ........................................................................................................................28
7
Treatments .........................................................................................................................................29
7.1
Treatments administered .........................................................................................................29
7.1.1
Medical device.......................................................................................................31
7.1.2
Diet and physical activity counselling ....................................................................32
7.2
Dose modification...................................................................................................................32
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7.3
Method of treatment assignment..............................................................................................33
7.4
Blinding..................................................................................................................................33
7.5
Preparation/Handling/Storage/Accountability..........................................................................33
7.6
Treatment compliance.............................................................................................................35
7.7
Concomitant medication..........................................................................................................35
7.7.1
Rescue medication.................................................................................................36
7.8
Treatment after the end of the trial...........................................................................................36
8
Discontinuation/Withdrawal criteria ................................................................................................36
8.1
Discontinuation of trial treatment ............................................................................................37
8.1.1
Temporary discontinuation of trial treatment..........................................................38
8.1.2
Rescue criteria .......................................................................................................38
8.2
Withdrawal from the trial........................................................................................................38
8.2.1
Replacement of subjects.........................................................................................39
8.3
Lost to follow-up.....................................................................................................................39
9
Trial assessments and procedures .....................................................................................................39
9.1
Efficacy assessments...............................................................................................................41
9.1.1
Body measurements...............................................................................................41
9.1.2
Clinical outcome assessments ................................................................................41
9.1.3
Self-measured plasma glucose................................................................................43
9.1.4
Clinical efficacy laboratory assessments.................................................................43
9.2
Adverse events........................................................................................................................44
9.2.1
Time period and frequency for collecting AE and SAE information........................44
9.2.1.1
Events for adjudication.....................................................................46
9.2.2
Method of detecting AEs and SAEs .......................................................................47
9.2.3
Follow-up on AEs and SAEs..................................................................................47
9.2.4
Regulatory reporting requirements for SAEs ..........................................................47
9.2.5
Cardiovascular and death events.............................................................................47
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE...................................................................................................................48
9.2.7
Pregnancies and associated adverse events .............................................................48
9.2.8
Medical device incidents (including malfunctions).................................................49
9.2.9
Technical complaints .............................................................................................49
9.3
Treatment of overdose.............................................................................................................49
9.4
Safety assessments ..................................................................................................................50
9.4.1
Mental health assessment instruments ....................................................................50
9.4.2
Physical examinations............................................................................................51
9.4.3
Vital signs..............................................................................................................51
9.4.4
Electrocardiograms ................................................................................................51
9.4.5
Eye examination ....................................................................................................52
9.4.6
Clinical safety laboratory assessments....................................................................52
9.4.7
Immunogenicity assessments .................................................................................53
9.5
Pharmacokinetics ....................................................................................................................53
9.6
Pharmacodynamics .................................................................................................................53
9.7
Genetics..................................................................................................................................53
9.8
Biomarkers .............................................................................................................................53
9.9
Severe hypersensitivity............................................................................................................54
10
Statistical considerations ...................................................................................................................54
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10.1
Sample size determination.......................................................................................................55
10.2
Definition of analysis sets........................................................................................................57
10.3
Statistical analyses ..................................................................................................................58
10.3.1
Primary endpoint ...................................................................................................58
10.3.2
Secondary endpoints..............................................................................................64
10.3.2.1
Confirmatory secondary endpoints ...................................................64
10.3.2.2
Supportive secondary endpoints .......................................................66
10.3.3
Exploratory endpoints............................................................................................68
10.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers.....................68
10.3.5
Other analyses .......................................................................................................68
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................68
11
Appendices .........................................................................................................................................69
Abbreviations and Trademarks.......................................................................................69
Appendix 1
Clinical laboratory tests ...................................................................................................72
Appendix 2
Trial governance considerations......................................................................................76
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting .....................................................................................................................................86
Contraceptive guidance and collection of pregnancy information ................................92
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting ................................................................................................................................95
Retention of human biosamples.......................................................................................97
Appendix 7
Hypoglycaemic episodes...................................................................................................99
Appendix 8
Monitoring of calcitonin.................................................................................................103
Appendix 9
Country-specific requirements ......................................................................................106
Appendix 10
12
References ........................................................................................................................................107
Attachment I Global list of key staff and relevant department and suppliers
Attachment II Country list of key staff and relevant department
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1
Synopsis
Rationale:
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate1-7. The medical and societal impacts are 
considerable and obesity is one of the most significant public health challenges worldwide1-7.
Obesity is associated with increased risk of a variety of comorbidities including hyperglycaemia, 
T2D, hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis, osteoarthritis, urinary 
incontinence, non-alcoholic steatohepatitis, cardiovascular diseases, certain types of cancer, and risk 
of early death8-22. Moreover, obesity adversely affects physical and mental health and reduces 
health related quality of life23, 24. Obesity is also associated with decreased cardiorespiratory fitness, 
which also increases the risk of cardiovascular diseases and all-cause mortality25.
The risk of obesity-related complications and comorbidities increases with increasing BMI, and a 
weight loss of 5-10% has significant health benefits in terms of slowing progression to T2D26-29.
Furthermore, a weight loss of 5-10% improves many other obesity related comorbidities as well as 
physical symptoms and quality of life30-37. Finally, studies suggest a beneficial impact of weight 
loss on cardiovascular risk and mortality in both people with diabetes and obesity38-40.
Subjects with T2D often have multiple unmet medical needs related to cardiovascular risks, 
including hypertension and dyslipidemia. It has been consistently demonstrated that weight loss in 
subjects with T2D has a beneficial impact not only on glycaemic control, but also on other 
cardiovascular risk markers41. The present trial has been designed to show the effects of 
semaglutide in inducing weight loss in overweight or obese subjects with T2D, while potentially 
improving markers of cardiovascular risk, clinical outcome assessments and glycaemic control.
Objectives and endpoints:
Primary objective
To compare the effect of semaglutide subcutaneous (s.c.) 2.4 mg once-weekly versus semaglutide
placebo I/II as an adjunct to a reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and type 2 diabetes (T2D) on body weight.
Secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on:
!
Cardiovascular risk factors 
!
Clinical Outcome Assessments 
!
Glycaemic control
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To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D on factors related to body weight.
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on glycaemic control.
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide
placebo I/II as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D.
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of starting rescue 
interventions (weight management drugs or bariatric surgery) (“effectiveness”/“treatment policy” 
estimand). The estimand will cover all effect-related objectives.
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of semaglutide s.c. 2.4 mg relative to 
semaglutide s.c. 1.0 mg after 68 weeks, as an adjunct to reduced-calorie diet and increased physical 
activity, in all randomised subjects regardless of adherence to treatment and regardless of starting 
rescue interventions.
Primary endpoint
The primary endpoints addressing the primary objective:
!
Change from baseline (week 0) to week 68 in body weight (%)
!
Subjects who after 68 weeks achieve (yes/no): 
o
Body weight reduction F 5% from baseline (week 0)
Confirmatory secondary endpoints
The confirmatory secondary endpoints are used to compare effect of semaglutide s.c. 2.4 mg once-
weekly versus semaglutide placebo I/II unless stated otherwise.
!
Subjects who after 68 weeks achieve (yes/no): 
o
Body weight reduction F 10% from baseline (week 0)
o
Body weight reduction F 15% from baseline (week 0)
!
Change from baseline (week 0) to week 68 in:
o
Waist circumference (cm)
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o
Body weight (%) (semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 
mg once-weekly)
o
Hemoglobin A1c (HbA1c) (%, mmol /mol) 
o
Systolic blood pressure (mmHg)
o
Physical functioning score (SF-36)
o
Physical function domain (5-items) score (IWQoL-Lite for CT) 
Supportive secondary endpoint
!
HbA1c (%, mmol/mol) (semaglutide s.c. 1.0 mg once-weekly versus semaglutide placebo 
I/II)
Overall design:
This is a 68-week, randomised, double-blinded, double dummy, placebo-controlled, three-armed, 
multi-centre, multinational clinical trial comparing semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo I/II once-weekly in subjects with overweight or obesity and T2D.
Key inclusion criteria
!
Male or female, age F 18 years at the time of signing informed consent.
!
Body Mass Index (BMI) F 27 kg/m2
!
History of at least one self-reported unsuccessful dietary effort to lose body weight
!
Diagnosed with T2D (HbA1c 7-10% (53-86 mmol/mol) (both inclusive)) F 180 days prior 
to the day of screening
Key exclusion criteria
!
A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
!
Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 30 
mL/min/1.73 m2 (< 60 ml/min/1.73 m2 in subjects treated with SGLT2i ) according to CKD-
EPI creatinine equation as defined by KDIGO 201242 by the central laboratory at screening
!
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or an 
equally qualified health care provider (e.g. optometrist) within the past 90 days prior to 
screening or in the period between screening and randomisation
Number of subjects:
Approximately 1412 subjects will be screened to achieve 1200 subjects randomly assigned to trial 
product.
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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 followed by randomisation. Eligible subjects fulfilling 
all randomisation criteria at visit 2 will be randomised in a 1:1:1 manner to receive either:
o
Semaglutide 2.4 mg and semaglutide placebo II once-weekly 
o
Semaglutide 1.0 mg and semaglutide placebo I once-weekly
o
Semaglutide placebo I and semaglutide placebo II once-weekly
all as an adjunct to a reduced-calorie diet and increased physical activity (Figure 5-1).
Randomisation will be stratified according to the following background diabetes treatment:
!
diet and physical activity only or treatment with single compound metformin or sodium-
glucose co-transporter 2 inhibitors (SGLT2i) treatment or
!
single compound oral antidiabetic drug (OAD) treatment (sulphonylurea (SU) or glitazone) 
or combination treatment with of up to 3 OADs (metformin, SU, SGLT2i or glitazone)
Subjects in the two above stratification groups will be further stratified into 2 groups by screening 
value of HbAlc (A. < 8.5% or B. F 8.5%).
Proportion of subjects treated with SU mono- or combination therapy will be restricted to a 
maximum of 30% of total randomised subjects. When the SU target is reached subjects treated with 
SU as background treatment should not be randomised to this trial. 
Dose escalation of semaglutide/semaglutide placebo will take place every 4 weeks during the first 
8-16 weeks after randomisation, depending on target dose 1.0 or 2.4 mg once-weekly. All subjects 
should aim at reaching the target dose of semaglutide 1.0 mg or 2.4 mg once-weekly. The treatment
continues until the ‘end of treatment’ visit followed by a 7 weeks follow-up period.
The following trial products will be supplied by Novo Nordisk A/S for the duration of the trial:
!
Semaglutide B 1.0 mg/mL PDS290 and semaglutide placebo I, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
!
Semaglutide B 3.0 mg/mL PDS290 and semaglutide placebo I, solution for injection, 3 mL 
PDS290 pre-filled pen-injector
!
Semaglutide 1.34 mg/mL and semaglutide placebo II, solution for injection, 1.5 mL PDS290 
pre-filled pen injector
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2
Flowchart
Scree-
ning
Rando-
misation
Dose escalation period
Maintenance period
End of 
treat-
ment
End of 
trial
Visit (V), Phone (P)
V1
V2
P3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 P19 V20 P21 V22 P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52
56
60
64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
0 to +5
SUBJECT RELATED 
INFORMATION AND 
ASSESSMENTS
Informed consent and Demographya
(Appendix 3)
X
Childbearing potentialb
(Appendix 5)
X
Inclusion criteria (6.1)
X
X
Exclusion criteria (6.2)
X
X
Randomisation criteria and 
randomisation (6.3)
X
Medical history/Concomitant illness
(9.4)
X
Weight History (9)
X
Diabetes history and complications
X
History of Gallbladder Disease 9.4
X
History of Breast Neoplasmb 9.4
X
History of Colon Neoplasm 9.4
X
History of Skin Cancer 9.4
X
History of Psychiatric disorder 9.4
X
Tobacco 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
Trial product compliance (7.1, 7.6)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Scree-
ning
Rando-
misation
Dose escalation period
Maintenance period
End of 
treat-
ment
End of 
trial
Visit (V), Phone (P)
V1
V2
P3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 P19 V20 P21 V22 P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52
56
60
64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
0 to +5
Evaluation of lipid-lowering 
treatment (9)
X
X
Evaluation of antihypertensive 
treatment (9)
X
X
Evaluation of Oral Anti Diabetes 
Medication (9)
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
      Waist Circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Fasting plasma glucose (Appendix 
2)
X
X
X
X
X
Fasting serum insulin
X
X
X
X
X
Self-measured fasting plasma 
glucose (9.1.3)
X
X
X
X
X
X
X
X
Lipids (Appendix 2)
X
X
X
Biomarkers (9.8, Appendix 2)
X
X
X
Vital Signs (6.4.2, 9.4.3)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
      Systolic Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Scree-
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Rando-
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Dose escalation period
Maintenance period
End of 
treat-
ment
End of 
trial
Visit (V), Phone (P)
V1
V2
P3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 P19 V20 P21 V22 P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52
56
60
64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
0 to +5
     Diastolic Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcome Assessments
(9.1.2)
      Impact of weight on quality of
      Life-lite (IWQoL-Lite)
X
X
X
X
X
X
X
      Patient Global Impression of
      Status (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
      Short Form-36 (SF-36)
X
X
X
X
X
X
X
      Six-minute walk test (6 MWT)
X
X
X
SAFETY
Physical examination (9.4.2)
X
X
Eye examination (9.4.5)
X
X
X
Urinalysis (9.4.6, Appendix 2)
X
X
X
Pregnancy test (9.4.6, 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
Hypoglycaemic episodes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaint (9.2.9, 
Appendix 6)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Breast neoplasms follow-upb 9.4
X
X
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Scree-
ning
Rando-
misation
Dose escalation period
Maintenance period
End of 
treat-
ment
End of 
trial
Visit (V), Phone (P)
V1
V2
P3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 P19 V20 P21 V22 P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52
56
60
64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
0 to +5
Colon neoplasms follow-up 9.4
X
X
Haematology (Appendix 2)
X
X
X
X
Biochemistry (Appendix 2)
X
X
X
X
Vital Signs (6.4.2, 9.4.3)
      Pulse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcome Assessments
(9.4.1)
      Patient Health Questionnaire –
9 (PHQ-9) 
X
X
X
X
X
X
X
      Columbia-Suicide Severity
Rating Scale (C-SSRS)
X
X
X
X
X
X
X
Anti-Semaglutide Antibody (9.4.7)
X
X
X
X
X
X
X
X
OTHER ASSESSMENTS
Semaglutide plasma concentration
(9.5)
X
X
X
X
X
X
X
Biosamples for future analysisd
(Appendix 7)
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)
X
X
X
X
X
X
X
X
X
X
      Dispensing visit
X
X
X
X
X
X
X
X
X
      Drug accountability
X
X
X
X
X
X
X
X
X
X
REMINDERS
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Scree-
ning
Rando-
misation
Dose escalation period
Maintenance period
End of 
treat-
ment
End of 
trial
Visit (V), Phone (P)
V1
V2
P3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 P19 V20 P21 V22 P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52
56
60
64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
0 to +5
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
Barriers and motivation interview
(9)
X
Diet and physical activity 
counselling (7.1.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Training in trial product, pen-
handling (7.1.1)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand out directions for use (7.1.1)
X
Hand out dose reminder card (7.1)
X
X
X
X
X
Hand out and instruct in food diary
(9)
X
Hand out and instruct in diabetes 
diary (9.1.3)
X
X
X
X
X
X
X
X
X
X
X
X
Hand out and instruct in PK diary 
(9)
X
X
X
X
X
X
Hand out ID card
X
Hand out and instruct in BG-meter
(7.1)
X
Attend visit fasting (6.4.1)
X
X
X
X
X
Xe
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
d Only for subjects where the separate informed consent for future research has been signed
e Fasting at V25 is defined as at least 2 hours without food and drink intake except water before attending the visit
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3
Introduction
3.1
Trial rationale
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate1-7. The medical and societal impacts are 
considerable and obesity is one of the most significant public health challenges worldwide1-7.
Obesity is associated with increased risk of a variety of comorbidities including hyperglycaemia, 
T2D, hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis, osteoarthritis, urinary 
incontinence, non-alcoholic steatohepatitis, cardiovascular diseases, certain types of cancer, and risk 
of early death8-22. Moreover, obesity adversely affects physical and mental health and reduces 
health related quality of life23, 24. Obesity is also associated with decreased cardiorespiratory fitness, 
which also increases the risk of cardiovascular diseases and all-cause mortality25.
The risk of obesity-related complications and comorbidities increases with increasing BMI, and a 
weight loss of 5-10% has significant health benefits in terms of slowing progression to T2D26-29.
Furthermore, a weight loss of 5-10% improves many other obesity related comorbidities as well as 
physical symptoms and quality of life30-37. Finally, studies suggest a beneficial impact of weight 
loss on cardiovascular risk and mortality in both people with diabetes and obesity38-40.
Subjects with T2D often have multiple unmet medical needs related to cardiovascular risks, 
including hypertension and dyslipidemia. It has been consistently demonstrated that weight loss in 
subjects with T2D has a beneficial impact not only on glycaemic control, but also on other 
cardiovascular risk markers41. The present trial has been designed to show the effects of
semaglutide in inducing weight loss in overweight or obese subjects with T2D, while potentially 
improving markers of cardiovascular risk, clinical outcome assessments and glycaemic control.
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss43-52. 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 costly43-48, 53, 54. Pharmacotherapy may therefore 
serve as a valuable adjunct to lifestyle intervention for individuals with obesity in order to achieve 
and sustain a clinically relevant weight loss, to improve comorbid conditions and to facilitate a 
healthier lifestyle. Few anti-obesity medications are currently available and there is a need for more 
safe and effective therapeutic options for treatment of obesity, especially treatments that also target 
weight maintenance, prevention and treatment of comorbidities43-47, 55, 56.
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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 dosing57. GLP-1 receptor agonist is a physiological regulator of appetite 
and GLP-1 receptors are present in several areas of the brain involved in appetite regulation58.
In subjects with T2D, treatment with semaglutide s.c. 1.0 mg once-weekly has shown a body weight 
loss of up to 7.0% of baseline body weight (and reductions in haemoglobin HbA1c of up to 1.85 
percentage-point) after 30 weeks with a safety and tolerability profile comparable to other GLP-1
RA59-63. In the trials investigating semaglutide s.c. 1.0 mg, subjects with diabetes were exposed to a 
lower dose of semaglutide for a shorter period and did not receive any dedicated lifestyle 
intervention. Consequently, body weight loss is expected to be greater in a population of subjects 
with T2D receiving a dedicated lifestyle intervention and a higher semaglutide dose.
A 52-week phase 2 dose-finding trial within weight management (NN9536-4153) has recently been 
completed. A total of 957 randomised subjects with obesity (without diabetes) were exposed to 
semaglutide (n=718), liraglutide 3.0 mg (n=103) or placebo (n=136). In this trial, an overall 
monotone dose-dependent weight loss was observed across the 5 semaglutide doses tested (0.05 to 
0.4 mg once-daily). The estimated weight loss at week 52 was 13.8% at the highest dose tested (0.4 
mg once-daily)64 compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone.
Clinical59-63 and non-clinical data65 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)64 and any updates hereof.
3.2.2
Trial population 
In the present trial, T2D is considered a comorbidity to overweight and obesity, therefore subjects 
with BMI F 27 kg/m2 will be in enrolled. Information about other 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
treated with insulin are not included in the trial as insulin promotes weight gain. However, as last 
rescue treatment option, insulin treatment can be initiated.
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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 guidelines66, 67.
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 
percentage points larger for the 0.4 mg group compared with placebo. Weight losses were 
accompanied by a consistent improvement in the weight-related comorbidities, indicated by 
cardiovascular risk factors, lipid profile and glycaemic factors, as well as improvements in clinical 
outcome assessments.
In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site and counselling by a dietician or a similar qualified healthcare professional, all of 
which will most likely result in intensified weight management.
3.3.2
Risks and precautions 
The sections below describe identified and potential risks associated with semaglutide treatment. 
The identified/potential risks are based on findings in non-clinical studies and clinical trials with 
semaglutide as well as other GLP-1 RAs. For each of these risks, mitigating actions have been 
implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
!
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported adverse events (AE)
in clinical trials with semaglutide were gastrointestinal AEs. A low starting dose and dose 
escalation steps will be implemented in the trial to mitigate the risk of gastrointestinal AEs.
!
Cholelithiasis
Events of cholelithiasis were the most frequently reported gallbladder events in the phase 2 weight 
management trial (NN9536-4153) and were in a few instances co-reported with the event 
adjudication committee (EAC) confirmed acute pancreatitis. As a precaution, if cholelithiasis is 
suspected, appropriate clinical follow-up is to be initiated at the investigator’s discretion.
!
Hypoglycaemia (in combination with SU and/or insulin) (identified for T2D patients)
There is a low risk of hypoglycaemic episodes when semaglutide is used as monotherapy. Subjects 
treated with semaglutide in combination with a sulphonylurea (SU) or insulin have an increased risk 
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of hypoglycaemia. The risk of hypoglycaemia can be lowered by reducing the dose of SU when 
initiating treatment with semaglutide (or insulin if subjects have been allowed to use insulin as 
rescue therapy).
!
Diabetic retinopathy complication (identified for T2D patients)
The cardiovascular outcome trial in the semaglutide T2D development programme showed an 
increased risk of events related to diabetic retinopathy complications in subjects treated with 
semaglutide compared to placebo, albeit the proportion of subjects with an event of diabetic 
retinopathy complications was low. The imbalance was driven by subjects with a history of diabetic 
retinopathy at baseline and subjects who were treated with insulin. As a precaution, subjects with a 
history of uncontrolled and potentially unstable diabetic retinopathy or maculopathy will be 
excluded from the trial, and fundus photography or slit-lamp biomicroscopy examination with 
pharmacologically dilated pupils will be performed according to flowchart (Section 2 and 9.4.5).
!
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. 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 type2 (MEN 2) 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.
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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 IB64 and any updates hereof.
4
Objectives and endpoints
4.1
Primary, secondary and exploratory objective(s)
4.1.1
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II
(please see the last paragraph in this section for an explanation of placebo I and II) as an adjunct to 
a reduced-calorie diet and increased physical activity in subjects with overweight or obesity and 
T2D on body weight.
4.1.2
Secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on:
!
Cardiovascular risk factors 
!
Clinical Outcome Assessments 
!
Glycaemic control
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D on factors related to body weight.
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To compare the effect of semaglutide s.c.1.0 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on glycaemic control.
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide
placebo I/II as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D.
4.1.3
Exploratory objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on:
!
Use of oral antidiabetic drug (OAD) medication
!
Use of medication for hypertension and dyslipidaemia
!
Work productivity
!
Treatment discontinuation
!
Liver indices
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide
placebo after 68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of starting rescue 
interventions (weight management drugs or bariatric surgery) (“effectiveness”/ “treatment policy” 
estimand). The estimand will cover all effect-related objectives.
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of semaglutide s.c. 2.4 mg relative to 
semaglutide s.c. 1.0 mg after 68 weeks, as an adjunct to reduced-calorie diet and increased physical 
activity, in all randomised subjects regardless of adherence to treatment and regardless of starting 
rescue interventions.
Secondary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, 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.
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4.2
Primary, secondary and exploratory endpoints 
4.2.1
Primary endpoint
The primary endpoints addressing the primary objective:
!
Change from baseline (week 0) to week 68 in body weight (%)
!
Subjects who after 68 weeks achieve (yes/no):
o
Body weight reduction F 5% from baseline (week 0)
4.2.2
Secondary endpoints
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
The confirmatory secondary endpoints are used to compare effect of semaglutide s.c. 2.4 mg once-
weekly versus semaglutide placebo I/II unless stated otherwise.
!
Subjects who after 68 weeks achieve (yes/no):
o
Body weight reduction F 10% from baseline (week 0)
o
Body weight reduction F 15% from baseline (week 0)
!
Change from baseline (week 0) to week 68 in:
o
Waist circumference (cm)
o
Body weight (%) (semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 
mg once-weekly)
o
Haemoglobin A1c (HbA1c) (%, mmol/mol)
o
Systolic blood pressure (mmHg)
o
Physical functioning score (SF-36)
o
Physical function domain (5-items) score (IWQoL-Lite for CT) 
4.2.2.2
Supportive secondary endpoints
Supportive secondary effect endpoints
The supportive secondary endpoints are used to compare the effect of semaglutide s.c. 2.4 mg once-
weekly versus semaglutide placebo I/II unless otherwise stated:
!
Change from baseline (week 0) to week 68 in:
o
Body weight (kg)
o
BMI (kg/m2)
o
HbA1c (%, mmol/mol) (semaglutide s.c. 1.0 mg once-weekly versus semaglutide 
placebo I/II)
o
Fasting plasma glucose (FPG) (mg/dL)
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o
Fasting serum insulin (mIU/L)
o
Diastolic blood pressure (mmHg)
o
Lipids (mg/dL)

Total cholesterol

High density lipoprotein (HDL) cholesterol

Low density lipoprotein (LDL) cholesterol

Very low density lipoprotein (VLDL) cholesterol

Free fatty acids (FFA)

Triglycerides
o
High sensitivity C-Reactive Protein (hsCRP) (mg/L)
o
Plasminogen Activator Inhibitor-1 (PAI-1) Activity (AU/mL)
o
SF-36

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
o
IWQoL-Lite for CT

pain/discomfort domain score

psychosocial domain score

total score
!
Subjects who after 68 weeks achieve (yes/no):
o
Responder definition value for SF-36 physical functioning score
o
Responder definition value for IWQoL-Lite for CT physical function domain (5-
items) score
o
HbA1c < 7.0% (53 mmol/mol)
o
HbA1c T 6.5% (48 mmol/mol)
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) from baseline (week 0) to week 75
!
Number of serious adverse events (SAEs) from baseline (week 0) to week 75
!
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes from baseline (week 0) to week 75
!
Change from baseline (week 0) to week 68 in:
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o
Pulse (bpm)
o
Amylase (U/L)
o
Lipase (U/L)
o
Calcitonin (ng/L)
4.2.3
Exploratory endpoints
Exploratory endpoints addressing the exploratory objectives:
The exploratory endpoints reflect the comparison of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo I/II.
!
Subjects who after 68 weeks achieve (yes/no) the following in:
o
New onset of persistent micro albuminuria (UACR F 30 and T 300 mg/g) in subjects 
without albuminuria (UACR < 30 mg/g) at randomisation (week 0)
o
New onset of persistent macro albuminuria (UACR > 300 mg/g) in subjects without 
macro albuminuria at randomisation (week 0)
o
Regression of micro albuminuria/macro albuminuria to normal (in subjects with 
either micro (UACR F 30 and T 300 mg/g ) or macro albuminuria (UACR > 300 
mg/g ) at baseline (week 0))
!
Change from baseline (week 0) to week 68 in:
o
Antihypertensive (decrease, no change, increase)
o
Lipid lowering medication (decrease, no change, increase)
o
Concomitant OAD medication (decrease, no change, increase)
o
6MWT (meters) (only for subjects with a BMI F 35 kg/m2)
o
Fatty liver index (FLI) score category (< 30, F 30 and < 60, F 60)
o
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 (week 0) to week 68 have permanently discontinued 
randomised trial product (yes/no)
!
Time to permanent discontinuation of randomised trial product (weeks)
Semaglutide placebo I is used when it is solution for injection with the 3 ml pre-filled PDS290 pen-
injector for the weight management placebo product whereas semaglutide placebo II is used when it 
is the 1.5 ml pre-filled PDS290 pen-injector for the diabetes placebo product.
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5
Trial design
5.1
Overall design
!
This is a 68-week, randomised, double-blinded, double dummy, placebo-controlled, multi-
centre trial. 
!
Subjects will be randomised in a 1:1:1 manner to receive either:
o
Semaglutide s.c. 2.4 mg and semaglutide placebo II once-weekly
o
Semaglutide s.c. 1.0 mg and semaglutide placebo I once-weekly
o
Semaglutide placebo I and semaglutide placebo II once-weekly
all as an adjunct to a reduced-calorie diet and increased physical activity.
!
There is a 1 week screening period followed by a randomisation visit and a 68-week 
treatment period. The treatment period is divided into a dose escalation period of 16 weeks
and a maintenance period of 52 weeks. Subsequently there is a follow-up period of 7 weeks.
!
The trial population will consist of subjects with BMI > 27 kg/m2 with T2D on 0-3 OADs, 
but not treated with insulin.
The trial design and rationale for the double dummy design is outlined in Figure 5-1.
Figure 5-1
A schematic diagram of the trial design, with the duration of the trial periods 
including follow-up period. As outlined in the figure the escalation is different 
between the two target doses of semaglutide, furthermore the injection volume 
and device are different as reflected in the product strength (Table 7-2). The 
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two active arms are represented with the respective placebo arms, and the 
placebo arm includes both regimens. All subjects therefore receive two 
injections per week as reflected in double dummy design.
5.2
Subject and trial completion
Approximately 1412 subjects will be screened to achieve 1200 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 the final scheduled visit.
Treatment period completion for a subject:
Treatment period completion is defined as when the randomised subject has attended the 'end of 
treatment' visit according to the flowchart.
5.3
End of trial definition
The end of the trial is defined as the date of the last visit of the last subject in the trial.
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 guidelines66, 67.
A randomised, double-blinded, double dummy, placebo-controlled, multi-centre trial design is 
chosen to minimise bias in the assessment of the effect and safety of semaglutide 2.4 mg,
semaglutide 1.0 mg, and semaglutide placebo I/II once-weekly, as an adjunct to a reduced calorie 
diet and increased physical activity.
The trial includes a screening visit to assess the subject’s eligibility followed by visits/phone 
contacts every second week during dose escalation. From week 20, visits/phone contacts will take 
place every fourth 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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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.
A treatment arm with semaglutide 1.0 mg once-weekly is included to be able to compare with the 
semaglutide s.c. T2D development programme (NN9535) and enables a comparison of the effect on 
body weight between the two semaglutide doses (1.0 and 2.4 mg) in subjects with overweight or 
obesity and T2D. 
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.
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 F 18 years at the time of signing informed consent.
3. Body Mass Index (BMI) F 27 kg/m2
4. History of at least one self-reported unsuccessful dietary effort to lose body weight
5. Diagnosed with T2D F 180 days prior to the day of screening
6. Subject treated with either:
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o
diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as 
single agent therapy or
o
up to 3 OADs (metformin, SU, SGLT2i or glitazone) according to local label
7. HbA1c 7-10% (53-86 mmol/mol) (both inclusive)
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
For country specific requirements, see Appendix 10.
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:
Diabetes related:
1. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior day of screening
2. Receipt of any other anti-diabetic investigational drug within 90 days prior to screening for this 
trial, or receipt of any investigational drugs not affecting diabetes within 30 days prior to 
screening for this trial
3. Treatment with a GLP-1 receptor agonist within 180 days prior to screening
4. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 30 
mL/min/1.73 m2 (< 60 mL/min/1.73 m2 in subjects treated with SGLT2i ) according to CKD-
EPI creatinine equation as defined by KDIGO 201242 by the central laboratory at screening
5. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or an 
equally qualified health care provider (e.g. optometrist) within the past 90 days prior to 
screening or in the period between screening and randomisation
Obesity related:
6. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
7. 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
8. Uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 
0.4 mIU/L as measured by central laboratory at screening
Mental Health:
9. History of major depressive disorder within 2 years before screening 
10. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder)
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11. A Patient Health Questionnaire-9 (PHQ-9) score of  F 15 at screening 
12. A lifetime history of a suicidal attempt
13. Suicidal behaviour within 30 days before screening 
14. 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:
15. Use of non-herbal Chinese medicine or other non-herbal local medicine with 
unknown/unspecified content within 90 days before screening
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 F 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. 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
21. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening
22. Subject presently classified as being in New York Heart Association (NYHA) Class IV
23. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator 
24. Known or suspected abuse of alcohol or recreational drugs
25. Known or suspected hypersensitivity to trial product(s) or related products
26. Previous participation in this trial. Participation is defined as signed informed consent 
27. Participation in another clinical trial within 90 days before screening 
28. Other subject(s) from the same household participating in any semaglutide trial
29. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing
potential and not using a highly effective contraceptive method
30. 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.
For country specific requirements see Appendix 10 and for contraceptive requirements see 
Appendix 5.
6.3
Randomisation criteria 
Subjects are eligible to be randomised in the trial only if all of the following criteria apply:
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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
Subject not fulfilling the randomisation criteria will be considered screen failure, see Section 6.5.
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. 
!
At the ‘end of trial’ visit only 2 hours of fasting is required prior to the anti-semaglutide 
antibody sampling.
!
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 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 
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exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
7
Treatments
7.1
Treatments administered
!
All trial products listed in Table 7-1 are considered investigational medicinal products (IMP)
!
Trial product must only be used, if it appears clear and colourless
Table 7-1
Trial products provided by Novo Nordisk A/S
Trial product 
name:
Semaglutide B
1.0 mg/mL PDS290 and 
semaglutide placebo I*
Semaglutide B
3.0 mg/mL PDS290 and
semaglutide placebo I
Semaglutide 
1.34 mg/mL PDS290 and
semaglutide placebo II
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
1.5 mL PDS290 pre-filled 
pen-injector
* Semaglutide B 1.0 mg/mL PDS290 and semaglutide placebo I will only be dispensed at the first 
dispensing visit.
!
Dose escalation of semaglutide/semaglutide placebo should take place during the first 8-16 
weeks after randomisation as described in Table 7-2. All subjects should aim at reaching the 
recommended target dose of semaglutide 1.0 mg and 2.4 mg once-weekly or the 
corresponding volume of placebo. Thus, all subjects will be exposed to both escalation 
regimens.
!
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 in the semaglutide 2.4 mg once-
weekly/semaglutide II placebo arms. The placebo II arm will follow the 
escalation regimen outlined in Table 7-3.
Trial product name
Dose
Volume
Value shown in dose 
counter*
Duration
Dose escalation period
Semaglutide B 1.0 mg/mL PDS290 and 
semaglutide placebo I
0.25 mg
0.25 mL
25*
4 weeks
Semaglutide B 1.0 mg/mL PDS290 and 
semaglutide placebo I
0.5 mg
0.50 mL
50*
4 weeks
Semaglutide B 3.0 mg/mL PDS290 and 
semaglutide placebo I
1.0 mg
0.34 mL
34*
4 weeks
Semaglutide B 3.0 mg/mL PDS290 and 
semaglutide placebo I
1.7 mg
0.57 mL
57*
4 weeks
Maintenance period
Semaglutide B 3.0 mg/mL PDS290 and 
semaglutide placebo I
2.4 mg
0.80 mL
80*
52 weeks
* Conversion to dose is calculated based on 0.01 mL/value for both strengths.
Table 7-3
Dose escalation and maintenance in the semaglutide 1.0 mg once-
weekly/semaglutide II placebo arms. The placebo I arm will follow the 
escalation regimen outlined in the above Table 7-2.
Trial product name
Dose
Volume
Value shown in 
dose counter
Duration
Dose escalation period
Semaglutide 1.34 mg/mL and semaglutide placebo II 0.25 mg
0.19 mL
0.25 mg
4 weeks
Semaglutide 1.34 mg/mL and semaglutide placebo II 0.5 mg
0.37 mL
0.5 mg
4 weeks
Maintenance period
Semaglutide 1.34 mg/mL and semaglutide placebo II 1.0 mg
0.74 mL
1.0 mg
60 weeks
!
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 
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administer a dose until the next scheduled dose. A missed dose should not affect the 
scheduled dosing day of the week.
!
If F 2 consecutive doses of trial product are missed, the subject should be encouraged to re-
commence the treatment if considered safe as per the investigator’s discretion and if the 
subject does not meet any of the discontinuation criteria (Section 8.1). The trial product 
should be continued as early as the situation allows. The missed doses should not affect the 
scheduled dosing day of the week. The start dose for re-initiation of trial product is at the 
investigator’s discretion. In case of questions related to re-initiation of trial product, the 
investigator should consult Novo Nordisk global medical experts. If doses are missed blood 
glucose should be more closely monitored if judged necessary by the investigator.
!
Auxiliary supplies will be provided in accordance with the trial materials manual (TMM)
please see Table 7-4.
Table 7-4
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 
DFU for 1.5 mL PDS290 pre-filled pen-injector
Not included in the dispensing unit and to be handed out separately 
BG-meters
Type of BG-meter used in the trial will be specified in the TMM
7.1.1
Medical device
Information about the PDS290 pre-filled pen-injector may be found in the IB64 and any updates 
hereof.
Information about the use of the PDS290 pre-filled pen-injector for semaglutide B 1.0 mg/mL 
PDS290, semaglutide B 3.0 mg/mL PDS290, and semaglutide placebo I can be found in the DFU. 
Information about the PDS290 pre-filled pen-injector for semaglutide 1.34 mg/mL and semaglutide 
placebo II can be found in the IB64.
Training in the PDS290 pre-filled pen-injector
The investigator must document that training in the DFUs has been given to the subjects orally and
in writing at the first dispensing visit. Training must be repeated, during the trial in accordance with 
the flowchart in order to ensure correct use of the medical device. Training is the responsibility of 
the investigator or a delegate.
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7.1.2
Diet and physical activity counselling
All subjects will receive counselling with regards to diet (500 kcal deficit per day relative to the 
estimated total daily energy expenditure (TEE) calculated once at randomisation) and physical 
activity (150 min of physical activity per week is encouraged, e.g. walking or use the stairs) taking 
subject’s diabetes into account. Counselling should be done by a dietician or a similar qualified 
healthcare professional every 4th week via visits/phone contacts.
Subjects will be asked to record their food intake and physical activity at least 3 days prior to the 
phone contacts and clinic visits according to the flowchart to assist their lifestyle intervention.
However, the subject should be encouraged to keep diary of their food intake and physical activity 
on a daily basis. After randomisation the subjects can use a tool of their own choice 
(paper/app/other tool) for recording, ensuring it can be reviewed during diet and physical activity 
counselling. Subjects must receive instructions in how to capture their physical activity and food 
intake. 
Calculation of estimated TEE
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (Table 7-5) with a 
Physical Activity Level value of 1.368.
TEE = BMR × 1.3
Table 7-5
Equation for estimated BMR
Sex
Age
BMR (kcal/day)
Men
18-30 years
31-60 years
> 60 years
15.057 ×weight at randomisation in kg + 692.2
11.472 ×weight at randomisation in kg + 873.1
11.711 × weight at randomisation in kg + 587.7
Women
18-30 years
31-60 years
> 60 years
14.818 × weight at randomisation in kg + 486.6
8.126 × weight at randomisation in kg + 845.6
9.082 × weight at randomisation in kg + 658.5
If a BMI T 22.5 kg/m2 is reached the recommended energy intake should be recalculated with no 
kcal deficit (maintenance diet) for the remainder of the trial. If deemed necessary the investigator 
could consult Novo Nordisk to discuss when maintenance diet can be initiated.
7.2
Dose modification
!
Not applicable for this trial. Please refer to Section 7.1 for description of missed dose(s). 
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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. 
!
Randomisation will be stratified according to the following background diabetes treatment 
categories:
o
Diet and physical activity counselling only or treatment with single compound 
metformin or sodium-glucose co-transporter 2 inhibitors (SGLT2i) treatment 
  or
o
Single compound OAD treatment (sulphonylurea (SU) or glitazone) or combination 
treatment with of up to 3 OADs (metformin, SU, SGLT2i or glitazone)
Subjects in the two stratification groups will be further stratified into 2 groups by screening
value of HbAlc (A. < 8.5% or B. F 8.5%).
!
Proportion of subjects treated with SU mono-or combination therapy will be restricted to a 
maximum of 30% of total randomised subjects. When the SU target is reached subjects 
treated with SU as background treatment must not be randomised to this trial.
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 I
!
Semaglutide B 3.0 mg/mL PDS290 / semaglutide placebo I
!
Semaglutide 1.34 mg/mL PDS290 / semaglutide placebo II
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the subject’s medical records.
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 7-6
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 I
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 I
Semaglutide 1.34 mg/mL 
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 II 
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 (Table 7-6) 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.
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!
All returned, expired or damaged trial products (for technical complaint samples, see 
Appendix 6) must be stored separately from non-allocated trial products. No temperature 
monitoring is required.
!
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site.
7.6
Treatment compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant the 
investigator will remind the subject of the importance of following the instructions given, including 
taking the trial products as prescribed.
Treatment compliance of trial product will be assessed by asking subject about missed doses and 
monitoring of PK dosing diaries. Information about compliance and missed doses should be 
described in the subject’s medical records.
7.7
Concomitant medication
Any medication (including over-the-counter or prescription medicines) other than the trial product 
that the subject is receiving at the time of the first visit or receives during the trial must be recorded 
along with:
!
Trade name or generic name
!
Indication
!
Dates of administration including start and stop dates
!
Dose (only to be recorded for OADs, anti-hypertensive and lipid-lowering medication)
Treatment with OADs is considered non-investigational medicinal products and should be used 
according to their respective labels and will be used open-label throughout the trial.
To mitigate SU induced hypoglycaemia, subjects treated with SU (either alone or in combination 
with other OADs) will be asked to reduce the SU dose by approximately 50% at the discretion of 
the investigator, from randomisation. In case of consistent hyperglycaemia, glycaemic rescue 
treatment could be initiated as described in Section 8.1.2. 
Investigators can switch OAD treatment within the same drug class, e.g. in case specific drugs 
become unavailable. If the investigator judges that treatment intensification is required but does not 
meet the rescue criteria of  FPG > 15 mmol/l, the subject should intensify treatment according to the 
American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 
guidelines69 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues). Medication should 
preferably be weight-neutral and should first be based on intensification of background OAD 
treatment or addition of new background OADs. This will not be considered as rescue medication 
and subjects can continue in the trial unchanged.
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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. 
7.7.1
Rescue medication
Glycaemic rescue medication, i.e. intensification of background OAD treatment or addition of new 
background OADs, should be implemented at the discretion of the investigator in case of persistent
hyperglycaemia.
The following guidelines should be used:
1. Rescue medication according to ADA/EASD guidelines69 (excluding GLP-1 RAs, DPP-4 
inhibitors and amylin analogues). Rescue medication should preferably be weight-neutral.
2. If deemed necessary at the discretion of the investigator, insulin rescue therapy can be initiated, 
if so it should be according to ADA/EASD guidelines69 and as short duration as possible.
Subjects that are started on rescue medication should continue to follow the protocol-specified visit 
schedule and stay on randomised treatment unless the investigator judge that it jeopardise safety. 
Rescue medication should be documented in medical records and reported in the case report form 
(CRF).
Rescue medication will not be supplied by Novo Nordisk, but reimbursed as long as subject is 
participating in the trial, if required according to local regulations Appendix 10.
7.8
Treatment after the end of the trial
After the end of the trial the subject should be treated at the discretion of the investigator.
8
Discontinuation/Withdrawal criteria 
The subject may be discontinued at any time during the trial at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons.
Efforts must be made to have the subjects, who discontinue trial product, to continue in the trial.  
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial.
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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 clinic visits efforts should be made to have the
visits converted to phone contacts. However, all effort 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 F 100 ng/L (Appendix 9)
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 criteria70 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. A 
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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 CRF, and final drug accountability must be performed. 
8.1.1
Temporary discontinuation of trial treatment
If a subject has discontinued trial product due to temporary safety concern not related to trial 
product and is allowed to resume, the subject should follow the guide for missed doses (Section 
7.1). Similarly, a subject who discontinues trial product on their own initiative should be 
encouraged to resume the trial product (Section 7.1). 
Each missed dose should be recorded in the CRF, as per subject’s recollection. If a ‘treatment 
status’ session previously has been made in IWRS to indicate discontinuation of trial product, a new 
‘treatment status’ session must be made to resume trial product.
8.1.2
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered rescue medication. If 
any of the FPG values (including protocol scheduled fasting self-measured plasma glucose 
(SMPG)) exceed 15 mmol/L (270 mg/dL) and no intercurrent cause of the hyperglycaemia can be 
identified, a confirmatory FPG (at central laboratory) should be obtained by calling the subject for a 
re-test. If the confirmatory measurement also exceeds 15 mmol/L (270 mg/dL) the subject must be 
offered rescue medication, at the discretion of the investigator, according to the ADA/EASD
guidelines69 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues).
For a description of rescue medication, please refer to Section 7.7.1.
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.
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Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the ‘end of trial’
form in the CRF.
8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
8.3
Lost to follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the trial site for a required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
trial.
!
Before a subject is deemed lost to follow-up, the investigator must make every effort to 
regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). If attempts have failed, family members or other contacts consented by the 
subject can be contacted for alternative contact details. These contact attempts should be 
documented in the subject's source document.
!
Should the subject continue to be unreachable at 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. 
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!
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
5. 6MWT
!
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, and 
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.
!
Subjects must receive training in how to collect dosing information prior to PK sampling in 
a designated paper diary.
!
Only the subject can make entries and corrections in the diaries, unless the section is 
specified for site staff.
!
The barriers and motivation interview identifies barriers to and motivation for lifestyle 
change and compliance with the protocol. The interview must be conducted at screening to 
assist in identifying subjects who are unable or unwilling to comply with protocol 
procedures as per the exclusion criteria. In addition, the interview will ensure that any minor 
barriers are addressed during lifestyle counselling.
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 diaries, 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.
!
The fatty liver index is based on an algorithm including BMI, waist circumference, 
triglycerides and gamma-glutamyl-tranferase (GGT).
!
For subjects receiving antihypertensive, lipid-lowering or OAD treatment, the investigator 
should evaluate changes in the subject’s treatment intensity within each therapeutic area. 
The evaluation should be based on whether an overall change from randomisation until the 
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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.
9.1
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the flowchart.
9.1.1
Body measurements
!
Body weight should be measured at all site visits without shoes, on an empty bladder and 
only wearing light clothing. It should be measured on a digital scale and recorded in 
kilograms or pounds (one decimal) using the same scale throughout the trial. The scale must 
be calibrated yearly as a minimum.
!
Height is measured without shoes in centimetres or inches (one decimal). BMI will be 
calculated by the CRF from screening data and must be in agreement with inclusion 
criterion no. 3.
!
Waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest. Measures must be obtained in standing position with a 
non-stretchable measuring tape and to the nearest cm or inch. The tape should touch the skin 
but not compress soft tissue and twists in the tape should be avoided. The subject should be 
asked to breathe normally. The same measuring tape should be used throughout the trial.
The measuring tape will be provided by Novo Nordisk to ensure standardisation.
9.1.2
Clinical outcome 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:
!
Impact of Weight on Quality of Life-Lite for Clinical Trials (IWQoL-Lite for CT)
version 3.0
o
The IWQoL-Lite for CT is a 20-item modified version of a questionnaire tool 
designed to assess the weight-related quality of life71.
!
Patient Global Impression of Status (PGI-S) (IWQoL-Lite for CT) for physical function 
version 1.0
!
Patient Global Impression of Change (PGI-C) (IWQoL-Lite for CT) for physical function 
version 1.0 
!
Work Productivity and Activity Impairment Questionnaire – Specific Health Problem 
(WPAI-SHP) version 2.0
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o
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.
For US only: 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 scores72.
!
6MWT
In addition to the patient reported outcome questionnaires, subjects with a BMI F 35 kg/m2 may 
also complete the 6MWT as specified in the flowchart. The 6MWT assesses the distance a 
subject can walk in 6 minutes. It is a direct and timed measure of walking ability, which is 
technically simple, reproducible, and when administrators are well trained, readily standardised. 
The goal is for the subject to walk as far as possible in six minutes without running. The subject 
is allowed to self-pace and rest as needed as they traverse back and forth along a marked 
walkway of 66 feet (20 m) (Figure 9-1). The primary outcome is the distance covered over 6 
minutes73, 74. 
Specifically, all investigators and 6MWT clinical site administrators will receive a manual, 
providing details for administration of the 6MWT. In addition to the manual, each 6MWT 
clinical site administrator will have a checklist that must be completed prior to initiating each 
test administration to confirm and document that specific test administration criteria are met 
(e.g., the test is assessed along a flat, straight, undisturbed room that is at least 6 feet (1.8 m) 
wide; proper footwear as judged by the investigator is worn by the subject or otherwise noted)75.
If the specific test administration criteria are not met, the 6MWT should not be performed. 
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Figure 9-1
Walkway marking for the six minute walk test
9.1.3
Self-measured plasma glucose 
Subjects will be provided with a BG meter including auxiliaries as well as instructions for use. The 
subjects will be instructed in how to use the device. Investigator should ensure throughout the trial 
that the subject is able to correctly measure BG at any time.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
The BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol.
SMPG measurements should be taken fasting (at least 8 hours overnight before the visit) and prior 
to taking any diabetes medication. SMPG should be taken either on the day of the clinic visit or on 
the day before, according to the flowchart. In case of suspicion of a hypoglycaemic event a SMPG 
should also be taken. Subjects should be instructed in how to record the results of the SMPG values 
in the diaries. The record of each SMPG value should include date, time and value. All data from 
the diary must be transcribed into the CRF during or following the contact. If obtained via phone 
and a discrepancy is later detected, the values in the CRF must be corrected.
Occasional review by the investigator of the BG meter values stored in the memory of the BG meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the CRF.
9.1.4
Clinical efficacy laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
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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 9-2.
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1 and the 
reporting timelines in Figure 9-2.
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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 9-2
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
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Table 9-1
AEs requiring additional data collection (via specific event form) and events for 
adjudication
Event type 
AE via with 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
Acute renal failure
X
Diabetic retinopathy
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.
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 (Table 9-1 and Appendix 4)
!
Death
!
AE Search (standardised screening): All AEs not directly reported by the investigator as 
requiring adjudication, will undergo screening to identify potential events for adjudication. 
The investigator can be queried to provide additional information related to the reported AE, 
e.g. alternative aetiology, underlying cause(s) and/or clinical details.
!
EAC-identified events: When reviewing source documents provided for another event for 
adjudication, the EAC can identify additional events in scope for adjudication that were not 
initially reported by the investigator. In these instances, the investigator will be notified of 
the newly identified event and has the option to report the EAC-identified event. Regardless 
of whether the investigator decides to report the event, it will undergo adjudication. 
Occasionally, EAC-identified events may require the investigator to collect additional 
source documents, which should be provided by uploading to the event adjudication system
(EAS).
With the exception of EAC-identified events, an event-specific adjudication form for the event in 
question should be completed in the CRF within 14 calendar days of the investigator’s first 
knowledge of the event.
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Copies of collected source documents should be labelled with trial ID, subject and AE number, 
redacted (anonymised of personal identifiers) and uploaded to the EAS within 4 weeks according to 
instructions outlined in the event adjudication site manual. If no, or insufficient source documents 
are provided to the adjudication supplier, the investigator can be asked to complete a clinical 
narrative 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.
9.2.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Novo Nordisk policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5
Cardiovascular and death events
Cardiovascular and death events will be handled and reported according to AE/SAEs description in 
Section 9.2.1.
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9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE
The following Disease-Related Events are common in subjects with T2D and can be serious/life 
threatening:
!
Hypoglycaemic episodes
Definitions, classification and reporting requirements are described in Appendix 8.
Hypoglycaemia
Non-serious hypoglycaemia must be reported on a hypoglycaemic episode form.
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above, an AE 
form and a safety information form must also be filled in. One AE form and safety information 
form can cover several hypoglycaemic episode forms, if the subject has not recovered between the 
episodes.
9.2.7
Pregnancies and associated adverse events
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until the ‘end of trial’ visit.
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in
Figure 9-3 and Appendix 5. 
Pregnancy outcome should be documented in the subject’s medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
Maternal form 1b
 14 calendar days after birth
Maternal form 1a
 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2  14 calendar days
Paternal form*1  14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent .
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-3
Decision tree for determining the forms to complete with associated timelines 
for pregnancy. 
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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 9-4.
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 9-4
Decision tree for determining the forms to complete with associated timelines 
for technical complaints.
9.3
Treatment of overdose
Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in clinical 
trials. The most commonly reported AE was nausea. All subjects recovered without complications.
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to subject’s clinical signs and symptoms.
The overdose must be reported as a medication error (Appendix 4) and for reporting timelines see
Section 9.2.1.
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities. A prolonged period of observation and treatment may be 
necessary, taking into account the long half-life of semaglutide of approximately one week.
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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 IB and any updates 
hereof64.
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 (Appendix 4) during the trial and any clinically significant worsening 
from baseline must be reported as an AE (Section 9.2).
9.4.1
Mental health assessment instruments
!
PHQ-976 is a 9-item depression module of the patient health questionnaire, which is a self -
administered diagnostic tool used for assessment of mental disorders. The questionnaire will 
be available in a linguistically validated translated version. 
!
C-SSRS77 is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation. 
The questionnaire will be administered as an interview by the investigator or a qualified 
delegate. The questionnaire (C-SSRS Baseline and C-SSRS Since Last Visit) will be 
available in a linguistically validated translated version.
o
Prior to administering the C-SSRS questionnaire, the investigator or qualified 
delegate must complete sufficient training.
If a subject has a PHQ-9 score of 10-14 both inclusive the subject should be referred to a mental 
health professional (MHP) if judged relevant by the investigator. If referral is not deemed relevant 
this, along with the reason why, must be documented in the subject’s medical records.
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A subject must be referred to a MHP if:
!
the subject has a PHQ-9 score F15 or
!
the subject has any suicidal behaviour or
!
the subject has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment or
!
in the opinion of the investigator, it is necessary for the safety of the subject
If one or more of the referral criteria are met, the investigator should explain to the subject why the 
referral and psychiatric evaluation by a MHP is needed. If the subject refuses to be referred to a 
MHP, the subject’s decision should be documented in subject’s medical record and the investigator 
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, respiratory, central and 
peripheral nervous systems. 
!
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.3
Vital signs
!
The method for measuring systolic and diastolic blood pressure needs to follow the standard 
clinical practice at site.
!
Blood pressure (diastolic and systolic) and pulse measurements should be preceded by at 
least 5 minutes of rest for the subject in a quiet setting without distractions (e.g. television, 
cell phones).
!
Blood pressure and pulse measurements will be assessed in a sitting position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
9.4.4
Electrocardiograms
!
12-lead ECG will be obtained as outlined in the flowchart using a local ECG machine that 
automatically calculates the heart rate and measures PR, QRS, and QT intervals.
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9.4.5
Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist, or equally qualified certified 
health care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a pre-corneal or corneal contact lens examination) and performed with 
pharmacologically dilated pupils.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base their evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the subject has experienced worsening of visual function since 
the last examination. If the applicable eye examination was performed before the subject signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial.
After randomisation an eye examination performed according to above must be performed as per 
the flowchart in Section 2. The investigator should indicate the outcome of each eye examination. 
Relevant findings prior to randomisation must be recorded as concomitant illness/medical history. 
While relevant findings occurring after randomisation should be reported as an AE, if applicable 
according to Section 9.2.
9.4.6
Clinical safety laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
!
If the laboratory finding based on the results from central laboratory meets the criteria for 
laboratory outliers, a laboratory outlier form in the CRF should be completed. Please refer to 
Appendix 2 for the criteria for the laboratory outliers.
!
Urine pregnancy tests provided by central laboratory must be performed for women of 
childbearing potential at screening and as specified in the flowchart. Urine pregnancy test 
must be repeated at any time during the trial if pregnancy is suspected. Further instructions 
can be found in the laboratory manual.
!
Urinalysis: Proteinuria should be assessed using a spot urine collection to measure urine 
albumin-to-creatinine ratio (UACR). The spot urine specimen should be collected on first 
morning samples. Persistent proteinuria is defined as having 2 out of 3 consecutive samples 
above the limit for macroalbuminuria or microalbunuria. Repeat UACR should be done for 
at least 4 weeks apart after positive UACR (F 30 mg/g) to confirm the finding.
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9.4.7
Immunogenicity assessments
Blood samples for determination of serum antibodies against semaglutide, including cross reactivity 
to endogenous GLP-1 RA will be taken during the trial at visits specified in the flowchart. Samples 
taken at the ‘end of trial’ visit which are positive for anti-semaglutide antibodies will be further 
characterised for in vitro neutralising effect towards semaglutide. In addition, if samples taken at the 
‘end of trial’ visit are also positive for cross-reactivity against endogenous GLP-1, the samples will 
be analysed for in vitro neutralising effect towards endogenous GLP-1. The results of the analysis 
will only be disclosed after completion of the clinical trial report (CTR) if required by local 
regulation.
9.5
Pharmacokinetics
!
Single blood samples for measuring plasma concentration of semaglutide will be drawn for 
both semaglutide and semaglutide placebo subjects on visits specified in the flowchart.
!
Subject must be instructed to withhold their trial product dose in the morning of the clinic
visit until blood sampling has been performed.
!
The PK dosing information should be transcribed into the CRF for the last 2 doses of trial 
product prior to the PK assessment as outlined in the flowchart.
!
The exact timing of obtaining the PK sample must be recorded on the laboratory form.
!
The dual purpose of measuring plasma semaglutide levels is to perform population PK (Pop-
PK) analyses and to assess the level of drug interference in the anti-semaglutide antibody 
analysis. Having Pop-PK in this trial will further support bridging of Pop-PK from trials 
conducted in other populations.
Samples will be used to evaluate the pharmacokinetics of semaglutide. Each plasma sample will be 
divided into 2 aliquots (e.g. one for pharmacokinetics and a backup,) and may also be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the trial. Residual 
sample material may be used for exploratory investigation of metabolites and bioanalysis assay 
development and troubleshooting in relation to the pharmacokinetic assay. 
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 efficacy objectives. 
The following samples must be conducted in accordance with the laboratory manual and the 
flowchart:
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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 
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 drug wash-out). Tryptase concentrations (if 
measured) as well as results of anti-semaglutide antibody and IgE isotype anti-semaglutide 
antibodies will be collected by Novo Nordisk and the results will be reported in the CTR.
10 Statistical considerations 
Taxonomy of week 68 assessments
For each subject a given assessment at week 68 may be available or missing and Table 10-1
describes the taxonomy for this. Note, this is done per assessment and per subject; subjects may be 
a different type for different assessments (a subject may have “available on randomised treatment 
(AT)” for body weight but “missing on randomised treatment (MT)” for waist circumference).
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Table 10-1
Taxonomy for subjects based on week 68 assessments
Assessment
at week 68
Subjects on 
randomised 
treatment at 
week 68
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised treatment with an assessment at week 68: 
Includes those that stop and restart trial product.
AT
No
Available but discontinued
Subjects who discontinued randomised treatment prematurely but returned to have an 
assessment at week 68. These are also called retrieved subjects
AD
Missing
Yes
Missing on randomised treatment:
Subjects who complete the trial on randomised treatment without an assessment at week 
68: Includes those that stop and restart trial product.
MT
No
Missing and discontinued:
Subjects who discontinued randomised treatment prematurely and did not return to have 
an assessment at week 68. These are also called non-retrieved subjects
MD
10.1
Sample size determination 
The sample size and thereby the power for this trial is primarily defined to support safety. However,
no formal statistical inference is planned based on number of adverse events. Given the trial sample 
size, the power of statistical tests for effect endpoints is described below.
The tests of superiority of semaglutide 2.4 mg to semaglutide placebo I/II (or semaglutide 1.0 mg) 
for the primary and confirmatory secondary endpoints are performed using the fixed-sequence 
statistical strategy. This strategy tests the endpoints using a predefined hierarchical order, all at the 
significance level of 5%, moving to test the next endpoint only after a statistically significant 
superiority result (p-value < 5%) on the previous endpoint. The test hierarchy is given in Table 10-2
with underlying assumptions, marginal power and effective power. The effective power is 
calculated under the assumption of independence of endpoints by multiplying the respective 
marginal powers successively. As the two primary endpoints are included in the statistical testing 
hierarchy, significant superiority of semaglutide 2.4 mg versus semaglutide placebo I/II must be 
demonstrated for each of the primary endpoints.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 68 for 
non-retrieved subjects (MD). The imputation is done separately within each treatment arm (see 
description below). However, for the power calculations missing values (MT and MD), regardless 
of treatment arm, are assumed to be similar to semaglutide placebo I/II subjects. These assumptions 
are likely conservative with respect to the power, and correspond to the jump to reference 
sensitivity analysis planned below.
Assumptions
The common assumptions for the power calculations are
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!
The significance level is 5%
!
The randomisation ratio is 1:1:1. 
!
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
o
20% of subjects discontinue permanently and
o
60% of these are retrieved (AD) at week 68 
!
All subjects in the semaglutide placebo I/II arm are assumed to have same effect as subjects 
who complete the trial on semaglutide placebo I/II (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 I/II [or 
semaglutide 1.0 mg]) 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 I/II (or semaglutide 1.0 mg) 
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. All tests except no. 6 are testing for superiority of semaglutide 2.4 mg to 
semaglutide placebo I/II. Test no. 6 is a test for superiority of semaglutide 2.4 mg to semaglutide 
1.0 mg for the primary endpoint change in body weight (%).
Given these assumptions, the sample size of 1200 subjects (400 in each arm), gives an effective 
power (marginal powers multiplied) of 94% for the first nine 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 1200 randomised 
subjects (400 in each arm)
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 I/II
Semaglutide
2.4 mg
1
% weight change #
11.6 (±10)
1.7 (±10)
10.2 (±11)
8.5%-points
> 99
> 99
2
5% responders
75%
37%
69%
1.8
> 99
> 99
3
10% responders
56%
20%
51%
2.6
> 99
> 99
4
15% responders
37%
9%
33%
3.7
> 99
> 99
5
WC change (cm) #
9.1 (±10)
2.8 (±10)
8.2 (±11)
5.4 cm
> 99
> 99
6
% weight change #, *
11.6 (±10)
8.1 (±10)
10.2 vs 7.2 (±11)
3.0%-points
97
97
7
HbA1c (%) change #
1.4 (±1.0)
0.5 (±1.0)
1.3 (±1.5)
0.8%-points
> 99
96
8
sBP change (mmHg) #
5.1 (±13)
0.4 (±13)
4.4 (±14)
4 mmHg
98
94
9
SF-36 PF score change
6 (±10)
2 (±10)
5.4 (±11)
3.4 score-
points
> 99
94
10
IWQoL-Lite PFD score 
change
To be confirmed. Is currently being validated in trial NN9536-4153 and NN9924-4233
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; 
PF = physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical 
function domain; # shown as a positive number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
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 
(regardless of pen) 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.
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o
In general, the on-treatment period will therefore be from the date of first trial 
product administration to date of last trial product administration excluding potential 
off-treatment time intervals triggered by at least two consecutive missed doses.
o
For the evaluation of adverse events and hypoglycaemic episodes the lag time for 
each on-treatment time interval is 7 weeks (49 days).
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 (or semaglutide 1.0 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 at least 5% from baseline (week 0) to week 68 is defined as 
5% responder = 1 if  % weight change T – 5%
0 if  % weight change > – 5%
Analyses addressing the primary estimand
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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 and stratification groups as factors and baseline body weight (kg) as 
covariate. The stratification group is defined by the OAD treatment stratification category and 
HbA1c stratification category as well as the interaction between these. The estimated treatment 
difference between semaglutide 2.4 mg and semaglutide placebo I/II will be reported together with 
the associated two-sided 95% confidence interval (CI) and corresponding p-value.
The analysis model for the 5% responder endpoint is a logistic regression using randomised 
treatment and stratification groups as factors and baseline body weight (kg) as covariate. The 
stratification group is defined by the OAD treatment stratification category and HbA1c stratification 
category as well as the interaction between these. The estimated odds ratio (OR) between 
semaglutide 2.4 mg and semaglutide placebo I/II 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 I/II will be carried out as 
follows for the two analysis models.
Let ^semaglutide and ^semaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo I/II group, respectively. The null and alternative hypotheses tested are
:     ! "#
$:  <   !.
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Let ORsemaglutide/semaglutide placebo denote the true odds ratio between semaglutide 2.4 mg and 
semaglutide placebo I/II. The null and alternative hypotheses tested are
: &'/  ! ) 1 "#
$: &'/  ! > 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 of the sensitivity 
analyses used to assess the robustness of the primary analysis results. The sensitivity analyses 
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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 I/II. An illustration of all imputation approaches for the effectiveness estimand is given in 
Figure 10-1.
Primary imputation approach for the primary estimand
Multiple imputation approach using retrieved subjects (RD-MI): The primary imputation approach 
for the primary estimand is a multiple imputation similar to the one described by McEvoy78. 
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, F40) and stratification groups (defined by 
stratification categories for OAD treatment and HbA1c) 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 95364374 as seed number.
Sensitivity analyses
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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 I/II group are imputed 
by sampling among all available assessments at week 68 in the semaglutide placebo I/II 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 I/II 
treatment as adjunct to reduced-calorie diet and increased physical activity79. The multiple 
imputation approach is done as above with the first step replaced by
1. Imputation: Defines an imputation model using semaglutide placebo I/II 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, 
F40) and stratification groups (defined by stratification categories for OAD treatment and 
HbA1c) 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 Sacks80 (S1-SI and S2-SI): Missing weight measurements 
at week 68 for non-retrieved subjects (MD) are imputed using a weight regain rate of 0.3 kg/month 
after LAO but truncated at no change from baseline whenever the extrapolation would lead to a 
positive weight gain relative to baseline. If a subject's weight at drug discontinuation represented a 
gain in weight relative to baseline, no additional gain will be imputed, and the unfavourable gain is 
carried forward to week 68. The weight regain imputation will be done for both randomised arms 
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo I/II 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 factors and 
covariate as for the primary analyses all nested within visit. An unstructured covariance matrix for 
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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 of 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 factors 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 I/II (or semaglutide 1.0 mg). 
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 s and covariate as for 
the primary endpoint % weight change with baseline body weight replaced by the basel ine 
assessment of the endpoint to be analysed. The statistical model for body weight responder 
endpoints will be logistic regression with factors 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.
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
%weight change*
6
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
HbA1c change (%, 
mmol/mol)
7
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
sBP change (mmHg)
8
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
9
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
IWQoL-Lite PFD score 
change
10
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; HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = 
Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical 
function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
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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 (or semaglutide 1.0 mg) to semaglutide placebo I/II. 
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 
factors 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 HbA1c responder endpoints and responder endpoints relating to clinical 
outcome assessments will be logistic regression with randomised treatment and stratification groups 
(defined by stratification categories for OAD treatment and HbA1c) as factors and the baseline 
assessment of the endpoint to be analysed as covariate.
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 serum insulin change 
(mIU/L)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
dBP change (mmHg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Total cholesterol change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
HDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
LDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
VLDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FFA change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Triglycerides change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
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
IWQoL-Lite PFD score responders 
##
Binary
Primary
FAS
LR
RD-MI
-
Secondary
IWQoL-Lite PDD score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
IWQoL-Lite PSD score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
IWQoL-Lite total score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
HbA1c < 7.0% responders**
Binary
Primary
FAS
LR
RD-MI
-
Secondary
HbA1c T 6.5% responders**
Binary
Primary
FAS
LR
RD-MI
-
Supportive secondary endpoints (safety related)
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Number of hypoglycaemia episodes
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; MMRM = mixed model for 
repeated measurements; BMI = body mass index; HbA1c = Hemoglobin A1c; FPG = fasting plasma glucose; dBP = diastolic blood pressure; HDL = 
high density lipoprotein; LDL = low density lipoprotein; VLDL = very low density lipoprotein; FFA = free fatty acids; hsCRP = high sensitivity C-
Reactive Protein; PAI-1 = Plasminogen Activator Inhibitor-1; LR = logistic regression; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for 
Clinical Trial; PFD = physical function domain; PDD = pain/discomfort domain; PSD = psychosocial domain;TEAEs = treatment emergent adverse 
events; SAEs = serious adverse events; # responder value = 4.3; ## responder value to be validated in trials NN9536-4153 and NN9924-4233; * 
comparison of semaglutide 1.0 mg vs semaglutide placebo I/II; ** comparison of semaglutide 2.4 mg vs semaglutide placebo I/II.
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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
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety and further to support the recommended dose of semaglutide in 
subjects with obesity. First, plasma semaglutide concentrations will be analysed using a population 
pharmacokinetic model, quantifying covariate (such as baseline body weight, age, gender, race, 
ethnicity, and injection site) effects on semaglutide exposure. Second, model based estimates of 
steady-state average concentrations will be derived for each subject, in order to facilitate subsequent 
exposure-response analyses. Relevant efficacy and safety endpoints will be related to steady-state 
average concentrations and subjected to model based analysis. 
The analyses will be conducted separately for each trial and be combined into a meta-analysis, 
including the phase 2 trial and phase 3a trials with PK sampling. A modelling analysis plan will be 
prepared before first database lock in the semaglutide phase 3a programme for weight management, 
outlining details of the analyses. The modelling will be performed by Quantitative Clinical 
Pharmacology at Novo Nordisk and will be reported separately from the clinical trial reports.
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11 Appendices
Abbreviations and Trademarks
Appendix 1
6MWT
six-minute walking test 
AD
available but discontinued 
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AT
available on randomised treatment
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate 
CI
confidential inverval
CLAE
clinical laboratory adverse event
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale 
DFU
direction for use 
DUN
dispensing unit number
EAC
event adjudication committee 
EAS
event adjudication system 
ECG
electrocardiogram
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 
GLP-1 RA
glucagon-like peptide-1 receptor agonist
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HbA1c
glycated haemoglobin
HDL
high density lipoprotein
HRT
hormone replacement therapy
hsCRP
high sensitive C-reactive protein 
IB
investigator’s brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IWQoL-Lite for CT
Impact of Weight on Quality of Life-Lite for Clinical Trials 
IRB
institutional review board
IWRS
interactive web response system
KDIGO
kidney disease improving global outcome
LAO
last available observation 
LDL
low-density lipoprotein
LPLV
last patient last visit
MD
missing and discontinued:
MEN2
multiple endocrine neoplasia type2
MMRM
mixed model for repeated measurements
MT
missing on randomised treatment
MTC
medullary thyroid cancer 
OAD
oral antidiabetic drug
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 Status
PHQ-9
Patient Health Questionaire-9  
PK
pharmacokinetic
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
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s.c.
subcutaneus
SD
standard deviation
Semaglutide, 1.0 mg/mL
Semaglutide B, 1.0 mg/mL PDS290 
Semaglutide, 1.34 mg/mL
Semaglutide, 1.34 mg/mL PDS290
Semaglutide, 3.0 mg/mL
Semaglutide B, 3.0 mg/mL PDS290 
SF-36
Short Form 36 v2.0 
SGLT2i
sodium–glucose co-transporter 2 inhibitor
SMPG
self-measured plasma glucose
SU
sulphonylurea
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes 
TEAE
treatment-emergent adverse event
TEE
total energy expenditure 
TMM
trial materials manual
TSH
thyroid stimulating hormone
UACR
urine albumin-to-creatinine ratio 
UNL
upper normal limit
VLDL
Very low density lipoprotein 
WOCBP
woman of child bearing potential
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Clinical laboratory tests
Appendix 2
!
The tests detailed in Table 11-1 and Table 11-2 will be performed by the central laboratory.
!
Laboratory samples specified in the protocol should be sent to the central laboratory for
analysis.
!
Additional tests may be performed at local laboratory at any time during the trial as
determined necessary by the investigator or required by local regulations.
!
The laboratory equipment may provide analyses not requested in the protocol but produced
automatically in connection with the requested analyses according to specifications in the
laboratory standard operating procedures. Such data will not be transferred to the trial
database, but abnormal values will be reported to the investigator.
!
The investigator must review all laboratory results for concomitant illnesses and AEs.
!
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report
except, antibody samples which will be stored until marketing authorisation or destroyed at
the latest 15 years from end of trial.
!
For haematology samples (differential count) where the test result is not normal, then a part
of the sample may be kept for up to two years or according to local regulations.
Table 11-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glycaemic control  
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 T 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a hypoglycaemic 
episode but as a clinical laboratory adverse event (CLAE) at the discretion of the investigator (Appendix 4).
A FPG result >16.7 mmol/L (300 mg/dL) should be reported as a CLAE at the discretion of the investigator (Appendix 
4).
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Table 11-2
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
Basophils
Eosinophils
Erythrocytes
Haematocrit
Haemoglobin
Leucocytes
Lymphocytes
Monocytes
Neutrophils
Thrombocytes
Biochemistry1
Alanine Aminotransferase (ALT)2
Albumin
Albumin corrected calcium
Alkaline phosphatase
Amylase3
Aspartate Aminotransferase (AST)2
Bicarbonate 
Calcitonin3
Creatinine kinase
Creatinine
Gamma Glutamyl Transferase (GGT)
Lipase3
Potassium
Sodium
Thyroid stimulating hormone (TSH)4
Total Bilirubin
Urea
Pregnancy Testing
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women 
of childbearing potential)5
Urinalysis
Urine albumin-to-creatinine ratio (UACR)
Other tests
Anti-semaglutide antibodies
eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 201242
by the central laboratory at screening.
Semaglutide plasma concentration 
(Tryptase in case of severe hypersensitivity, see Section 9.9)
Notes :
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 4 (Hy’s Law) and Section 8.1.
2If ALT or AST > 3 upper normal limit (UNL), additional blood sample should be taken from the subject to analyse
international normalised ratio (INR) by central laboratory (except at screening visit). Repeat testing of the abnormal 
laboratory assessments should be performed via central laboratory for the subject until abnormalities return to normal or 
baseline state.
3Not collected at week 52.
4If TSH level is out of normal range, additional testing will be performed by central lab: total and free T3 and T4 except 
at screening visit.
5Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
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!
Anti-semaglutide antibodies and semaglutide plasma concentration will be performed at a 
specialised laboratory.
!
Laboratory/analyte results that could unblind the trial (e.g. antibodies) will only be disclosed 
after completion of the clinical trial report (CTR) if required by local regulation.
!
Laboratory outlier: If the following laboratory parameters are above/below the cut-off 
values in Table 11-3 they are considered to be laboratory outliers and should be reported by 
completing a laboratory outlier form in the CRF:
Table 11-3
Criteria for laboratory outliers
Cut-off
Haematology
Leucocytes
< 1 x 109/L
Lymphocytes 
< 25 x 109/L
Thrombocytes 
< 25 x 109/L
Biochemistry
Albumin corrected calcium
< 1.5 mmol/L > 3.4 mmol/L
Alkaline phosphatase
> 20 x UNL
Calcitonin
> 100 ng/L
Creatinine
> 6 x UNL
Creatine kinase
> 10 x UNL
Potassium
< 2.5 mmol/L > 7 mmol/L
Sodium
< 120 mmol/L > 160 mmol/L
Hepatic laboratory outlier: If the following hepatic laboratory parameters are above the cut-off 
values in Table 11-4, it is considered to be hepatic laboratory outlier and should be reported by 
completing a hepatic event form in the CRF. It is at the investigator’s discretion to determine 
whether it should also be reported as an adverse event (Appendix 4).
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Table 11-4
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 
Helsinki81 and applicable ICH Good Clinical Practice (GCP) Guideline82
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 fro m 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 subinvestigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial.
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest.
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 guidelines82, Declaration of Helsinki81 and the 
IRB/IEC or trial site
!
The medical record must include a statement that written informed consent was obtained 
before any trial related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial related activity.
!
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in 
accordance with local requirements.
!
Subjects must be re-consented to the most current version of the informed consent form(s)
during their participation in the trial.
!
A copy of the informed consent form(s) must be provided to the subject.
4) Information to subjects during trial
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
Different initiatives for subject retention will be implemented throughout this trial. Site retention 
activities may include cooking classes, group meetings, and others. Materials and items will be 
supplied if locally acceptable. The retention items will be relevant for the subjects’ participation in 
the trial and/or their obesity and will not exceed local fair market value.
The initiatives for subject retention must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
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 
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leaving out certain identifiers will be enforced to protect the identity of subjects as required 
by local, regional and national requirements. 
!
The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also 
be explained to the subject. 
!
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities.
6) Committee structure
Novo Nordisk safety committee
Novo Nordisk will constitute an internal Semaglutide s.c. safety committee to perform ongoing 
safety surveillance. The Semaglutide s.c. safety committee may recommend unblinding of any data 
for further analysis, and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel.
Event adjudication committee
An independent external EAC is established to perform ongoing blinded adjudication of selected 
types of events and deaths (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 obesity83. In addition, events of acute pancreatitis will be adjudicated because Novo Nordisk 
monitors these events closely as treatment with GLP-1 RA 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 publications84.
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 84.
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)85, the Food and Drug Administration Amendment 
Act (FDAAA)86, European Commission Requirements87, 88 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations.
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
trial Last Subject First Treatment (LSFT) + 68 weeks corresponding to ‘end of treatment’ visit. If 
the last subject is withdrawn early, the PCD is considered the date when the last subject would have 
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). 
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!
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements.
!
Monitoring will be conducted using a risk based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites. 
!
Monitors will review the subject’s medical records and other source data e.g. the diaries and 
mental health assessment instruments, to ensure consistency and/or identify omissions 
compared to the CRF. 
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the inve stigator 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. 
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!
Subjects completing electronic patient reported outcome instruments are the data 
originators. Data will be transmitted to a technology service provider database, thus the 
service provider database is the source.
!
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who was contacted.
!
Definition of what constitutes source data can be found in a source document agreement at 
each trial site. There will only be one source document defined at any time for any data 
element.
11) Retention of clinical trial documentation
!
Records and documents, including signed informed consent forms, pertaining to the conduct 
of this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No r ecords 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 req uired 
documents and trial supplies have been collected and a trial site closure visit has been performed.
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
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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 
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. 
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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
!
Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
!
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
Note:
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
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
!
The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
!
This definition is not intended to include experience of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
!
Is a congenital anomaly/birth defect
!
Important medical event:
!
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations. This includes important medical events that may not be immediately life-threatening or result in 
death or hospitalisation, but may jeopardise the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion.
!
The following AEs must always be reported as SAEs using the important medical event criterion, if no other 
seriousness criteria are applicable:

suspicion of transmission of infectious agents via the trial product. 

risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
Description of AEs requiring additional data collection (via specific event form) and events for adjudication. 
AEs requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the evaluation of the safety of 
the trial product (Table 9-1). The selection of these events is based on the non-clinical and clinical data with 
semaglutide, knowledge from the GLP-1 RA drug class as well as regulatory requirements.
Event type
Description
Acute gallbladder disease
Events of symptomatic acute gallbladder disease (including gallstones and 
cholecystitis)
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following three 
features:
(1) abdominal pain consistent with acute pancreatitis (acute onset of a 
persistent, severe, epigastric pain often radiating to the back)
(2) serum lipase activity (and/or amylase activity) at least three times 
greater than the upper limit of normal
(3) characteristic findings of acute pancreatitis on imaging
Malignant neoplasm
Malignant neoplasm by histopathology or other substantial clinical 
evidence
Hepatic event
Hepatic event defined as:
– Disorders of the liver including cholestatic conditions and liver related 
signs and symptoms
– ALT or AST > 3x UNL and total bilirubin > 2x UNL or INR > 1.5*
– ALT or AST > 3x UNL with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
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*Please note that in case of a hepatic event defined as ALT or AST > 3x 
UNL and total bilirubin > 2x UNL, where no alternative aetiology exists 
(Hy's law), this must be reported as an SAE using the important medical 
event criterion if no other seriousness criteria are applicable.
Acute renal failure
Events of an abrupt or rapid decline in renal filtration function. This 
condition is usually marked by a rise in serum creatinine concentration or 
by azotemia (a rise in blood urea nitrogen [BUN] concentration)
Diabetic retinopathy
New onset or worsening of diabetic retinopathy
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 
!
Heart failure hospitalisation
!
Urgent heart failure visit
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failure)
Acute pancreatitis
The diagnosis of acute pancreatitis 
requires two of the following three 
features:
(1) abdominal pain consistent with 
acute pancreatitis (acute onset of a 
persistent, severe, epigastric pain 
often radiating to the back)
(2) serum lipase activity (and/or 
amylase activity) at least three 
times greater than the upper limit 
of normal
(3) characteristic findings of acute 
pancreatitis on imaging
!
Acute pancreatitis
!
Mild
!
Moderately severe
!
Severe
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.
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! Possible - A causal relationship is conceivable and cannot be dismissed.
! Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated.
The investigator should use the IB for the assessment. For each AE/SAE, the investigator must document in the medical 
records that he/she has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal information to include in the 
initial report. However, it is important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up report 
with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting requirements.
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 
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unavailable for more than 5 calendar days then the site will use the paper safety information form (see box below).
! The site will enter the SAE data into the CRF as soon as it becomes available, see Section 9.2.1.
! After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a 
previously reported SAE after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone.
SAE reporting via paper CRF
!
Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail or 
courier.
!
Initial notification via telephone is acceptable, although it does not replace the need for the investigator to complete 
the AE and safety information form within the designated reporting time frames (as illustrated in Figure 9-2):
! AE form within 24 hours.
! Safety information form within 5 calendar days. 
! Both forms must be signed within 7 calendar days.
Contact details for SAE reporting can be found in the investigator trial master file.
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Contraceptive guidance and collection of 
Appendix 5
pregnancy information
It must be recorded in the CRF whether female subjects are of childbearing potential. 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
1. Premenarcheal 
2. Premenopausal female with one of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview.
3. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high Follicle Stimulating Hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or Hormonal Replacement Therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
!
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrolment.
Contraception guidance
Male subjects 
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely.
Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table(s) below:
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Table 11-5
Highly effective contraceptive methods
Highly effective contraceptive methods that are user dependent a and b
Failure rate of <1% per year when used consistently and correctly.
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
! oral 
! intravaginal 
! transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
! oral 
! injectable 
Highly effective methods that are user independent b
Implantable progestogen only hormonal contraception associated with inhibition of ovulation
! Intrauterine Device
! Intrauterine hormone-releasing System
! Bilateral tubal occlusion
Vasectomised partner 
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
Notes: 
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
bContraception should be utilised during the treatment period and for at least 49 days after the last dose of trial product.
For country specific requirements see Appendix 10.
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with:
1) known intolerance to the highly effective methods mentioned in Table 11-5 or where the use of 
any of the listed highly effective contraceptive measures are contraindicated in the individual 
subject, and/or  
2) if the risk of initiating treatment with a specific highly effective method outweighs the benefit for 
the female.
Justification for accepting double barrier method should be at the discretion of the investigator 
taking into consideration his/hers knowledge about the female’s obesity history, concomitant 
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illness, concomitant medication and observed AEs. The justification must be stated in the medical 
records.
Pregnancy testing
!
WOCBP should only be included after a negative highly sensitive urine pregnancy test.
!
Urine pregnancy testing should be performed at every site visit (every 4-8 weeks) during the 
treatment period, at end of treatment and after the 7 weeks off-drug follow-up period 
according to the flow chart.
!
Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period, if required locally (Appendix 10).
!
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 Section 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 
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available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on the technical 
complaint form. If several samples are shipped in one shipment, the sample and the corresponding technical complaint 
form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID.
All technical complaints are handled by Customer Complaint Center, Novo Nordisk. Only technical 
complaints related to adverse events will be included in the clinical trial report.
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Retention of human biosamples
Appendix 7
Antibody samples
!
Antibody samples will be retained for potential later analysis for further characterisation of 
antibody responses towards drug, if required by health authorities or for safety reasons.
!
Only Novo Nordisk staff and personnel from the specialised laboratory will have access to 
the stored specimens. 
!
The samples will be stored at the specialised laboratory or Novo Nordisk after end of trial 
and until marketing authorisation approval or until the research project terminates, but no 
longer than 15 years from end of trial after which they will be destroyed. 
!
Samples might be transferred to other countries, if not prohibited by local regulations. 
!
The subject’s identity will remain confidential and the samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the 
subject will be stored together with the samples. The analyses will not have any medical 
consequences for the subjects or their relatives. 
!
Subjects can contact the investigator if they wish to be informed about results derived from 
stored biosamples obtained from their own body.
Biosamples for future analysis
!
The trial will involve collection of human biosamples to be stored in a central archive.
!
Subjects must sign and date a separate informed consent form before biosamples are 
collected to be stored for future analysis.
!
The material to be collected is serum collected at baseline and end of treatment. A total of 5 
aliquots will be stored for each subject at both time points.
!
As new biomarkers related to the disease and/or safety, efficacy or mechanism of action of 
semaglutide may evolve during the conduct of the trial, the analyses of the stored 
biosamples may also include biomarkers that are unknown at present or have not been 
included in the scientific hypotheses at initiation of the trial. 
!
The biosamples will be stored at a central laboratory for 6 months and at a central storage 
facility contracted by Novo Nordisk for up to 15 years after end of trial. Only Novo Nordisk 
and storage facility employees will be able to access the stored biosamples. The biosamples 
may be transferred to other countries for analysis and will be destroyed at the latest 15 years 
after end of trial.
!
The subject may request the stored biosamples to be destroyed by withdrawing the 
designated informed consent. 
!
The results obtained from any already performed analyses of the samples will still be used.
In the event that the collected biosamples (serum) will be used in the future, the investigator 
will become directly informed by Novo Nordisk about the results if the findings are deemed 
clinically relevant and analytically valid and quantifiable. In such case, a written summary of 
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the findings, including listings of subject specific values, will be provided once a firm 
conclusion from the results has been drawn by Novo Nordisk.
!
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-
treatable diseases, or any other abnormal findings could be part of the observations. Subjects 
can contact the investigator if they wish to be informed about results derived from stored 
biosamples obtained from their own body.
See Appendix 10 for country specific requirements for Algeria.
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Hypoglycaemic episodes
Appendix 8
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose (PG) level of 3.1 
mmol/L (56 mg/dL)89. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below 
this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (Figure 11-1) in addition to the ADA 
classification90:
1. Severe hypoglycaemia according to the ADA classification90.
2. Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
3. Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
4. BG confirmed hypoglycaemia: The union of 2. and 3.
5. Severe or BG confirmed symptomatic hypoglycaemia: The union of 1. and 2.
6. Severe or BG confirmed hypoglycaemia: The union of 1., 2. and 3.
For hypoglycaemic episodes reported with missing information related to the classification, the 
following applies when classifying the episode according to the Novo Nordisk classification:
!
A hypoglycaemic episode with missing information on symptoms will be classified as 
without symptoms. 
!
A hypoglycaemic episode with missing information on being able to self-treat will be 
regarded as an episode where the subject was able to self-treat and classified in accordance 
with the able to self-treat classifications.
Episodes that cannot be classified according to the above, are included in one of the following 
categories:
!
‘Novo Nordisk unclassifiable’ includes episodes where subjects were able to self-treat and 
with PG F3.1 mmol/L (56 mg/dL) and hypoglycaemic episodes for a subject able to self-
treat with missing PG as it is to be treated as an episode with PG >3.9 mmol/L (70 mg/dL).
!
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able to 
self-treat but neither of the following conditions were reported: PG T3.9 mmol/L (70 
mg/dL), alleviation of symptoms, seizure, unconscious/comatose or fatal.
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Hypoglycaemic
episode
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
2. Symptomatic 
BG confirmed 
hypoglycaemia
3. Asymptomatic 
BG confirmed 
hypoglycaemia
Yes
No
5. Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
4. BG confirmed 
hypoglycaemia
6. Severe or 
BG confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
1.Severe 
hypoglycaemia
(ADA 2013)
Figure 11-1
Novo Nordisk classification of hypoglycaemia
ADA classification90 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon or take other corrective actions. PG concentrations may not be available 
during an event, but neurological recovery following the return of PG to normal is considered 
sufficient evidence that the event was induced by a low PG concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration T 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration T 3.9 mmol/L (70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a PG determination but that was presumably caused by a PG 
concentration T 3.9 mmol/L (70 mg/dL).
For hypoglycaemic episodes reported with missing information related to the classification, the 
following applies when classifying the episode according to the ADA classification:
!
A hypoglycaemic episode with missing information on symptoms will be classified as without 
symptoms. 
!
A hypoglycaemic episode with missing information on being able to self-treat will be regarded 
as an episode where the subject was able to self-treat and classified in accordance with the able 
to self-treat classifications
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Episodes that cannot be classified according to the above, are included in one of the following 
categories
!
‘ADA unclassifiable’ includes episodes where subjects were able to self-treat and with PG >3.9 
mmol/L (70 mg/dL) or missing PG, and with no information on symptoms.
!
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able to 
self-treat but neither of the following conditions were reported: PG T 3.9 mmol/L (70 
mg/dL), alleviation of symptoms, seizure, unconscious/comatose or fatal.
Hypoglycaemic 
episode 
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 11-2
ADA classification of hypoglycaemia
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent, if the onset of 
the episode occurs in the on-treatment period (see definition in Section 10.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia90.
Reporting of hypoglycaemic episodes:
PG should always be measured and recorded when a hypoglycaemic episode is suspected. 
All PG values:
T 3.9 mmol/L (70 mg/dL) or 
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> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms should be 
reported as a hypoglycaemic episode according to the flowchart and instructions below. When a 
subject experiences a hypoglycaemic episode, subject should record the general information in 
relation to the hypoglycaemia (timing, PG measurements, symptoms etc. as described in the diary). 
In case a subject is not able to fill in the diary (e.g. in case of hospitalisation or at the ‘follow-up 
phone contact’), then investigator should report the hypoglycaemic episode directly in the CRF.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines90.
Repeated SMPG measurements and/or symptoms will by default be considered as one 
hypoglycaemic episode until a succeeding SMPG value is > 3.9 mmol/L (70 mg/dL) and/or 
symptoms have been resolved. One hypoglycaemic episode form is to cover these measurements 
and/or symptoms. 
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first low SMPG value and/or symptom.
The investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e. whether 
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
For low SMPG values for hypoglycaemic episodes where the subject was able to self-treat: If a 
hypoglycaemic episode form is not completed within 7 calendar days of the SMPG measurement, 
the episode should be reported on a hypoglycaemic episode form with as much information as 
possible. Novo Nordisk will not query for additional data except for the start date, SMPG value and 
whether the subject was able to self-treat due to decreased validity of such data91, 92.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
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Monitoring of calcitonin
Appendix 9
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 F 10 ng/L, the algorithm outlined in Figure 11-3 and 
described below should be followed. The algorithm applies for all calcitonin values in the trial.
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Evaluation of 
calcitonin results
Calcitonin < 10 ng/L
Calcitonin > 10 ng/L and < 50 ng/L
Calcitonin > 50 ng/L and < 100 ng/L
Calcitonin > 100 ng/L 
Calcitonin > 10 ng/L and last 
measurement in the trial
No action
!
Investigate potential confounding 
factors
!
Continue sampling of calcitonin 
according to protocol
!
Discontinue trial product
!
Refer to thyroid specialist
!
Refer to thyroid specialist
!
Refer to thyroid specialist
Figure 11-3
Flow of calcitonin monitoring
Calcitonin H 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 8.1.1). 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 disease93. 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 H 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 disease93. 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 H 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 disease 93. 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.93 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 conclusions94, 95.
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Country-specific requirements
Appendix 10
Novo Nordisk accepts liability in accordance with:
Section 6.1 Inclusion criterion no. 2
For Algeria: Age F 19 years at the time of signing informed consent.
For Japan: Age F 20 years at the time of signing informed consent.
Section 7.5 Preparation/Handling/Storage/Accountability
For Japan: According to Japanese GCP, storage and drug accountability of the trial products at the 
study site is not in charge of Investigator, but in charge of the head of study site. 
The head of study site should assign some or all of the responsibilities for accountability of the trial 
products at the sites to a trial product storage manager (a pharmacist in principle). The trial product 
storage manager should control and take accountability of the trial products in accordance with 
procedures specified by the sponsor. The head of study site or the trial product storage manager 
must ensure the availability of proper storage conditions, and record and evaluate the temperature.
Section 7.7 Concomitant medication
For Argentina: All OADs will be reimbursed by Novo Nordisk Pharma Argentina S.A., in 
accordance with local regulations. 
Section 9.4 Safety assessments:
For United States: For the eye examination: Fundoscopy/fundusphotography will be performed by 
the investigator or a local ophthalmologist/optometrist according to local practice. 
Appendix 3, 1) Regulatory and ethical considerations
For Russia: The trial will be conducted in compliance with the protocol and Ministry of Healthcare 
of Russian Federation’ order #200H from April, 01, 2016 “Approval of rules of good clinical 
practice”.
For Japan: A seal is accepted as a signature
Appendix 5 Contraception guidance 
For Argentina: The following contraceptive measures are considered adequate: barrier methods 
(condoms or diaphragm) with spermicide, contraceptive pills or intrauterine device (IUD). The 
contraceptive methods will be reimbursed by the sponsor.
Appendix 7 Retention of human biosamples
For Algeria: No genetic testing and bio banking in central archive is allowed as per Algerian local 
requirements.
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Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
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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 
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laws, regulations and administrative provisions of the Member States relating to the 
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products for human use, article 11. Official Journal of the European Communities. 01 May 
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726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
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Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
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Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
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for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
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Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
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Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive 
value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma 
in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 
2007;92(2):450-5.
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Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer. 
2009;16(1):243-53.
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Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
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Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
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Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4374 (STEP 2)
Clinical Trial Report
Appendix 16.1.1
03 Jul 2020
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Protocol Amendment no 1
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Protocol Amendment
no 1
to Protocol, version 2.0
dated 21 December 2017
Trial ID: NN9536-4374
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly in subjects with 
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to Argentina
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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Date:
19 January 2018
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Trial ID:NN9536-4374
Version:
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Status:
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Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 1
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Version:
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1
Introduction including rationale for the protocol amendment
Global Safety has noticed that the local requirement on contraceptive methods in Appendix 10 in 
the protocol is less strict than the global requirements in Appendix 5, i.e. barrier methods are not 
allowed in this trial.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Appendix 10 Country-specific requirements 
Appendix 5 Contraception guidance 
For Argentina: the following contraceptive measures are considered adequate: barrier methods 
(condoms or diaphragm) with spermicide, contraceptive pills or intrauterine device (IUD). The 
contraceptive methods will be reimbursed by the sponsor.
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Protocol Amendment no 2
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Protocol Amendment
no 2
to Protocol, version 2.0
dated 21 December 2017
Trial ID: NN9536-4374
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly in subjects with 
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to United States
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 2
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Date:
16 March 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
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Page:
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 2
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Date:
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Version:
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Status:
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1
Introduction including rationale for the protocol amendment
US specific eye examination requirements outlined in Appendix 10 have been removed as the US 
should perform the eye examination according to the global standards and what is described in the 
protocol section 9.4.5.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Appendix 10 country specific requirements:
Section 9.4 Safety Assessments For United States: For the eye examination: Fundoscopy / 
fundusphotography will be performed by the investigator or a local ophthalmologist / optometrist 
according to local practice.
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Protocol Amendment no 3
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Protocol Amendment
no 3
to Protocol, version 2.0
dated 21 December 2017
Trial ID: NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with overweight or obesity 
and type 2 diabetes
Trial phase: 3a
Applicable to UK
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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parties.


Protocol Amendment no 3
CONFIDENTIAL
Date:
16 March 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
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Page:
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Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 3
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Date:
16 March 2018
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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1
Introduction including rationale for the protocol amendment
The use of double barrier methods mentioned in Appendix 5 is not applicable for UK. Therefore 
appendix 10 ‘country specific requirements’ is updated and must be followed in UK.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Appendix 10 Country specific requirements will be updated with the following:
For UK: Contraceptive measures considered adequate include highly effective contraceptive 
methods as listed in Table 11-5 ‘Highly effective contraceptive methods’ in Appendix 5.
This means that the use of double barrier methods is not applicable for UK.
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Protocol Amendment no 4
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Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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Protocol Amendment
no 4
to Protocol, version 2
dated 21 Dec 2017
Trial ID:NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
1.0
Status:
Final
Page:
2 of 10
Table of Contents    
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 2 Flowchart...................................................................................................................3
2.2
Section 3.2  Background............................................................................................................4
2.2.1
Section 3.2.1  Semaglutide.......................................................................................4
2.3
Section 3.3 Benefit-risk assessment...........................................................................................4
2.3.1
3.3.2  Risks and precautions.....................................................................................4
2.4
Section 4.2 Primary, secondary and exploratory endpoints.........................................................5
2.4.1
Section 4.2.3 Exploratory endpoints.........................................................................5
2.5
Section 6.1 Inclusion criteria .....................................................................................................5
2.6
Section 7.1  Treatments administered ........................................................................................5
2.7
Section 8  Discontinuation/Withdrawal criteria..........................................................................6
2.7.1
Section 8.1  Discontinuation of trial treatment..........................................................6
2.8
Section 9.4 Safety assessment ...................................................................................................6
2.8.1
Section 9.4.5  Eye examination ................................................................................6
2.8.2
Section 9.4.6 Clinical safety laboratory assessments.................................................7
2.9
Section 9.7  Genetics.................................................................................................................7
2.10
Section 9.8  Biomarkers and biosamples for future analysis.......................................................7
2.11
Section 10.1 Sample size determination.....................................................................................8
2.11.1
Table 10-2 Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm).....................................................................8
2.12
Section 10.3 Statistical analyses ................................................................................................8
2.12.1
Section 10.3.2.1 Confirmatory secondary endpoints .................................................8
2.12.1.1
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............................................................................................8
2.13
Appendix 2  Clinical laboratory tests.........................................................................................9
2.13.1
Table 11-2 Protocol-required safety laboratory assessments .....................................9
2.13.2
Table 11-3  Criteria for laboratory outliers ...............................................................9
2.14
Appendix 3  Trial governance considerations ............................................................................9
2.14.1
9) Data quality assurance .........................................................................................9
2.14.1.1
Protocol compliance...........................................................................9
2.15
Appendix 5  Contraceptive guidance and collection of pregnancy information...........................9
2.15.1
Table 11-5  Highly effective contraceptive methods .................................................9
2.16
Appendix 7 Retention of human biosamples and genetics..........................................................9
2.16.1
Biosamples for future analysis .................................................................................9
2.17
Section 12 References .............................................................................................................10
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Protocol Amendment no 4
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Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
To implement genetic biosamples for future analysis, for those countries where it will be 
applicable. The rationale for implementation is to ensure a better characterisation of the 
population in scope as new technologies and hypothesis develops. The collection of whole 
blood at baseline (visit 2) and end of treatment (visit 24) will allow for future genetic analysis 
thereby increasing the understanding of obesity, obesity treatment and -related diseases in the 
future.
!
As the scope of the biosampling for future analysis has broadened to cover obesity and -related 
diseases with this amendment, some paragraphs in appendix 7 has been revised. Furthermore, 
the informed consent has been updated to reflect the broader scope. A separate protocol will be 
developed before the biosamples from trial NN9536-4374 can be analysed in the future. This 
will include rationale for the analysis as well as reporting requirements.
!
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.
!
Removal of the persistent criteria from the exploratory endpoint in section 4.2.3 and update of 
section 9.4.6 accordingly, since the exploratory endpoint about onset of micro or macro 
albuminuria as well as regression to normoalbuminuria could not be adequately assessed with 
the definition of persistent and current trial design. This is due to the fact that the final 
assessment at week 68 should be confirmed with 2 confirmatory assessments after end of 
treatment.
!
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 2
Flowchart
Biosamples for future analysisd (9.7, 9.8, Appendix 7)
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Protocol Amendment no 4
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2.2
Section 3.2 
Background
2.2.1
Section 3.2.1 Semaglutide
GLP-1 receptor agonist is a physiological regulator of appetite and GLP-1 receptors are present in 
several areas of the brain involved in appetite regulation58.
Clinical59-63,65 and non-clinical data 6566 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.
2.3
Section 3.3
Benefit-risk assessment
2.3.1
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)
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Protocol Amendment no 4
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Trial ID: NN9536-4374
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Status:
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Studies in animals have shown reproductive toxicity. There are limited data from the use of
semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy.
Exclusion and discontinuation criteria related to pregnancy have been implemented in the trial.
2.4
Section 4.2
Primary, secondary and exploratory endpoints
2.4.1
Section 4.2.3 Exploratory endpoints
The exploratory endpoints reflect the comparison of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo I/II.
Subjects who after 68 weeks achieve (yes/no) the following in:
!
New onset of persistent micro albuminuria (UACR D 30 and E 300 mg/g) in subjects 
without albuminuria (UACR < 30 mg/g) at randomisation (week 0) 
!
New onset of persistent macro albuminuria (UACR > 300 mg/g) in subjects without macro 
albuminuria at randomisation (week 0)
!
Regression of micro albuminuria/macro albuminuria to normal (in subjects with either 
micro (UACR D 30 and E 300 mg/g ) or macro albuminuria (UACR > 300 mg/g ) at 
baseline (week 0))
2.5
Section 6.1
Inclusion criteria
6. Subject treated with either:
!
diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as single 
agent therapy or
!
up to 3 OADs (metformin, SU, SGLT2i or glitazone) according to local label
Any approved and marketed metformin, glitazone, SGLT2i or SU product or combination products 
are allowed. Treatment with oral agents should be stable (same drug(s), dose and dosing 
frequency) for at least 90 days prior to screening.
2.6
Section 7.1 
Treatments administered
!
If a subject does not tolerate the designated recommended target dose of (1.0 or 2.4 mg once 
weekly), the subject may stay at a 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 designated recommended target dose,of 
2.4 mg once-weekly as per the investigator’s discretion. Both pens should be used during down-
and re-escalation.
Table 7-2: Dose escalation and maintenance in the semaglutide 2.4 mg once-weekly/semaglutide II
placebo arms. The placebo II arm will follow the escalation regimen outlined in Table 7-3.
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Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
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!
Injections may be administered in the thigh, abdomen or upper arm, at any time of day
irrespective of meals. Subjects should be encouraged to inject in the same area throughout the 
trial, but changing between left and right side is allowed.
2.7
Section 8 
Discontinuation/Withdrawal criteria
2.7.1
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 D 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 criteria70 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).
2.8
Section 9.4 Safety assessment
2.8.1
Section 9.4.5 Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist, or equally qualified certified 
health care provider (e.g. optometrist) or another suitably qualified health care provider must be 
available and evaluated by the investigator before randomisation to assess eligibility. The eye 
examination should be performed as a fundus photography (e.g. 2-field 60 degree or better, colour 
or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-corneal or corneal contact 
lens examination) and performed with pharmacologically dilated pupils.
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Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
7 of 10
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her their evaluation upon the results of that examination. The examination 
must be repeated before randomisation if the subject has experienced worsening of visual function 
since the last examination. If the applicable eye examination was performed before the subject 
signed the informed consent form, it must be documented that the reason for performing the 
examination was not related to this trial.
2.8.2
Section 9.4.6 Clinical safety laboratory assessments
Urinalysis: Proteinuria should be assessed using a spot urine collection to measure urine albumin-
to-creatinine ratio (UACR). The spot urine specimen should be collected on first morning samples. 
Persistent proteinuria is defined as having 2 out of 3 consecutive samples above the limit for 
macroalbuminuria or microalbunuria. Repeat UACR should be done for at least 4 weeks apart after 
positive UACR (D 30 mg/g) to confirm the finding.
2.9
Section 9.7 
Genetics
Not applicable for this trial.
A blood sample for genetic analysis will be collected from patients who have consented to 
participate in the optional biobank component of the trial. Refer to section 9.8 and Appendix 7 for 
further details.
2.10
Section 9.8 
Biomarkers and biosamples for future analysis 
Collection of samples for biomarker research is part of this trial to support the efficacy objectives. 
The following samples must be collected 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)
Collection of biosamples for future analysis (stored in a biobank) is a component of this trial. 
Participation in the biobank component is optional. Patients who do not wish to participate in the 
biobank component may still participate in the trial. For the biobank, samples will be collected 
according to the flowchart and stored for future use.
The samples are collected for the purpose of allowing future analyses of biomarkers, both genetic 
and circulating, at a later point in time when new knowledge or improved measurement techniques 
may have become available. The analyses may include biomarkers currently known or discovered 
in the future.
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Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
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Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
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Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome with the purpose of understanding and predicting response to semaglutide as well as to 
understand obesity or other related diseases.
Analyses of circulating biomarkers will measure hormones, metabolites or other non-genetic  serum 
entity with the purpose of understanding and predicting response to semaglutide as well as 
understanding obesity or other related diseases.
These samples need to be frozen and should be sent in batches to the central laboratory. The 
analyses are likely to be performed after the trial has come to an end, and results will therefore not 
be part of the clinical trial report. The biobank samples may be stored up to 15 years after end of 
trial at a central laboratory (see Appendix 7).
2.11
Section 10.1
Sample size determination 
2.11.1
Table 10-2
Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm)
Foot note: SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-
36 = Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on 
Quality of Life-Lite for Clinical Trials; PFD = physical function domain; # shown as a positive 
number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
All tests in the hierarchy are based on the primary estimand.
2.12
Section 10.3
Statistical analyses
2.12.1
Section 10.3.2.1
Confirmatory secondary endpoints
2.12.1.1
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; 
HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; 
PFD = physical function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 10-2.
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Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
9 of 10
2.13
Appendix 2 
Clinical laboratory tests
2.13.1
Table 11-2
Protocol-required safety laboratory assessments
Other tests: eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 2012 
by the central laboratory at screening.
2.13.2
Table 11-3 
Criteria for laboratory outliers
Lymphocytes < 25 0.2 x 109/L
2.14
Appendix 3 
Trial governance considerations
2.14.1
9) Data quality assurance
2.14.1.1
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
2.15
Appendix 5 
Contraceptive guidance and collection of pregnancy information
2.15.1
Table 11-5 
Highly effective contraceptive methods
Sexual abstinenceb
2.16
Appendix 7
Retention of human biosamples and genetics
2.16.1
Biosamples for future analysis
In countries where applicable, the trial will involve collection of human biosamples to be stored in 
a central archive for future use.
!
The material to be collected is serum collected at baseline (visit 2) and end of treatment (Visit 
24) is: A total of 5 aliquots will be stored for each subject at both time points.
!
Whole blood (for genetic analysis)
!
Serum (for analyses of circulating biomarkers)
!
The results obtained from any already performed analyses of the samples will still be used. In 
the event that the collected biosamples (serum) will be used in the future, the investigator will 
become directly informed by Novo Nordisk about the results if the findings are deemed
clinically relevant and analytically valid and quantifiable. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm
conclusion from the results has been drawn by Novo Nordisk.
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Protocol Amendment no 4
CONFIDENTIAL
Date:
04 June 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
10 of 10
!
Potentially, observations of neoplastic diseases, serious hereditary diseases, other untreatable
diseases, or any other abnormal findings could be part of the observations. Subjects can contact 
the investigator if they wish to be informed about results derived from stored biosamples 
obtained from their own body.
In case the subject withdraws his/her informed consent for biosamples for future analysis and 
genetics, the monitor must contact the trial manager at Novo Nordisk as soon as possible in order 
to have the samples withdrawn from storage.
2.17
Section 12
References
66: Lu T, et al. Presented at the 77th scientific sessions of the American diabetes association, 9-13 
June 2017, San Diego, CA, USA.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
1 of 9
Protocol Amendment
no 5
to Protocol, version 2
dated 21 Dec 2017
Trial ID:NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to UK
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
Status:
Final
Page:
2 of 9
Table of Contents    
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 2 Flowchart...................................................................................................................3
2.2
Section 3.2  Background............................................................................................................3
2.2.1
Section 3.2.1  Semaglutide.......................................................................................3
2.3
Section 3.3 Benefit-risk assessment...........................................................................................4
2.3.1
3.3.2  Risks and precautions.....................................................................................4
2.4
Section 4.2 Primary, secondary and exploratory endpoints.........................................................5
2.4.1
Section 4.2.3 Exploratory endpoints.........................................................................5
2.5
Section 6.1 Inclusion criteria .....................................................................................................5
2.6
Section 7.1  Treatments administered ........................................................................................5
2.7
Section 9.4 Safety assessment ...................................................................................................6
2.7.1
Section 9.4.5  Eye examination ................................................................................6
2.7.2
Section 9.4.6 Clinical safety laboratory assessments.................................................6
2.8
Section 9.7  Genetics.................................................................................................................6
2.9
Section 9.8  Biomarkers and biosamples for future analysis.......................................................6
2.10
Section 10.1 Sample size determination.....................................................................................7
2.10.1
Table 10-2 Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm).....................................................................7
2.11
Section 10.3 Statistical analyses ................................................................................................8
2.11.1
Section 10.3.2.1 Confirmatory secondary endpoints .................................................8
2.11.1.1
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............................................................................................8
2.12
Appendix 2  Clinical laboratory tests.........................................................................................8
2.12.1
Table 11-2 Protocol-required safety laboratory assessments .....................................8
2.12.2
Table 11-3  Criteria for laboratory outliers ...............................................................8
2.13
Appendix 3  Trial governance considerations ............................................................................8
2.13.1
9) Data quality assurance .........................................................................................8
2.13.1.1
Protocol compliance...........................................................................8
2.14
Appendix 5  Contraceptive guidance and collection of pregnancy information...........................8
2.14.1
Table 11-5  Highly effective contraceptive methods .................................................8
2.15
Appendix 7 Retention of human biosamples and genetics..........................................................9
2.15.1
Biosamples for future analysis .................................................................................9
2.16
Section 12 References ...............................................................................................................9
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
3 of 9
1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
To implement genetic biosamples for future analysis, for those countries where it will be 
applicable. The rationale for implementation is to ensure a better characterisation of the 
population in scope as new technologies and hypothesis develops. The collection of whole 
blood at baseline (visit 2) and end of treatment (visit 24) will allow for future genetic analysis 
thereby increasing the understanding of obesity, obesity treatment and -related diseases in the 
future.
!
As the scope of the biosampling for future analysis has broadened to cover obesity and -related 
diseases with this amendment, some paragraphs in appendix 7 has been revised. Furthermore, 
the informed consent has been updated to reflect the broader scope. A separate protocol will be 
developed before the biosamples from trial NN9536-4374 can be analysed in the future. This 
will include rationale for the analysis as well as reporting requirements.
!
Removal of the persistent criteria from the exploratory endpoint in section 4.2.3 and update of 
section 9.4.6 accordingly, since the exploratory endpoint about onset of micro or macro 
albuminuria as well as regression to normoalbuminuria could not be adequately assessed with 
the definition of persistent and current trial design. This is due to the fact that the final 
assessment at week 68 should be confirmed with 2 confirmatory assessments after end of 
treatment.
!
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 2
Flowchart
Biosamples for future analysisd (9.7, 9.8, Appendix 7)
2.2
Section 3.2 
Background
2.2.1
Section 3.2.1 Semaglutide
GLP-1 receptor agonist is a physiological regulator of appetite and GLP-1 receptors are present in 
several areas of the brain involved in appetite regulation58.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
4 of 9
Clinical59-63,65 and non-clinical data 6566 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.
2.3
Section 3.3
Benefit-risk assessment
2.3.1
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.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
5 of 9
2.4
Section 4.2
Primary, secondary and exploratory endpoints
2.4.1
Section 4.2.3 Exploratory endpoints
The exploratory endpoints reflect the comparison of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo I/II.
Subjects who after 68 weeks achieve (yes/no) the following in:
!
New onset of persistent micro albuminuria (UACR C 30 and D 300 mg/g) in subjects 
without albuminuria (UACR < 30 mg/g) at randomisation (week 0) 
!
New onset of persistent macro albuminuria (UACR > 300 mg/g) in subjects without macro 
albuminuria at randomisation (week 0)
!
Regression of micro albuminuria/macro albuminuria to normal (in subjects with either 
micro (UACR C 30 and D 300 mg/g ) or macro albuminuria (UACR > 300 mg/g ) at 
baseline (week 0))
2.5
Section 6.1
Inclusion criteria
6. Subject treated with either:
!
diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as single 
agent therapy or
!
up to 3 OADs (metformin, SU, SGLT2i or glitazone) according to local label
Any approved and marketed metformin, glitazone, SGLT2i or SU product or combination products 
are allowed. Treatment with oral agents should be stable (same drug(s), dose and dosing 
frequency) for at least 90 days prior to screening.
2.6
Section 7.1 
Treatments administered
!
If a subject does not tolerate the designated recommended target dose of (1.0 or 2.4 mg once 
weekly), the subject may stay at a 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 designated recommended target dose,of 
2.4 mg once-weekly as per the investigator’s discretion. Both pens should be used during down-
and re-escalation.
Table 7-2: Dose escalation and maintenance in the semaglutide 2.4 mg once-weekly/semaglutide II
placebo arms. The placebo II arm will follow the escalation regimen outlined in Table 7-3.
!
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.
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.
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
6 of 9
2.7
Section 9.4 Safety assessment
2.7.1
Section 9.4.5 Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist, or equally qualified certified 
health care provider (e.g. optometrist) or another suitably qualified health care provider must be 
available and evaluated by the investigator before randomisation to assess eligibility. The eye 
examination should be performed as a fundus photography (e.g. 2-field 60 degree or better, colour 
or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-corneal or corneal contact 
lens examination) and performed with pharmacologically dilated pupils.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her their evaluation upon the results of that examination. The examination 
must be repeated before randomisation if the subject has experienced worsening of visual function 
since the last examination. If the applicable eye examination was performed before the subject 
signed the informed consent form, it must be documented that the reason for performing the 
examination was not related to this trial.
2.7.2
Section 9.4.6 Clinical safety laboratory assessments
Urinalysis: Proteinuria should be assessed using a spot urine collection to measure urine albumin-
to-creatinine ratio (UACR). The spot urine specimen should be collected on first morning samples. 
Persistent proteinuria is defined as having 2 out of 3 consecutive samples above the limit for 
macroalbuminuria or microalbunuria. Repeat UACR should be done for at least 4 weeks apart after 
positive UACR (C 30 mg/g) to confirm the finding.
2.8
Section 9.7 
Genetics
Not applicable for this trial.
A blood sample for genetic analysis will be collected from patients who have consented to 
participate in the optional biobank component of the trial. Refer to section 9.8 and Appendix 7 for 
further details.
2.9
Section 9.8 
Biomarkers and biosamples for future analysis 
Collection of samples for biomarker research is part of this trial to support the efficacy objectives. 
The following samples must be collected in accordance with the laboratory manual and the 
flowchart:
Biomarkers linked to cardiovascular risk:
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Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
7 of 9
!
Plasminogen Activator Inhibitor-1 (PAI-1) Activity will be analysed by activity assay.
!
High sensitive C-reactive protein (hsCRP)
Collection of biosamples for future analysis (stored in a biobank) is a component of this trial. 
Participation in the biobank component is optional. Patients who do not wish to participate in the 
biobank component may still participate in the trial. For the biobank, samples will be collected 
according to the flowchart and stored for future use.
The samples are collected for the purpose of allowing future analyses of biomarkers, both genetic 
and circulating, at a later point in time when new knowledge or improved measurement techniques 
may have become available. The analyses may include biomarkers currently known or discovered 
in the future.
Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome with the purpose of understanding and predicting response to semaglutide as well as to 
understand obesity or other related diseases.
Analyses of circulating biomarkers will measure hormones, metabolites or other non-genetic  serum 
entity with the purpose of understanding and predicting response to semaglutide as well as 
understanding obesity or other related diseases.
These samples need to be frozen and should be sent in batches to the central laboratory. The 
analyses are likely to be performed after the trial has come to an end, and results will therefore not 
be part of the clinical trial report. The biobank samples may be stored up to 15 years after end of 
trial at a central laboratory (see Appendix 7).
2.10
Section 10.1
Sample size determination 
2.10.1
Table 10-2
Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm)
Foot note: SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-
36 = Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on 
Quality of Life-Lite for Clinical Trials; PFD = physical function domain; # shown as a positive 
number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
All tests in the hierarchy are based on the primary estimand.
1.0
.
CONFIDENTIAL


Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
8 of 9
2.11
Section 10.3
Statistical analyses
2.11.1
Section 10.3.2.1
Confirmatory secondary endpoints
2.11.1.1
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; 
HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; 
PFD = physical function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 10-2.
2.12
Appendix 2 
Clinical laboratory tests
2.12.1
Table 11-2
Protocol-required safety laboratory assessments
Other tests: eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 2012 
by the central laboratory at screening.
2.12.2
Table 11-3 
Criteria for laboratory outliers
Lymphocytes < 25 0.2 x 109/L
2.13
Appendix 3 
Trial governance considerations
2.13.1
9) Data quality assurance
2.13.1.1
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
2.14
Appendix 5 
Contraceptive guidance and collection of pregnancy information
2.14.1
Table 11-5 
Highly effective contraceptive methods
Sexual abstinenceb
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CONFIDENTIAL


Protocol Amendment no 5
CONFIDENTIAL
Date:
23 July 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
9 of 9
2.15
Appendix 7
Retention of human biosamples and genetics
2.15.1
Biosamples for future analysis
In countries where applicable, the trial will involve collection of human biosamples to be stored in 
a central archive for future use.
!
The material to be collected is serum collected at baseline (visit 2) and end of treatment (Visit 
24) is: A total of 5 aliquots will be stored for each subject at both time points.
!
Whole blood (for genetic analysis)
!
Serum (for analyses of circulating biomarkers)
!
The results obtained from any already performed analyses of the samples will still be used. In 
the event that the collected biosamples (serum) will be used in the future, the investigator will 
become directly informed by Novo Nordisk about the results if the findings are deemed
clinically relevant and analytically valid and quantifiable. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm
conclusion from the results has been drawn by Novo Nordisk.
!
Potentially, observations of neoplastic diseases, serious hereditary diseases, other untreatable
diseases, or any other abnormal findings could be part of the observations. Subjects can contact 
the investigator if they wish to be informed about results derived from stored biosamples 
obtained from their own body.
In case the subject withdraws his/her informed consent for biosamples for future analysis and 
genetics, the monitor must contact the trial manager at Novo Nordisk as soon as possible in order 
to have the samples withdrawn from storage.
2.16
Section 12
References
66: Lu T, et al. Presented at the 77th scientific sessions of the American diabetes association, 9-13 
June 2017, San Diego, CA, USA.
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Protocol Amendment no 6
CONFIDENTIAL
Date:
01 August 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
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Protocol Amendment
no 6
to Protocol, version 2.0
dated 21 December 2017
Trial ID: NN9536-4374
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly in subjects with overweight 
or obesity and type 2 diabetes
Trial phase: 3a
Applicable to United Arab Emirates
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 6
CONFIDENTIAL
Date:
01 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 6
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Date:
01 August 2018
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Version:
1.0
     
Status:
Final
     
Page:
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1
Introduction including rationale for the protocol amendment
For some sites in United Arab Emirates, Ethics committee have not approved genetic and/or bio 
banking for future analysis. Appendix 7 and Appendix 10 have been updated with this information. 
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 Appendix 7 Retention of human biosamples
See Appendix 10 for country specific requirements for Algeria and United Arab Emirates
2.2  Appendix 10 country specific requirements:
Appendix 7 Retention of human biosamples
For Algeria: No genetic testing and bio banking in central archive is allowed as per Algerian local 
requirements.
For United Arab Emirates: Not all sites have received IRB/IEC approval for genetic and/or bio 
banking. Sites will follow the relevant IRB/IEC decision.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
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Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
1 of 9
Protocol Amendment
no 7
to Protocol, version 2
dated 21 Dec 2017
Trial ID:NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to Germany
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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parties.


Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
2 of 9
Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 2 Flowchart...................................................................................................................3
2.2
Section 3.2  Background............................................................................................................3
2.2.1
Section 3.2.1  Semaglutide.......................................................................................3
2.3
Section 3.3 Benefit-risk assessment...........................................................................................4
2.3.1
3.3.2  Risks and precautions.....................................................................................4
2.4
Section 4.2 Primary, secondary and exploratory endpoints.........................................................5
2.4.1
Section 4.2.3 Exploratory endpoints.........................................................................5
2.5
Section 6.1 Inclusion criteria .....................................................................................................5
2.6
Section 7.1  Treatments administered ........................................................................................5
2.7
Section 9.4 Safety assessment ...................................................................................................6
2.7.1
Section 9.4.5  Eye examination ................................................................................6
2.7.2
Section 9.4.6 Clinical safety laboratory assessments.................................................6
2.8
Section 9.7  Genetics.................................................................................................................6
2.9
Section 9.8  Biomarkers and biosamples for future analysis.......................................................6
2.10
Section 10.1 Sample size determination.....................................................................................7
2.10.1
Table 10-2 Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm).....................................................................7
2.11
Section 10.3 Statistical analyses ................................................................................................8
2.11.1
Section 10.3.2.1 Confirmatory secondary endpoints .................................................8
2.11.1.1
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............................................................................................8
2.12
Appendix 2  Clinical laboratory tests.........................................................................................8
2.12.1
Table 11-2 Protocol-required safety laboratory assessments .....................................8
2.12.2
Table 11-3  Criteria for laboratory outliers ...............................................................8
2.13
Appendix 3  Trial governance considerations ............................................................................8
2.13.1
9) Data quality assurance .........................................................................................8
2.13.1.1
Protocol compliance...........................................................................8
2.14
Appendix 5  Contraceptive guidance and collection of pregnancy information...........................8
2.14.1
Table 11-5  Highly effective contraceptive methods .................................................8
2.15
Appendix 7 Retention of human biosamples and genetics..........................................................9
2.15.1
Biosamples for future analysis .................................................................................9
2.16
Section 12 References ...............................................................................................................9
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
3 of 9
1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
To implement genetic biosamples for future analysis, for those countries where it will be 
applicable. The rationale for implementation is to ensure a better characterisation of the 
population in scope as new technologies and hypothesis develops. The collection of whole 
blood at baseline (visit 2) and end of treatment (visit 24) will allow for future genetic analysis 
thereby increasing the understanding of obesity, obesity treatment and -related diseases in the 
future.
!
As the scope of the biosampling for future analysis has broadened to cover obesity and -related 
diseases with this amendment, some paragraphs in appendix 7 has been revised. Furthermore, 
the informed consent has been updated to reflect the broader scope. A separate protocol will be 
developed before the biosamples from trial NN9536-4374 can be analysed in the future. This 
will include rationale for the analysis as well as reporting requirements.
!
Removal of the persistent criteria from the exploratory endpoint in section 4.2.3 and update of 
section 9.4.6 accordingly, since the exploratory endpoint about onset of micro or macro 
albuminuria as well as regression to normoalbuminuria could not be adequately assessed with 
the definition of persistent and current trial design. This is due to the fact that the final 
assessment at week 68 should be confirmed with 2 confirmatory assessments after end of 
treatment.
!
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 2
Flowchart
Biosamples for future analysisd (9.7, 9.8, Appendix 7)
2.2
Section 3.2 
Background
2.2.1
Section 3.2.1 Semaglutide
GLP-1 receptor agonist is a physiological regulator of appetite and GLP-1 receptors are present in 
several areas of the brain involved in appetite regulation58.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
4 of 9
Clinical59-63,65 and non-clinical data 6566 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.
2.3
Section 3.3
Benefit-risk assessment
2.3.1
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.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
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Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
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2.4
Section 4.2
Primary, secondary and exploratory endpoints
2.4.1
Section 4.2.3 Exploratory endpoints
The exploratory endpoints reflect the comparison of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo I/II.
Subjects who after 68 weeks achieve (yes/no) the following in:
!
New onset of persistent micro albuminuria (UACR B 30 and C 300 mg/g) in subjects 
without albuminuria (UACR < 30 mg/g) at randomisation (week 0) 
!
New onset of persistent macro albuminuria (UACR > 300 mg/g) in subjects without macro 
albuminuria at randomisation (week 0)
!
Regression of micro albuminuria/macro albuminuria to normal (in subjects with either 
micro (UACR B 30 and C 300 mg/g ) or macro albuminuria (UACR > 300 mg/g ) at 
baseline (week 0))
2.5
Section 6.1
Inclusion criteria
6. Subject treated with either:
!
diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as single 
agent therapy or
!
up to 3 OADs (metformin, SU, SGLT2i or glitazone) according to local label
Any approved and marketed metformin, glitazone, SGLT2i or SU product or combination products 
are allowed. Treatment with oral agents should be stable (same drug(s), dose and dosing 
frequency) for at least 90 days prior to screening.
2.6
Section 7.1 
Treatments administered
!
If a subject does not tolerate the designated recommended target dose of (1.0 or 2.4 mg once 
weekly), the subject may stay at a 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 designated recommended target dose,of 
2.4 mg once-weekly as per the investigator’s discretion. Both pens should be used during down-
and re-escalation.
Table 7-2: Dose escalation and maintenance in the semaglutide 2.4 mg once-weekly/semaglutide II
placebo arms. The placebo II arm will follow the escalation regimen outlined in Table 7-3.
!
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.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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2.7
Section 9.4 Safety assessment
2.7.1
Section 9.4.5 Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist or equally qualified certified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a pre-corneal or corneal contact lens examination) and performed with 
pharmacologically dilated pupils.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her their evaluation upon the results of that examination. The examination 
must be repeated before randomisation if the subject has experienced worsening of visual function 
since the last examination. If the applicable eye examination was performed before the subject 
signed the informed consent form, it must be documented that the reason for performing the 
examination was not related to this trial.
2.7.2
Section 9.4.6 Clinical safety laboratory assessments
Urinalysis: Proteinuria should be assessed using a spot urine collection to measure urine albumin-
to-creatinine ratio (UACR). The spot urine specimen should be collected on first morning samples. 
Persistent proteinuria is defined as having 2 out of 3 consecutive samples above the limit for 
macroalbuminuria or microalbunuria. Repeat UACR should be done for at least 4 weeks apart after 
positive UACR (B 30 mg/g) to confirm the finding.
2.8
Section 9.7 
Genetics
Not applicable for this trial.
A blood sample for genetic analysis will be collected from patients who have consented to 
participate in the optional biobank component of the trial. Refer to section 9.8 and Appendix 7 for 
further details.
2.9
Section 9.8 
Biomarkers and biosamples for future analysis 
Collection of samples for biomarker research is part of this trial to support the efficacy objectives. 
The following samples must be collected in accordance with the laboratory manual and the 
flowchart:
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Protocol Amendment no 7
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Date:
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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Biomarkers linked to cardiovascular risk:
!
Plasminogen Activator Inhibitor-1 (PAI-1) Activity will be analysed by activity assay.
!
High sensitive C-reactive protein (hsCRP)
Collection of biosamples for future analysis (stored in a biobank) is a component of this trial. 
Participation in the biobank component is optional. Patients who do not wish to participate in the 
biobank component may still participate in the trial. For the biobank, samples will be collected 
according to the flowchart and stored for future use.
The samples are collected for the purpose of allowing future analyses of biomarkers, both genetic 
and circulating, at a later point in time when new knowledge or improved measurement techniques 
may have become available. The analyses may include biomarkers currently known or discovered 
in the future.
Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome with the purpose of understanding and predicting response to semaglutide as well as to 
understand obesity or other related diseases.
Analyses of circulating biomarkers will measure hormones, metabolites or other non-genetic  serum 
entity with the purpose of understanding and predicting response to semaglutide as well as 
understanding obesity or other related diseases.
These samples need to be frozen and should be sent in batches to the central laboratory. The 
analyses are likely to be performed after the trial has come to an end, and results will therefore not 
be part of the clinical trial report. The biobank samples may be stored up to 15 years after end of 
trial at a central laboratory (see Appendix 7).
2.10
Section 10.1
Sample size determination 
2.10.1
Table 10-2
Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm)
Foot note: SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-
36 = Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on 
Quality of Life-Lite for Clinical Trials; PFD = physical function domain; # shown as a positive 
number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
All tests in the hierarchy are based on the primary estimand.
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
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Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
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2.11
Section 10.3
Statistical analyses
2.11.1
Section 10.3.2.1
Confirmatory secondary endpoints
2.11.1.1
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; 
HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; 
PFD = physical function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 10-2.
2.12
Appendix 2 
Clinical laboratory tests
2.12.1
Table 11-2
Protocol-required safety laboratory assessments
Other tests: eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 2012 
by the central laboratory at screening.
2.12.2
Table 11-3 
Criteria for laboratory outliers
Lymphocytes < 25 0.2 x 109/L
2.13
Appendix 3 
Trial governance considerations
2.13.1
9) Data quality assurance
2.13.1.1
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
2.14
Appendix 5 
Contraceptive guidance and collection of pregnancy information
2.14.1
Table 11-5 
Highly effective contraceptive methods
Sexual abstinenceb
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Protocol Amendment no 7
CONFIDENTIAL
Date:
13 August 2018
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Trial ID: NN9536-4374
Version:
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Status:
Final
     
Page:
9 of 9
2.15
Appendix 7
Retention of human biosamples and genetics
2.15.1
Biosamples for future analysis
In countries where applicable, the trial will involve collection of human biosamples to be stored in 
a central archive for future use.
!
The material to be collected is serum collected at baseline (visit 2) and end of treatment (Visit 
24) is: A total of 5 aliquots will be stored for each subject at both time points.
!
Whole blood (for genetic analysis)
!
Serum (for analyses of circulating biomarkers)
!
The results obtained from any already performed analyses of the samples will still be used. In 
the event that the collected biosamples (serum) will be used in the future, the investigator will 
become directly informed by Novo Nordisk about the results if the findings are deemed
clinically relevant and analytically valid and quantifiable. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm
conclusion from the results has been drawn by Novo Nordisk.
!
Potentially, observations of neoplastic diseases, serious hereditary diseases, other untreatable
diseases, or any other abnormal findings could be part of the observations. Subjects can contact 
the investigator if they wish to be informed about results derived from stored biosamples
obtained from their own body.
In case the subject withdraws his/her informed consent for biosamples for future analysis and 
genetics, the monitor must contact the trial manager at Novo Nordisk as soon as possible in order 
to have the samples withdrawn from storage.
2.16
Section 12
References
66: Lu T, et al. Presented at the 77th scientific sessions of the American diabetes association, 9-13 
June 2017, San Diego, CA, USA.
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Protocol Amendment no 8
CONFIDENTIAL
Date:
24 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
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Protocol Amendment
no 8
to Protocol, version 2
dated 21 Dec 2017
Trial ID:NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to United Arab Emirates
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.
1.0
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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 8
CONFIDENTIAL
Date:
24 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
Status:
Final
Page:
2 of 10
Table of Contents    
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................4
2.1
Section 2 Flowchart...................................................................................................................4
2.2
Section 3.2  Background............................................................................................................4
2.2.1
Section 3.2.1  Semaglutide.......................................................................................4
2.3
Section 3.3 Benefit-risk assessment...........................................................................................4
2.3.1
3.3.2  Risks and precautions.....................................................................................4
2.4
Section 4.2 Primary, secondary and exploratory endpoints.........................................................5
2.4.1
Section 4.2.3 Exploratory endpoints.........................................................................5
2.5
Section 6.1 Inclusion criteria .....................................................................................................5
2.6
Section 7.1  Treatments administered ........................................................................................5
2.7
Section 8  Discontinuation/Withdrawal criteria..........................................................................6
2.7.1
Section 8.1  Discontinuation of trial treatment..........................................................6
2.8
Section 9.4 Safety assessment ...................................................................................................6
2.8.1
Section 9.4.5  Eye examination ................................................................................6
2.8.2
Section 9.4.6 Clinical safety laboratory assessments.................................................7
2.9
Section 9.7  Genetics.................................................................................................................7
2.10
Section 9.8  Biomarkers and biosamples for future analysis.......................................................7
2.11
Section 10.1 Sample size determination.....................................................................................8
2.11.1
Table 10-2 Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm).....................................................................8
2.12
Section 10.3 Statistical analyses ................................................................................................8
2.12.1
Section 10.3.2.1 Confirmatory secondary endpoints .................................................8
2.12.1.1
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............................................................................................8
2.13
Appendix 2  Clinical laboratory tests.........................................................................................9
2.13.1
Table 11-2 Protocol-required safety laboratory assessments .....................................9
2.13.2
Table 11-3  Criteria for laboratory outliers ...............................................................9
2.14
Appendix 3  Trial governance considerations ............................................................................9
2.14.1
9) Data quality assurance .........................................................................................9
2.14.1.1
Protocol compliance...........................................................................9
2.15
Appendix 5  Contraceptive guidance and collection of pregnancy information...........................9
2.15.1
Table 11-5  Highly effective contraceptive methods .................................................9
2.16
Appendix 7 Retention of human biosamples and genetics..........................................................9
2.16.1
Biosamples for future analysis .................................................................................9
2.17
Appendix 10 country specific requirements .............................................................................10
2.18
Section 12 References .............................................................................................................10
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Protocol Amendment no 8
CONFIDENTIAL
Date:
24 August 2018
Novo Nordisk
Trial ID: NN9536-4374
Version:
1.0
     
Status:
Final
     
Page:
3 of 10
1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
To implement genetic biosamples for future analysis, for those countries where it will be 
applicable. The rationale for implementation is to ensure a better characterisation of the 
population in scope as new technologies and hypothesis develops. The collection of whole 
blood at baseline (visit 2) and end of treatment (visit 24) will allow for future genetic analysis 
thereby increasing the understanding of obesity, obesity treatment and -related diseases in the 
future.
!
As the scope of the biosampling for future analysis has broadened to cover obesity and -related 
diseases with this amendment, some paragraphs in appendix 7 has been revised. Furthermore, 
the informed consent has been updated to reflect the broader scope. A separate protocol will be 
developed before the biosamples from trial NN9536-4374 can be analysed in the future. This 
will include rationale for the analysis as well as reporting requirements.
!
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.
!
Removal of the persistent criteria from the exploratory endpoint in section 4.2.3 and update of 
section 9.4.6 accordingly, since the exploratory endpoint about onset of micro or macro 
albuminuria as well as regression to normoalbuminuria could not be adequately assessed with 
the definition of persistent and current trial design. This is due to the fact that the final 
assessment at week 68 should be confirmed with 2 confirmatory assessments after end of 
treatment.
!
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.
!
For some sites in United Arab Emirates, Ethics committee have not approved genetic and/or bio 
banking for future analysis. Appendix 7 and Appendix 10 have been updated with this 
information.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Protocol Amendment no 8
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Date:
24 August 2018
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2
Changes
2.1
Section 2
Flowchart
Biosamples for future analysisd (9.7, 9.8, Appendix 7)
2.2
Section 3.2 
Background
2.2.1
Section 3.2.1 Semaglutide
GLP-1 receptor agonist is a physiological regulator of appetite and GLP-1 receptors are present in
several areas of the brain involved in appetite regulation58.
Clinical59-63,65 and non-clinical data 6566 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.
2.3
Section 3.3
Benefit-risk assessment
2.3.1
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 
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Protocol Amendment no 8
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MTC and elevated plasma levels of calcitonin (biomarker for MTC) have been implemented in the 
trial.
Other risks
!
Pregnancy and fertility (based on non-clinical data)
Studies in animals have shown reproductive toxicity. There are limited data from the use of
semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy.
Exclusion and discontinuation criteria related to pregnancy have been implemented in the trial.
2.4
Section 4.2
Primary, secondary and exploratory endpoints
2.4.1
Section 4.2.3 Exploratory endpoints
The exploratory endpoints reflect the comparison of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo I/II.
Subjects who after 68 weeks achieve (yes/no) the following in:
!
New onset of persistent micro albuminuria (UACR C 30 and D 300 mg/g) in subjects 
without albuminuria (UACR < 30 mg/g) at randomisation (week 0) 
!
New onset of persistent macro albuminuria (UACR > 300 mg/g) in subjects without macro 
albuminuria at randomisation (week 0)
!
Regression of micro albuminuria/macro albuminuria to normal (in subjects with either 
micro (UACR C 30 and D 300 mg/g ) or macro albuminuria (UACR > 300 mg/g ) at 
baseline (week 0))
2.5
Section 6.1
Inclusion criteria
6. Subject treated with either:
!
diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as single 
agent therapy or
!
up to 3 OADs (metformin, SU, SGLT2i or glitazone) according to local label
Any approved and marketed metformin, glitazone, SGLT2i or SU product or combination products 
are allowed. Treatment with oral agents should be stable (same drug(s), dose and dosing 
frequency) for at least 90 days prior to screening.
2.6
Section 7.1 
Treatments administered
!
If a subject does not tolerate the designated recommended target dose of (1.0 or 2.4 mg once 
weekly), the subject may stay at a 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 designated recommended target dose,of 
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Protocol Amendment no 8
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2.4 mg once-weekly as per the investigator’s discretion. Both pens should be used during down-
and re-escalation.
Table 7-2: Dose escalation and maintenance in the semaglutide 2.4 mg once-weekly/semaglutide II
placebo arms. The placebo II arm will follow the escalation regimen outlined in Table 7-3.
!
Injections may be administered in the thigh, abdomen or upper arm, at any time of day
irrespective of meals. Subjects should be encouraged to inject in the same area throughout the 
trial, but changing between left and right side is allowed.
2.7
Section 8 
Discontinuation/Withdrawal criteria
2.7.1
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 C 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 criteria70 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).
2.8
Section 9.4 Safety assessment
2.8.1
Section 9.4.5 Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist, or equally qualified certified 
health care provider (e.g. optometrist) or another suitably qualified health care provider must be 
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Protocol Amendment no 8
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available and evaluated by the investigator before randomisation to assess eligibility. The eye 
examination should be performed as a fundus photography (e.g. 2-field 60 degree or better, colour 
or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-corneal or corneal contact 
lens examination) and performed with pharmacologically dilated pupils.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her their evaluation upon the results of that examination. The examination 
must be repeated before randomisation if the subject has experienced worsening of visual function 
since the last examination. If the applicable eye examination was performed before the subject 
signed the informed consent form, it must be documented that the reason for performing the 
examination was not related to this trial.
2.8.2
Section 9.4.6 Clinical safety laboratory assessments
Urinalysis: Proteinuria should be assessed using a spot urine collection to measure urine albumin-
to-creatinine ratio (UACR). The spot urine specimen should be collected on first morning samples. 
Persistent proteinuria is defined as having 2 out of 3 consecutive samples above the limit for 
macroalbuminuria or microalbunuria. Repeat UACR should be done for at least 4 weeks apart after 
positive UACR (C 30 mg/g) to confirm the finding.
2.9
Section 9.7 
Genetics
Not applicable for this trial.
A blood sample for genetic analysis will be collected from patients who have consented to 
participate in the optional biobank component of the trial. Refer to section 9.8 and Appendix 7 for 
further details.
2.10
Section 9.8 
Biomarkers and biosamples for future analysis 
Collection of samples for biomarker research is part of this trial to support the efficacy objectives. 
The following samples must be collected 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)
Collection of biosamples for future analysis (stored in a biobank) is a component of this trial. 
Participation in the biobank component is optional. Patients who do not wish to participate in the 
biobank component may still participate in the trial. For the biobank, samples will be collected 
according to the flowchart and stored for future use.
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Protocol Amendment no 8
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The samples are collected for the purpose of allowing future analyses of biomarkers, both genetic 
and circulating, at a later point in time when new knowledge or improved measurement techniques 
may have become available. The analyses may include biomarkers currently known or discovered 
in the future.
Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome with the purpose of understanding and predicting response to semaglutide as well as to 
understand obesity or other related diseases.
Analyses of circulating biomarkers will measure hormones, metabolites or other non-genetic  serum 
entity with the purpose of understanding and predicting response to semaglutide as well as 
understanding obesity or other related diseases.
These samples need to be frozen and should be sent in batches to the central laboratory. The 
analyses are likely to be performed after the trial has come to an end, and results will therefore not 
be part of the clinical trial report. The biobank samples may be stored up to 15 years after end of 
trial at a central laboratory (see Appendix 7).
2.11
Section 10.1
Sample size determination 
2.11.1
Table 10-2
Assumptions, marginal power and effective power for each endpoint 
in the hierarchical testing procedure given an anticipated number 1200 
randomised subjects (400 in each arm)
Foot note: SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-
36 = Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on 
Quality of Life-Lite for Clinical Trials; PFD = physical function domain; # shown as a positive 
number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
All tests in the hierarchy are based on the primary estimand.
2.12
Section 10.3
Statistical analyses
2.12.1
Section 10.3.2.1
Confirmatory secondary endpoints
2.12.1.1
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; 
HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
1.0
.
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Protocol Amendment no 8
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Date:
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Trial ID: NN9536-4374
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Status:
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Page:
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physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; 
PFD = physical function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 10-2.
2.13
Appendix 2 
Clinical laboratory tests
2.13.1
Table 11-2
Protocol-required safety laboratory assessments
Other tests: eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 2012 
by the central laboratory at screening.
2.13.2
Table 11-3 
Criteria for laboratory outliers
Lymphocytes < 25 0.2 x 109/L
2.14
Appendix 3 
Trial governance considerations
2.14.1
9) Data quality assurance
2.14.1.1
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
2.15
Appendix 5 
Contraceptive guidance and collection of pregnancy information
2.15.1
Table 11-5 
Highly effective contraceptive methods
Sexual abstinenceb
2.16
Appendix 7
Retention of human biosamples and genetics
2.16.1
Biosamples for future analysis
In countries where applicable, the trial will involve collection of human biosamples to be stored in 
a central archive for future use.
!
The material to be collected is serum collected at baseline (visit 2) and end of treatment (Visit 
24) is: A total of 5 aliquots will be stored for each subject at both time points.
!
Whole blood (for genetic analysis)
!
Serum (for analyses of circulating biomarkers)
!
The results obtained from any already performed analyses of the samples will still be used. In 
the event that the collected biosamples (serum) will be used in the future, the investigator will 
become directly informed by Novo Nordisk about the results if the findings are deemed
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Protocol Amendment no 8
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clinically relevant and analytically valid and quantifiable. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm
conclusion from the results has been drawn by Novo Nordisk.
!
Potentially, observations of neoplastic diseases, serious hereditary diseases, other untreatable
diseases, or any other abnormal findings could be part of the observations. Subjects can contact 
the investigator if they wish to be informed about results derived from stored biosamples 
obtained from their own body.
In case the subject withdraws his/her informed consent for biosamples for future analysis and 
genetics, the monitor must contact the trial manager at Novo Nordisk as soon as possible in order 
to have the samples withdrawn from storage.
See Appendix 10 for country specific requirements for Algeria and United Arab Emirates
2.17
Appendix 10 country specific requirements
2.17.1          Appendix 7 Retention of human biosamples
For Algeria: No genetic testing and bio banking in central archive is allowed as per Algerian local 
requirements.
For United Arab Emirates: Not all sites have received IRB/IEC approval for genetic and/or bio 
banking. Sites will follow the relevant IRB/IEC decision.
2.18
Section 12
References
66: Lu T, et al. Presented at the 77th scientific sessions of the American diabetes association, 9-13 
June 2017, San Diego, CA, USA.
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Protocol Amendment no 9
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Date:
08 November 2018
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Trial ID: NN9536-4374
Version:
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Protocol Amendment
no 9
to Protocol, version 3
dated 06 June 2018
Trial ID:NN9536-4374
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity and type 2 diabetes
Trial phase: 3a
Applicable to South Africa
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
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Protocol Amendment no 9
CONFIDENTIAL
Date:
08 November 2018
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Trial ID: NN9536-4374
Version:
1.0
Status:
Final
Page:
2 of 3
Table of Contents
1 
Introduction including rationale for the protocol amendment .............................................................3 
2 
Changes......................................................................................................................................................3 
2.1 
Section 2 Flowchart .......................................................................................................................3 
2.2 
Section 9.7  Genetics .....................................................................................................................3 
2.3 
Appendix 7 Retention of human biosamples and genetics ............................................................3 
2.3.1 
Biosamples for future analysis.....................................................................................3 
2.4 
Appendix 10 country specific requirements ..................................................................................3 
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Protocol Amendment no 9
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Date:
08 November 2018
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Trial ID: NN9536-4374
Version:
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Status:
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Page:
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1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
x
All sites in South Africa will not participate in genetic and/or bio banking for future analysis as 
application for Storage of Samples for future research to IRB/IEC was withdrawn by Novo 
Nordisk. Appendix 7 and Appendix 10 have been updated with this information.
In this protocol amendment:
x
Any new text is written in italics.
x
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 2
Flowchart
Biosamples for future analysisd (9.7, 9.8, Appendix 7)
2.2
Section 9.7 
Genetics
A blood sample for genetic analysis will be collected from patients who have consented to
participate in the optional biobank component of the trial. Refer to section 9.8 and Appendix 7 for
further details.
2.3
Appendix 7
Retention of human biosamples and genetics
2.3.1
Biosamples for future analysis
See Appendix 10 for country specific requirements for Algeria and South Africa
2.4
Appendix 10 country specific requirements
2.4.1          Appendix 7 Retention of human biosamples
For Algeria: No genetic testing and bio banking in central archive is allowed as per Algerian local 
requirements.
For South Africa:  No genetic testing and bio banking will be performed as the application for 
Storage of Samples for future research to IRB/IEC was withdrawn by Novo Nordisk.
1.0
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SAP_003.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03552757 
Sponsor trial ID: 
NN9536-4374 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly in 
subjects with overweight or obesity and type 2 diabetes 
Document date*: 
0D\ 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
MedDRA search terms.......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4374 (STEP 2)
Clinical Trial Report
Appendix 16.1.9
04 August 2020
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16.1.9 Documentation of statistical methods
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Statistical Analysis Plan
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EudraCT No.: 2017-003414-10
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Statistical Analysis Plan
Trial ID: NN9536-4374
STEP 2
Effect and safety of semaglutide 2.4 mg once-weekly in
subjects with overweight or obesity and type 2 diabetes
Author
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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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
Page:
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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 
1.1.1.3 
Exploratory objectives...........................................................................6 
1.1.2 
Estimands.....................................................................................................................6 
1.1.2.1 
Primary estimand...................................................................................6 
1.1.2.2 
Secondary estimand...............................................................................6 
1.1.3 
Endpoints .....................................................................................................................6 
1.1.3.1 
Primary endpoints .................................................................................6 
1.1.3.2 
Secondary endpoints .............................................................................7 
1.1.4 
Type of trial ...............................................................................................................10 
1.2 
Scope of the statistical analysis plan............................................................................................11 
2 
Statistical considerations ........................................................................................................................12 
2.1 
Sample size determination...........................................................................................................12 
2.2 
Definition of analysis sets............................................................................................................14 
2.3 
Statistical analyses.......................................................................................................................15 
2.3.1 
Primary endpoints......................................................................................................15 
2.3.2 
Secondary endpoints..................................................................................................21 
2.3.2.1 
Confirmatory secondary endpoints .....................................................21 
2.3.2.2 
Supportive secondary endpoints..........................................................23 
2.3.3 
Exploratory endpoints................................................................................................25 
2.3.4 
Explorative statistical analysis for pharmacogenetics and biomarkers......................25 
2.3.5 
Other analyses............................................................................................................26 
2.3.6 
Pharmacokinetic and/or pharmacodynamic modelling..............................................26 
3 
Changes to the statistical analyses planned in the protocol.................................................................27 
3.1 
Trial-specific changes..................................................................................................................27 
3.2 
Changes applied across STEP trials.............................................................................................27 
4 
References................................................................................................................................................30 
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Statistical Analysis Plan
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List of abbreviations
6MWT
six-minute walking test
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
CRF
case report form
CTR
clinical trial report
dBP
diastolic blood pressure
EAC
event adjudication committee
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
IWQoL-Lite for CT
Impact of Weight on Quality of Life-Lite for Clinical Trials
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
OAD
oral antidiabetic drug
OR
odds ratio
PAI-1
plasminogen activator inhibitor-1
PCS
physical component summary
PD
physical domain
PF
physical functioning
PFD
physical function domain
PK
pharmacokinetics
PSD
psychosocial domain
PYE
patient years of exposure
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Statistical Analysis Plan
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PYO
patient years of observation
RE
role-emotional
RP
role-physical
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
sBP
systolic blood pressure
SD
standard deviation
SF
social functioning
SF-36
Short Form-36
T2D
type 2 diabetes
TEAE
treatment-emergent adverse event
VLDL
very low density lipoprotein
VT
vitality
WC
waist circumference
WRSSM
Weight Related Sign and Symptom Measure
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Statistical Analysis Plan
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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 I/II 
(please see the last paragraph in this section for an explanation of placebo I and II) as an adjunct to 
a reduced-calorie diet and increased physical activity in subjects with overweight or obesity and 
type 2 diabetes (T2D) 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 I/II as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on:
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments 
x
Glycaemic control
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D on:
x
Body weight
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments 
x
Glycaemic control
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus semaglutide placebo I/II as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and T2D on glycaemic control.
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo I/II as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and T2D.
1.0
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1.1.1.3
Exploratory objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II as an
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or
obesity and T2D on:
x
Use of oral antidiabetic drug (OAD) medication
x
Use of medication for hypertension and dyslipidaemia
x
Work productivity
x
Treatment discontinuation
x
Liver indices
1.1.2
Estimands
1.1.2.1
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of initiating 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 objectives related to weight,
cardiovascular risk factors, clinical outcome assessments, and glycaemic control. The estimand will 
quantify the average treatment effect of semaglutide s.c. 2.4 mg relative to semaglutide s.c. 1.0 mg 
after 68 weeks, as an adjunct to reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of initiating other anti-
obesity therapies (i.e., weight management drugs or bariatric surgery).
1.1.2.2
Secondary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all 
randomised subjects had they remained on their randomised treatment for the entire planned 
duration of the trial and not initiated 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
The primary endpoints addressing the primary objective:
x
Change from baseline (week 0) to week 68 in body weight (%)
x
Subjects who after 68 weeks achieve (yes/no):
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o
Body weight reduction  5% from baseline (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
The confirmatory secondary endpoints are used to compare effect of semaglutide s.c. 2.4 mg once-
weekly versus semaglutide placebo I/II unless stated otherwise.
Subjects who after 68 weeks achieve (yes/no):
x
Body weight reduction  10% from baseline (week 0)
x
Body weight reduction  15% from baseline (week 0)
Change from baseline (week 0) to week 68 in:
x
Waist circumference (cm)
x
Body weight (%) (semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 mg 
once-weekly)
x
Haemoglobin A1c (HbA1c) (%, mmol/mol)
x
Systolic blood pressure (mmHg)
x
Physical functioning score (SF-36)
x
Physical function domain (5-items) score (IWQoL-Lite for CT) 
Supportive secondary endpoints
Effect endpoints
The supportive secondary effect endpoints are used to compare the effect of semaglutide s.c. 2.4 mg 
once-weekly versus semaglutide placebo I/II unless otherwise stated.
Change from baseline (week 0) to week 68 in:
x
Body weight (kg)
x
BMI (kg/m2)
x
HbA1c (%, mmol/mol) (semaglutide s.c. 1.0 mg once-weekly versus semaglutide placebo 
I/II)
x
Fasting plasma glucose (FPG) (mg/dL, mmol/L)
x
Fasting serum insulin (mIU/L, pmol/L)
x
Diastolic blood pressure (mmHg)
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x
Lipids (mg/dL, mmol/L):
o
Total cholesterol
o
High density lipoprotein (HDL) cholesterol
o
Low density lipoprotein (LDL) cholesterol
o
Very low density lipoprotein (VLDL) cholesterol
o
Free fatty acids (FFA)
o
Triglycerides
x
High sensitivity C-Reactive Protein (hsCRP) (mg/L)
x
Plasminogen Activator Inhibitor-1 (PAI-1) Activity (AU/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
x
IWQoL-Lite for CT:
o
physical domain score
o
psychosocial domain score
o
total score
Subjects who after 68 weeks achieve (yes/no):
x
Responder definition value for SF-36 physical functioning score
x
Responder definition value for IWQoL-Lite for CT physical function domain (5-items) 
score
x
HbA1c < 7.0% (53 mmol/mol)
x
HbA1c  6.5% (48 mmol/mol)
x
Body weight reduction  10% and HbA1c < 7.0%
x
Body weight reduction  15% and HbA1c < 7.0%
x
Body weight reduction  20% from baseline (week 0)
Safety endpoints
x
Number of treatment-emergent adverse events (TEAEs) from baseline (week 0) to week 75
x
Number of serious adverse events (SAEs) from baseline (week 0) to week 75
x
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes from baseline (week 0) to week 75
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Change from baseline (week 0) to week 68 in:
x
Pulse (bpm)
x
Amylase (U/L)
x
Lipase (U/L)
x
Calcitonin (ng/L)
Exploratory endpoints
The exploratory endpoints are addressing the exploratory objectives and reflect the comparison of 
semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo I/II.
Subjects who after 68 weeks achieve (yes/no) the following in:
x
New onset of micro albuminuria (UACR  30 and  300 mg/g) in subjects without 
albuminuria (UACR < 30 mg/g) at randomisation (week 0)
x
New onset of macro albuminuria (UACR > 300 mg/g) in subjects without macro 
albuminuria at randomisation (week 0)
x
Regression of micro albuminuria/macro albuminuria to normal (in subjects with either micro 
(UACR  30 and  300 mg/g) or macro albuminuria (UACR > 300 mg/g) at baseline (week 
0))
Change from baseline (week 0) to week 68 in:
x
Antihypertensives (decrease, no change, increase)
x
Lipid lowering medication (decrease, no change, increase)
x
Concomitant OAD medication (decrease, no change, increase)
x
Six-minute walking test (6MWT) (meters) (only for subjects with a BMI  35 kg/m2)
x
Fatty liver index (FLI) score category (< 30,  30 and < 60,  60)
x
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem V2.0 
(WPAI-SHP)
x
Work time missed due to weight (%)
x
Impairment while working due to weight (%)
x
Overall work impairment due to weight (%)
x
Activity impairment due to weight (%)
Subjects who from randomisation (week 0) to week 68 have permanently discontinued randomised 
trial product (yes/no):
x
Time to permanent discontinuation of randomised trial product (weeks)
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Semaglutide placebo I is used when it is solution for injection with the 3 ml pre-filled PDS290 pen-
injector for the weight management placebo product whereas semaglutide placebo II is used when it 
is the 1.5 ml pre-filled PDS290 pen-injector for the diabetes placebo product.
1.1.4
Type of trial
This is a 68-week, randomised, double-blinded, double dummy, placebo-controlled, multi-centre 
trial. 
Subjects will be randomised in a 1:1:1 manner to receive either:
x
Semaglutide s.c. 2.4 mg and semaglutide placebo II once-weekly
x
Semaglutide s.c. 1.0 mg and semaglutide placebo I once-weekly
x
Semaglutide placebo I and semaglutide placebo II once-weekly
all as an adjunct to a reduced-calorie diet and increased physical activity. 
There is a 1-week screening period followed by a randomisation visit and a 68-week treatment 
period. The treatment period is divided into a dose escalation period of 16 weeks and a maintenance 
period of 52 weeks. Subsequently there is a follow-up period of 7 weeks.
The trial population will consist of subjects with BMI > 27 kg/m2 with T2D on 0-3 OADs, but not 
treated with insulin.
The trial design and rationale for the double dummy design is outlined in Figure 1.
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Figure 1
A schematic diagram of the trial design, with the duration of the trial periods 
including follow-up period. As outlined in the figure the escalation is different 
between the two target doses of semaglutide, furthermore the injection volume 
and device are different as reflected in the product strength. The two active 
arms are represented with the respective placebo arms, and the placebo arm 
includes both regimens. All subjects therefore receive two injections per week as 
reflected in double dummy design.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol for trial NN9536-4374 “Effect and 
safety of semaglutide 2.4 mg once-weekly in subjects with overweight or obesity and type 2 
diabetes” version 3.0 (06 June 2018), 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 0.
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2
Statistical considerations
Taxonomy of week 68 assessments
For each subject a given assessment at week 68 may be available or missing and Table 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 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 I/II (or semaglutide 1.0 mg) 
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
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 versus semaglutide placebo I/II must be 
demonstrated for each of the primary endpoints.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 68 for 
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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 I/II subjects. These assumptions 
are likely conservative with respect to the power, and correspond to the jump to reference 
sensitivity analysis planned below.
Assumptions
The common assumptions for the power calculations are:
x
The significance level is 5%
x
The randomisation ratio is 1:1:1
x
For continuous endpoints the t-test on the mean difference assuming equal variances is used
x
For binary endpoints the Pearson chi-square test for two independent proportions is used 
x
Based on data from NN9536-4153
o
20% of subjects discontinue permanently and
o
60% of these are retrieved (AD) at week 68 
x
All subjects in the semaglutide placebo I/II arm are assumed to have same effect as subjects 
who complete the trial on semaglutide placebo I/II (AT)
x
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 I/II [or 
semaglutide 1.0 mg]) of subjects who complete the trial on semaglutide 2.4 mg (AT)
x
Non-retrieved subjects (MD) in the semaglutide 2.4 mg arm are assumed to have an effect 
corresponding to semaglutide placebo I/II (or semaglutide 1.0 mg) 
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. All tests except no. 6 are testing for superiority of semaglutide 2.4 mg to 
semaglutide placebo I/II. Test no. 6 is a test for superiority of semaglutide 2.4 mg to semaglutide 
1.0 mg for the primary endpoint change in body weight (%).
Given these assumptions, the sample size of 1200 subjects (400 in each arm), gives an effective 
power (marginal powers multiplied) of 94% for the first nine 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
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number 1200 randomised 
subjects (400 in each arm)
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 I/II
Semaglutide 
2.4 mg
1
% weight change #
11.6 (±10)
1.7 (±10)
10.2 (±11)
8.5%-points
> 99
> 99
2
5% responders
75%
37%
69%
1.8
> 99
> 99
3
10% responders
56%
20%
51%
2.6
> 99
> 99
4
15% responders
37%
9%
33%
3.7
> 99
> 99
5
WC change (cm) #
9.1 (±10)
2.8 (±10)
8.2 (±11)
5.4 cm
> 99
> 99
6
% weight change #, *
11.6 (±10)
8.1 (±10)
10.2 vs 7.2 (±11)
3.0%-points
97
97
7
HbA1c (%) change #
1.4 (±1.0)
0.5 (±1.0)
1.3 (±1.5)
0.8%-points
> 99
96
8
sBP change (mmHg) #
5.1 (±13)
0.4 (±13)
4.4 (±14)
4 mmHg
98
94
9
SF-36 PF score change
6 (±10)
2 (±10)
5.4 (±11)
3.4 score-
points
> 99
94
10
IWQoL-Lite PFD score 
change
24 (±20)
13 (±20)
22.5 (±21)
9.5 score-
points
> 99
94
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; 
PF = physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical 
function domain; # shown as a positive number; * semaglutide 2.4 mg vs semaglutide 1.0 mg
All tests in the hierarchy are based on the primary estimand.
2.2
Definition of analysis sets
Two analysis sets are defined:
x
The full analysis set (FAS) includes all randomised subjects according to the intention-to-
treat principle. Subjects in the FAS will contribute to the evaluation “as randomised”.
x
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 
(regardless of pen) 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.
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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
The on-treatment period as described above (i.e. employing a lag time of 2 weeks 
[14 days]) applies to all effect assessments, safety laboratory assessments, physical 
examination and pulse
o
For the evaluation of adverse events, hypoglycaemic episodes, adjudicated events, 
ECG, eye examination and antibodies the lag time for each on-treatment time 
interval is 7 weeks (49 days).
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
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 (or semaglutide 1.0 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 endpoints
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 at least 5% from baseline (week 0) to week 68 is defined as 
5% responder = ൜1 if  % weight change  Ȃ 5%
0 if  % weight change > Ȃ 5%
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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 and stratification groups as factors and baseline body weight (kg) as 
covariate. The stratification group is defined by the OAD treatment stratification category and 
HbA1c stratification category as well as the interaction between these. The estimated treatment 
difference between semaglutide 2.4 mg and semaglutide placebo I/II will be reported together with 
the associated two-sided 95% confidence interval (CI) and corresponding p-value.
The analysis model for the 5% responder endpoint is a logistic regression using randomised 
treatment and stratification groups as factors and baseline body weight (kg) as covariate. The 
stratification group is defined by the OAD treatment stratification category and HbA1c stratification 
category as well as the interaction between these. The estimated odds ratio (OR) between
semaglutide 2.4 mg and semaglutide placebo I/II 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 I/II will be carried out as 
follows for the two analysis models.
Let ȝsemaglutide and ȝsemaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo I/II 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 I/II. 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 
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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 I/II. An illustration of all imputation approaches for the primary estimand is given in Figure 
2.
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:
1. Imputation: Defines an imputation model using retrieved subjects (AD) from FAS and done 
within groups defined by randomised treatment. The model will be a linear regression of body 
weight (kg) at week 68 with gender (male/female), baseline BMI (kg/m2) (in categories <35, 35-
<40, 40), timing of the LAO-OT of body weight and stratification groups (defined by 
stratification categories for OAD treatment and HbA1c) 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 one 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), then removing stratification factors (OAD treatment and then 
HbA1c) 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.
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.
1.0
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Trial ID: NN9536-4374
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UTN: U1111-1200-8148
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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 95364374 as seed number. In addition to the seed 
number, it is specified that the dataset is sorted by subject ID.
Sensitivity analyses
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
68 (MT and MD) for both the semaglutide 2.4 mg and semaglutide placebo I/II group are imputed 
by sampling among all available assessments at week 68 in the semaglutide placebo I/II 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 I/II 
treatment as adjunct to reduced-calorie diet and increased physical activity2. The multiple 
imputation approach is done as above with the first step replaced by:
1. Imputation: Defines an imputation model using semaglutide placebo I/II 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) and stratification groups (defined by stratification categories for OAD treatment and 
HbA1c) 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), then removing stratification factors (OAD treatment and then 
HbA1c) 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 Sacks2 (S1-SI and S2-SI): Missing weight measurements 
at week 68 for non-retrieved subjects (MD) are imputed using a weight regain rate of 0.3 kg/month 
after LAO but truncated at no change from baseline whenever the extrapolation would lead to a 
positive weight gain relative to baseline. If a subject's weight at drug discontinuation represented a 
gain in weight relative to baseline, no additional gain will be imputed, and the unfavourable gain is 
carried forward to week 68. The weight regain imputation will be done for both randomised arms 
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo I/II arm uses last available observation (corresponding to a weight regain 
1.0
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
Page:
19 of 30
rate of 0 kg/month) will be performed (S2-SI). For both versions, missing weight measurements at 
week 68 for subjects on randomised treatment (MT) are imputed by using LAO. 
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Then, a penalty is added to the imputed values at week 
68. The approach is to explore a range of penalties for both treatment groups, and the impact these 
would have on the study conclusions. The 2-dimensional space of penalties covering the range from 
-30% to 30% will be explored for both treatment groups. This sensitivity analysis evaluates the 
robustness of the superiority conclusions to departures from the observed change in body weight in 
both treatment groups.
Mixed model for repeated measurements (MMRM): This ‘MMRM for effectiveness’ will use all 
assessments regardless of adherence to randomised treatment, including assessments at week 68 for 
retrieved drop-outs (AD). The MMRM for effectiveness will be fitted using the same factors 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.
1.0
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
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Figure 2
Illustration of imputation approaches for the primary estimand
Analysis addressing the secondary estimand
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Statistical Analysis Plan
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Date:
14 May 2020
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
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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 (i.e., weight management drugs or bariatric 
surgery) before completion of 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 
factors 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 3.
2.3.2
Secondary endpoints
2.3.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in section 1.1.3 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 I/II (or semaglutide 1.0 mg). 
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 factors 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 
1.0
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
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endpoints will be logistic regression with factors and covariate as for the primary endpoint 5% 
responders.
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 primary and secondary
estimands for confirmatory secondary endpoints is given in Table 3.
Table 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
%weight change*
6
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
HbA1c change (%, 
mmol/mol)
7
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
8
Continuous
Primary
FAS 
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
SF-36 PF score change
9
Continuous
Primary
FAS 
ANCOVA 
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
IWQoL-Lite PFD score 
change
10
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 
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
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UTN: U1111-1200-8148
Status:
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EudraCT No.: 2017-003414-10
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repeated measurements; LR = logistic regression; WC = waist circumference; HbA1c = Hemoglobin A1c; sBP = systolic blood pressure; SF-36 = 
Short Form 36 v2.0 acute; PF = physical functioning; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical 
function domain; * comparison of semaglutide 2.4 mg vs semaglutide 1.0 mg
Test order refers to the order of the endpoints in the statistical test hierarchy outlined in Table 2.
2.3.2.2
Supportive secondary endpoints
Supportive secondary endpoints are listed in section 1.1.3.2. All tests are tests of superiority of 
semaglutide 2.4 mg (or semaglutide 1.0 mg) to semaglutide placebo I/II as well as semaglutide 2.4 
mg to semaglutide 1.0 mg.
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 
factors 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 HbA1c responder endpoints and responder endpoints relating to clinical 
outcome assessments will be logistic regression with randomised treatment and stratification groups 
(defined by stratification categories for OAD treatment and HbA1c) as factors and the baseline
assessment of the endpoint to be analysed as covariate. 
For the weight loss and HbA1c composite responder endpoints, the same imputation factors are used 
for both endpoints, i.e. the reduction of imputation model needed for both sets of imputations to be
successful is applied to both endpoints.
For lipids, biomarkers and fasting serum insulin 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. The effect-related supportive secondary endpoints related to the secondary objective will 
also be analysed to address the secondary estimand using the same MMRM for efficacy described 
for the primary endpoints, however, only the semaglutide 2.4 mg vs semaglutide placebo I/II 
contrast will be presented.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
Analysis of safety endpoints
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Statistical Analysis Plan
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Date:
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UTN: U1111-1200-8148
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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 4.
Table 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
Supportive secondary endpoints (effect related)
Primary
Weight change (kg)
Continuous
Primary AB 
FAS
ANCOVA
RD-MI
Secondary AB
FAS 
MMRM
-
Primary
Weight change (%)
Continuous
Secondary B
FAS
MMRM
-
Primary
Waist circumference (cm)
Continuous
Secondary B
FAS
MMRM
-
Primary
BMI change (kg/m2)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS 
MMRM
-
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary BC 
FAS 
ANCOVA
RD-MI
Secondary B
FAS
MMRM
-
Secondary
FPG change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
Fasting serum insulin change (uIU/mL,
pmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
sBP change (mmHg)
Continuous
Secondary B
FAS
MMRM
-
Secondary
dBP change (mmHg)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
Total cholesterol change (mg/dL,
mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
HDL change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
LDL change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
VLDL change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
FFA change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
Triglycerides change (mg/dL, mmol/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
hsCRP change (mg/L)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
PAI-1 change (AU/mL)
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 PF score change
Continuous
Secondary B
FAS
MMRM
-
Secondary
SF-36 PF score responders #
Binary
Primary AB
FAS
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Secondary
SF-36 RP score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 BP score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 GH score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
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Secondary
SF-36 VT score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 SF score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 RE score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 MH score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 PCS score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
SF-36 MCS score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
IWQoL-Lite PFD score change
Continuous
Secondary B
FAS
MMRM
-
Secondary
IWQoL-Lite PFD score responders ##
Binary
Primary AB
FAS
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Secondary
IWQoL-Lite PD score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
IWQoL-Lite PSD score change
Continuous
Primary AB
FAS
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
IWQoL-Lite total score change
Continuous
Primary AB 
FAS 
ANCOVA
RD-MI
Secondary AB
FAS
MMRM
-
Secondary
HbA1c < 7.0% responders
Binary
Primary AB 
FAS 
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Secondary 
HbA1c  6.5% responders
Binary
Primary AB 
FAS 
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Secondary
Weight loss  10% and HbA1c < 7.0%
Binary
Primary AB
FAS
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Secondary
Weight loss  15% and HbA1c < 7.0%
Binary
Primary AB
FAS
LR
RD-MI
Secondary AB
FAS
LR
MMRM
Supportive secondary endpoints (safety related)
Secondary 
Number of TEAEs AB
Count
-
SAS
-
-
Secondary 
Number of SAEs AB
Count
- 
SAS 
-
-
Secondary
Number of hypoglycaemia episodes AB
Count
-
SAS
-
-
Secondary 
Pulse change (bpm) AB
Continuous
- 
SAS 
MMRM
-
Secondary 
Amylase change (U/L) AB
Continuous
- 
SAS 
-
-
Secondary 
Lipase change (U/L) AB
Continuous
- 
SAS 
-
-
Secondary 
Calcitonin change (ng/L) AB
Continuous
- 
SAS 
-
-
FAS = full analysis set; SAS = safety 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; sBP = 
systolic blood pressure; 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; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical function domain; PD = physical domain; PSD 
= psychosocial domain; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; # responder value = 4.3; ## responder value =
20.
A comparison of semaglutide 2.4 mg vs semaglutide placebo I/II.
Bcomparison of semaglutide 2.4 mg vs semaglutide 1.0 mg.
C comparison of semaglutide 1.0 mg vs semaglutide placebo I/II.
No sensitivity analyses are planned.
2.3.3
Exploratory endpoints
Exploratory endpoints are listed in section 1.1.3. 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 2.3.2.2.
1.0
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2.3.5
Other analyses
All collected data that were not defined as endpoints will be summarised by descriptive statistics.
2.3.6
Pharmacokinetic and/or pharmacodynamic modelling
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety and further to support the recommended dose of semaglutide in 
subjects with obesity. First, plasma semaglutide concentrations will be analysed using a population 
pharmacokinetic model, quantifying covariate (such as baseline body weight, age, gender, race, 
ethnicity, and injection site) effects on semaglutide exposure. Second, model based estimates of 
steady-state average concentrations will be derived for each subject, in order to facilitate subsequent 
exposure-response analyses. Relevant efficacy and safety endpoints will be related to steady-state 
average concentrations and subjected to model based analysis. 
The analyses will be conducted separately for each trial and be combined into a meta-analysis, 
including the phase 2 trial and phase 3a trials with PK sampling. A modelling analysis plan will be 
prepared before first database lock in the semaglutide phase 3a programme for weight management, 
outlining details of the analyses. The modelling will be performed by Quantitative Clinical 
Pharmacology at Novo Nordisk and will be reported separately from the clinical trial reports.
1.0
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
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3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9536-4374. However, 
clarifications and more detailed descriptions of endpoints and analyses are provided in this SAP. 
The changes from the protocol of NN9536-4374 are summarised below:
3.1
Trial-specific changes
The following bullets were added to the single secondary objective for semaglutide 2.4 mg vs 
semaglutide 1.0 mg:
x
Body weight
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments 
x
Glycaemic control
The following bullet is added as an exploratory endpoint comparing semaglutide s.c. 2.4 mg vs. 1.0 
mg once-weekly:
x
HbA1c change (%, mmol/mol)
The supportive secondary endpoints were added:
x
Weight loss  10% and HbA1c < 7.0%
x
Weight loss  15% and HbA1c < 7.0%
The expansion of the primary estimand now also includes: cardiovascular risk factors, clinical 
outcome assessments, and glycaemic control.
The supportive secondary endpoints are expanded from only comparing the effect of semaglutide 
s.c. 2.4 mg once-weekly versus semaglutide placebo I/II (as listed in protocol section 4.2.2.2) to
also include the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly, unless otherwise stated.
The treatment contrast between semaglutide 2.4 mg and placebo will also be shown addressing the 
secondary estimand.
The model reduction in the multiple imputation model has been clarified further in the “Multiple 
imputation approach using retrieved subjects (RD-MI)” and the “Jump to reference multiple 
imputation approach (J2R-MI)”.
3.2
Changes applied across STEP trials
x
It has been added that the secondary estimand will cover all effect-related objectives
1.0
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
Final
EudraCT No.: 2017-003414-10
Page:
28 of 30
x
The sample size calculation has been updated to include the power for change in IWQOL-
Lite PF score based on results from NN9536-4153 and NN9924-4233 (4373/4374)
x
The supportive secondary endpoint “Body weight reduction  20% from baseline at week 0” 
was added
x
The supportive secondary endpoint “pain/discomfort domain score” was replaced by 
“physical domain score” in agreement with the final version of the 20 item version of 
IWQoL-Lite for CT
x
Units for PAI-1 corrected to AU/mL (4373/4374/4375)
x
Analyses for lipids and FPG updated to include the unit: “mmol/L”
x
Analyses for fasting serum insulin updated to include the unit: “pmol/L”
x
It was clarified that subjects in the FAS/SAS will be evaluated “as randomised”/“as treated”
x
In the text describing that “In general, the on-treatment period will therefore be from the 
date of first trial product administration to date of last trial product administration” the 
following has been added “(+14 days)” to emphasize that the lag-time after last trial product 
administration is included in the on-treatment period
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
All AEs will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) coding
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 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 
model cannot be fit due to inadequate numbers of retrieved subjects in one or more groups
x
It is clarified that if no post-baseline LAO-OT exist, then LAO-OT will be the baseline 
value and the timing of LAO-OT will be the first interval
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
The rational for the changed TP-MI procedure is as follows: “To confirm the 
robustness of superiority conclusions using a tipping point analysis, we believe that 
a 2-way tipping point analysis represents the real-world situation for missing data 
from the both treatment arms (semaglutide and placebo). We would like to see 
departures from the treatment difference by varying both treatment arms rather than 
only adding a penalty to the active treatment arm (semaglutide). Additionally, please 
1.0
.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
Final
EudraCT No.: 2017-003414-10
Page:
29 of 30
include interpretations for the varying scenarios and how likely they would be seen 
in a real-world setting.” (from FDA response letter 17 May 2018).
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 % weight change only when % weight 
change 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
It has been clarified for fasting serum insulin that 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.
x
It has been added in the footnote to Table 4 that the responder definition value is 20 for 
IWQoL-Lite for CT physical function domain (5-items) score
x
It is specified that, for the following assessments, a time-point is considered ‘on-treatment’ 
if any dose has been administered within the prior 2 weeks (14 days):
o
all effect assessments and for safety laboratory assessments, physical examination,
and pulse
x
It is specified that, for the following assessments, a time-point is considered ‘on-treatment’ 
if any dose has been administered within the prior 7 weeks (49 days):
o
adverse events, hypoglycaemic episodes (STEP 2 only), adjudicated events, ECG,
eye examination, antibodies
1.0
.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 May 2020
Novo Nordisk
Trial ID: NN9536-4374
Version:
2.0
UTN: U1111-1200-8148
Status:
Final
EudraCT No.: 2017-003414-10
Page:
30 of 30
4
References
1. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6.
2. 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.
1.0
.
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
Novo Nordisk
Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
1 of 7
Clinical Trial Report
Trial ID: NN9536-4374 (STEP 2)
MedDRA searches within safety focus areas
Author
Novo Nordisk
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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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:
19 May 2020
Novo Nordisk
Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
2 of 7
Table of contents
Page
Table of contents.........................................................................................................................................2
List of abbreviations and definitions of terms............................................................................................3
1
MedDRA searches for safety focus areas in project NN9536 .............................................................4
2
Abuse and misuse.................................................................................................................................4
3
Acute renal failure ...............................................................................................................................4
4
Allergic reactions .................................................................................................................................4
5
Cardiovascular disorders.....................................................................................................................4
6
Drug-related hepatic disorders............................................................................................................5
7
Gallbladder-related disorders .............................................................................................................5
8
Gastrointestinal disorders....................................................................................................................5
9
Injection site reactions .........................................................................................................................5
10
Malignant tumours ..............................................................................................................................5
11
Medication errors ................................................................................................................................6
12
Neoplasms ............................................................................................................................................6
13
Overdose...............................................................................................................................................6
14
Pancreatitis...........................................................................................................................................6
15
Psychiatric disorders............................................................................................................................7
16
Rare events...........................................................................................................................................7
17
Retinal disorders..................................................................................................................................7
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Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
Novo Nordisk
Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
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
1.0
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CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
Novo Nordisk
Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
4 of 7
1
MedDRA searches for safety focus areas in project NN9536
The MedDRA search strings in this document (ordered alphabetically) were used for the NN9536
submission documents. The same search strings were used for the STEP 1:4 clinical trial reports. 
The MedDRA version used was 22.1.
2
Abuse and misuse
Custom query (NNMQ Abuse and Misuse):
!
SMQ Drug abuse and dependence, narrow terms only
!
HLT Intentional product misuses 
!
Additional PTs: 
o
Poisoning deliberate
o
Intentional dose omission
o
Performance enhancing product use
o
Completed suicide
o
Intentional self-injury
o
Suicide attempt
o
Assisted suicide
o
Suspected suicide attempt
o
Suspected suicide.
3
Acute renal failure
SMQ Acute renal failure, narrow terms only
4
Allergic reactions
Custom Query (NNMQ Allergic reactions) – only narrow terms from the following:
!
SMQ Anaphylactic reaction 
!
SMQ Angioedema 
!
SMQ Severe cutaneous adverse reactions 
!
SMQ Anaphylactic/anaphylactoid shock conditions 
!
SMQ Hypersensitivity
5
Cardiovascular disorders
Custom query (NNMQ Cardiovascular disorders). Broad and narrow terms from the following:
!
SMQ Central nervous system vascular disorders 
!
SMQ Vasculitis 
1.0
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Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
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Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
5 of 7
!
SMQ Ischaemic heart disease 
!
SMQ Cardiac arrhythmias 
!
SMQ Cardiac failure 
!
SMQ Cardiomyopathy 
!
SMQ Embolic and thrombotic events 
!
SMQ Shock 
!
SMQ Torsade de pointes/QT prolongation
6
Drug-related hepatic disorders
SMQ Drug related hepatic disorders - comprehensive search
7
Gallbladder-related disorders
Custom query (NNMQ Gallbladder-related disorders). Narrow terms from the following:
!
SMQ Functional, inflammatory and gallstone related biliary disorders
!
SMQ Infectious biliary disorders
8
Gastrointestinal disorders
Custom query (NNMQ Gastrointestinal disorders SOC):
!
SOC Gastrointestinal disorders, primary terms only
9
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 
10 Malignant tumours
SMQ Malignant tumours
1.0
.
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
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Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
6 of 7
11 Medication errors
SMQ Medication errors.
12 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
13 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
14 Pancreatitis
Custom query (NNMQ Pancreatitis), narrow terms from the following:
!
SMQ Acute pancreatitis
!
HLT Acute and chronic pancreatitis, primary and secondary terms
1.0
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CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
19 May 2020
Novo Nordisk
Trial ID: NN9536-4374 (STEP 2)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
7 of 7
15 Psychiatric disorders
Custom query: 
!
SOC Psychiatric disorders, primary terms only 
16 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
17 Retinal disorders
Custom query (NNMQ Retinal disorders and visual impairment):
!
SMQ Retinal disorders, narrow terms only 
!
HLT Visual impairment and blindness (excl colour blindness), primary terms only
1.0
.
CONFIDENTIAL