Effect and Safety of Semaglutide 2.4 mg Once-weekly on Weight Management in Subjects With Overweight or Obesity.
Phase: PHASE3
Conditions: Overweight, Obesity, Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04251156 
Sponsor trial ID: 
NN9536-4379 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly on 
weight management in subjects with overweight or obesity 
Document date: 
06 January 2021 
*Document date refers to the date on which the document was most recently updated. 
 
 

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Protocol
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly on weight management 
in subjects with overweight or obesity
Substance name: semaglutide
Universal Trial Number: U1111-1212-2189
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 No unpublished information contained herein may be 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.
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 No unpublished information contained herein may be 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 summary of changes table
DOCUMENT HISTORY
Document version
Date
Applicable in countries 
Protocol version 6.0
06 January 2021
For all countries
Protocol version 5.0
17 February 2020
For all countries
Original protocol version 4.0
16 December 2019
For all countries
Protocol version 6.0 (06 January 2021)
Overall rationale for preparing protocol, version 6.0:
The rationale for preparing the protocol amendment is to correct information in for instance the 
flowchart (see all changes below) in order to avoid misunderstanding of the trial procedures. This
amendment is considered non-substantial.
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Section # and name
Description of change
Brief rationale
Synopsis
The layout of how inclusion criteria 
is changed (no changes to the actual 
inclusion criteria).
Clarification of previous presentation 
of inclusion criteria.
Section 2 Flowchart
Removal of “X”es in headers for 
“Body measurements”, “Vital Signs” 
and “Administration of trial 
product”.
Correction of mistake.
Section 2 Flowchart
Addition of “X”es for IWRS.
Correction of mistake.
Section 2 Flowchart
Reference to section 9.4.3, not 9.4.2, 
for “Vital Signs”.
Correction of mistake.
Section 2 Flowchart
“X” removed at V18 for PK diary.
Correction of mistake.
Section 2 Flowchart
Correction of “drink” to “liquid” in 
footnote f) specifying fasting at V19.
Correction of misleading phrasing.
Section 6.1 Inclusion criteria
The layout of how inclusion criteria 
is changed (no changes to the actual 
inclusion criteria).
Clarification of previous presentation 
of inclusion criteria.
Section 7.1.2 Diet and physical 
activity counselling
Precision of interval between 
counselling.
Clarification of previous statement.
Appendix 5 Contraceptive guidance 
and collection of pregnancy 
information
Precision of the definition of women 
of childbearing potential.
Update of protocol template text has 
occurred since last protocol version.
Appendix 10
Deletion of the China-specific 
exclusion criterion regarding females 
of childbearing potential.
To be aligned with ICH M3 and the 
uniform standard of a global trial.
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Table of Contents   
Page
Protocol amendment summary of changes table...........................................................................................2 
Table of Contents..............................................................................................................................................4 
1 
Synopsis......................................................................................................................................................7 
2 
Flowchart .................................................................................................................................................11 
3 
Introduction.............................................................................................................................................16 
3.1 
Trial rationale...............................................................................................................................16 
3.2 
Background..................................................................................................................................17 
3.2.1 
Semaglutide ...............................................................................................................17 
3.2.2 
Trial population..........................................................................................................17 
3.3 
Benefit-risk assessment................................................................................................................18 
3.3.1 
Benefits......................................................................................................................18 
3.3.2 
Risks and precautions ................................................................................................18 
3.3.3 
Conclusion on benefit-risk profile .............................................................................20 
4 
Objectives and endpoints........................................................................................................................20 
4.1 
Primary and secondary objective(s).............................................................................................20 
4.1.1 
Primary objective.......................................................................................................20 
4.1.2 
Secondary objectives .................................................................................................20 
4.2 
Primary and secondary endpoints ................................................................................................21 
4.2.1 
Primary endpoint........................................................................................................21 
4.2.2 
Secondary endpoints..................................................................................................21 
4.2.2.1 
Confirmatory secondary endpoints .....................................................21 
4.2.2.2 
Supportive secondary endpoints..........................................................22 
5 
Trial design ..............................................................................................................................................24 
5.1 
Overall design..............................................................................................................................24 
5.2 
Subject and trial completion ........................................................................................................25 
5.3 
End of trial definition...................................................................................................................25 
5.4 
Scientific rationale for trial design...............................................................................................25 
5.5 
Justification for dose....................................................................................................................25 
6 
Trial population.......................................................................................................................................26 
6.1 
Inclusion criteria ..........................................................................................................................26 
6.2 
Exclusion criteria.........................................................................................................................27 
6.3 
Randomisation criteria.................................................................................................................29 
6.4 
Lifestyle restrictions ....................................................................................................................29 
6.4.1 
Meals and dietary restrictions....................................................................................29 
6.4.2 
Caffeine and tobacco .................................................................................................30 
6.5 
Screen failures..............................................................................................................................30 
7 
Treatments...............................................................................................................................................30 
7.1 
Treatments administered..............................................................................................................30 
7.1.1 
Medical devices .........................................................................................................32 
7.1.2 
Diet and physical activity counselling .......................................................................33 
7.2 
Dose modification........................................................................................................................34 
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7.3 
Method of treatment assignment..................................................................................................34 
7.4 
Blinding .......................................................................................................................................34 
7.5 
Preparation/Handling/Storage/Accountability.............................................................................35 
7.6 
Treatment compliance..................................................................................................................36 
7.7 
Concomitant medication..............................................................................................................36 
7.7.1 
Rescue criteria............................................................................................................36 
7.7.2 
Rescue medication.....................................................................................................36 
7.7.3 
Concomitant medication criteria................................................................................37 
7.8 
Treatment after the end of the trial ..............................................................................................38 
8 
Discontinuation/Withdrawal criteria ....................................................................................................38 
8.1 
Discontinuation of trial treatment ................................................................................................38 
8.1.1 
Temporary discontinuation of trial treatment ............................................................39 
8.2 
Withdrawal from the trial.............................................................................................................39 
8.2.1 
Replacement of subjects ............................................................................................40 
8.3 
Lost to follow-up .........................................................................................................................40 
9 
Trial assessments and procedures .........................................................................................................41 
9.1 
Efficacy assessments....................................................................................................................42 
9.1.1 
Body measurements...................................................................................................42 
9.1.2 
Clinical outcome assessments....................................................................................42 
9.1.3 
Self-measured plasma glucose...................................................................................43 
9.1.4 
Clinical efficacy laboratory assessments ...................................................................43 
9.2 
Adverse events.............................................................................................................................43 
9.2.1 
Time period and frequency for collecting AE and SAE information ........................44 
9.2.1.1 
Event for adjudication.........................................................................46 
9.2.2 
Method of detecting AEs and SAEs ..........................................................................46 
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 
Hypoglycaemic episodes ...........................................................................................47 
9.2.7 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE........................................................................................................................47 
9.2.8 
Pregnancies and associated adverse events................................................................48 
9.2.9 
Medical device incidents (including malfunctions)...................................................48 
9.2.10 
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 ........................................................................................................51 
9.4.6 
Clinical safety laboratory assessments.......................................................................52 
9.4.7 
Immunogenicity assessments.....................................................................................52 
9.5 
Pharmacokinetics.........................................................................................................................53 
9.6 
Pharmacodynamics ......................................................................................................................53 
9.7 
Genetics .......................................................................................................................................53 
9.8 
Biomarkers...................................................................................................................................53 
9.9 
Severe hypersensitivity................................................................................................................53 
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10 Statistical considerations ........................................................................................................................53
10.1
Sample size determination...........................................................................................................54
10.2
Definition of analysis sets............................................................................................................56
10.3
Statistical analyses .......................................................................................................................57
10.3.1
Primary endpoint........................................................................................................57
10.3.2
Secondary endpoints..................................................................................................63
10.3.2.1
Confirmatory secondary endpoints .....................................................63
10.3.2.2
Supportive secondary endpoints..........................................................65
10.3.3
Explorative statistical analysis for pharmacogenetics and biomarkers......................67
10.3.4
Other analyses............................................................................................................67
10.4
Pharmacokinetic and/or pharmacodynamic modelling................................................................67
11 Appendices...............................................................................................................................................68
Abbreviations and Trademarks ..........................................................................................68
Clinical laboratory tests .......................................................................................................71
Trial governance considerations .........................................................................................74
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
and reporting...........................................................................................................................................84
Contraceptive guidance and collection of pregnancy information...................................91
Technical complaints: Definition and procedures for recording, evaluation, follow-
up and reporting......................................................................................................................................95
Retention of human biosamples ..........................................................................................96
Hypoglycaemic episodes.......................................................................................................97
Monitoring of calcitonin.....................................................................................................101
Country-specific requirements..........................................................................................104
Protocol amendment history..............................................................................................106
12 Reference................................................................................................................................................107
Attachment I Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments
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1
Synopsis
Rationale:
The 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. In 
China, the prevalence of overweight and obesity is estimated to be 25.7% and 22.8%, and 5.0% and 
5.5% for males and females, respectively, according to WHO criteria8. Obesity is associated with
increased risk of a variety of comorbidities including hyperglycaemia, type 2 diabetes (T2D), 
hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis, osteoarthritis, urinary 
incontinence, non-alcoholic steatohepatitis, cardiovascular diseases, certain types of cancer and risk 
of early death9-20. Moreover, obesity adversely affects physical and mental health and reduces 
health related quality of life21, 22. Obesity is also associated with decreased cardiorespiratory fitness, 
which also increases the risk of cardiovascular diseases and all-cause mortality23.
The risk of obesity-related complications and comorbidities increases with increasing body mass 
index (BMI), and a weight loss of 5-10% has significant health benefits in terms of slowing 
progression to T2D24-27. Furthermore, a weight loss of 5-10% improves many other obesity related 
comorbidities as well as physical symptoms and quality of life28-35. Finally, studies suggest a 
beneficial impact of weight loss on cardiovascular risk and mortality in both people with diabetes 
and obesity36-38.
People with T2D often have multiple unmet medical needs related to cardiovascular risks, including 
hypertension and dyslipidaemia. It has been consistently demonstrated that weight loss in people 
with T2D has a beneficial impact not only on glycaemic control, but also on other cardiovascular 
risk markers39.
The present 44-week trial is designed to compare the effect and safety of semaglutide s.c. 2.4 mg 
once weekly versus semaglutide placebo as an adjunct to a reduced-calorie diet and increased 
physical activity in subjects with obesity or with overweight and weight-related comorbidities. The 
trial is a multiregional clinical trial (MRCT) including China and other countries. In the trial, 
subjects with obesity or overweight, and with and without T2D will be included. The subjects with 
T2D will be allowed to be treated with 0-3 oral anti diabetes drugs (OADs), but no insulin treatment 
is allowed. 
Objectives and endpoints
Primary objective 
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity with and without T2D on body weight.
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Key secondary objectives
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity with and without T2D on:
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments (COAs)
x
Glucose metabolism
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo as an adjunct to a reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity with and without T2D.
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 44 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) (“treatment policy” estimand). The 
estimand will cover all effect-related objectives.
Primary endpoint
The primary endpoints addressing the primary objective:
x
Change from baseline at week 0 to week 44 in body weight (%)
x
Subjects who after 44 weeks achieve (yes/no):
o
Body weight reduction ≥ 5% from baseline at 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.
Subjects who after 44 weeks achieve (yes/no):
x
Body weight reduction ≥ 10% from baseline at week 0
x
Body weight reduction ≥ 15% from baseline at week 0
Change from baseline at week 0 to week 44 in:
x
Waist circumference (cm)
x
Systolic blood pressure (mmHg)
x
Physical functioning score (SF-36)
x
Physical function domain (5-items) score (IWQoL-Lite for CT)
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Overall design:
This is a 44-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre, multiregional clinical trial (MRCT) comparing semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo in subjects with obesity or with overweight and weight-related comorbidities.
Key inclusion criteria
x
Male or female, age ≥ 18 years at the time of signing informed consent
x
History of at least one self-reported unsuccessful dietary effort to lose body weight
For subjects without T2D at screening:
x
Body mass index (BMI) of 
o
≥ 30 kg/m2
o
≥ 27 kg/m2 with the presence of at least one of the following weight-related 
comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep 
apnoea or cardiovascular disease
For subjects with T2D at screening:
x
Diagnosed with T2D ≥ 180 days prior to the day of screening
x
Treated with either:
o
diet and exercise alone or
o
stable treatment (same drug(s), dose and dosing frequency) for at least 60 days prior 
to the day of screening with up to 3 oral antidiabetic medications alone or in any 
combination (metformin, α-glucosidase inhibitor (AGI), SU, glinides, SGLT2i or 
glitazone) according to local label
x
HbA1c 7.0-10.0% (53-86 mmol/mol) (both inclusive)
x
BMI ≥ 27 kg/m2
Key exclusion criteria
x
A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
For subjects without T2D at screening:
x
HbA1c ≥ 6.5% (48 mmol/mol) as measured by the central laboratory at screening 
For subjects with T2D at screening:
x
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 201239 by the central laboratory at screening
x
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
fundus examination performed within the past 90 days prior to screening or in the period 
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between screening and randomisation. Pharmacological pupil-dilation is a requirement 
unless using a digital fundus photography camera specified for non-dilated examination.
Number of subjects:
Approximately 625 subjects will be screened to achieve 375 subjects randomly assigned to trial 
product.
Planned number of subjects to be randomised in China and Hong Kong is 300.
A sub population of 20% - 30% (75-113 subjects) will have T2D at screening, aiming to be evenly 
distributed between all allocated countries.  
Treatment groups and duration:
The total trial duration for the individual subject will be approximately 52 weeks. The trial includes 
a screening period of approximately 1 week. Eligible subjects fulfilling all randomisation criteria at 
visit 2 will be randomised in a 2:1 manner to receive either semaglutide s.c. 2.4 mg once-weekly or 
semaglutide placebo as an adjunct to a reduced-calorie diet and increased physical activity. Subjects 
will in the first 16 weeks be dose escalated every 4 weeks from 0.25 mg once-weekly until the 
target dose of 2.4 mg is reached. The treatment continues until the ‘end of treatment’ visit (week 
44) followed by a 7 weeks follow-up period.
The following trial products will be supplied by Novo Nordisk A/S 
x
Semaglutide B 0.68 mg/mL PDS290 and semaglutide placebo, solution for injection, 1.5 mL 
PDS290 pen-injector
x
Semaglutide B 1.34 mg/mL PDS290, and semaglutide placebo, solution for injection, 1.5 
mL PDS290 pen-injector 
x
Semaglutide B 1.34 mg/mL PDS290, and semaglutide placebo, solution for injection, 3 mL 
PDS290 pen-injector 
x
Semaglutide B 2.27 mg/mL PDS290, and semaglutide placebo, solution for injection, 3 mL 
PDS290 pen-injector 
x
Semaglutide B 3.2 mg/mL PDS290, and semaglutide placebo, solution for injection, 3 mL 
PDS290 pen-injector
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3
Introduction
3.1
Trial rationale
The prevalence of obesity has been increasing during the last 30 years1 and globally, more than 600 
million people have obesity2. In China, the prevalence of overweight and obesity has increased 
during the past decade. Over the 20 year period from 1991 to 2011, the prevalence of obesity in 
China increased from 2.88% to 11.8% among men and from 4.55% to 11.0% among women 
according to China obesity criteria (BMI ≥ 28 kg/m2). Recently published data showed that from 
1980 to 2015 the prevalence of obesity increased from 0.33% to 5.02% among men and from 0.9% 
to 5.51% among women according to WHO obesity criteria (BMI ≥ 30 kg/m2)8, 40. Obesity is 
associated with an increased risk of developing type 2 diabetes (T2D)3, 4, dyslipidaemia, 
hypertension5, cardiovascular disease, obstructive sleep apnoea6, non-alcoholic fatty liver 
disease/non-alcoholic steatohepatitis (NAFLD/NASH)7, urinary incontinence9, several types of 
cancers10, and increased mortality41, 42. In addition to these pathophysiologic changes, individuals 
with obesity experience reduced health-related quality of life including physical function13-15. In 
recognition of the seriousness of obesity, several professional associations and organisations 
worldwide16-18 now classify obesity as a disease.
The risk of obesity-related complications and comorbidities increases with increasing body mass 
index (BMI), and even a body weight loss of 5–10% has been shown to have significant health 
benefits in individuals with obesity in terms of decreasing the risk of developing T2D19, improving 
hypertension20, dyslipidaemia21, NAFLD/NASH22 and reducing cardiovascular death23. In addition, 
improvements in patient-reported health-related quality of life including physical function have 
been demonstrated with body weight loss24. Therefore, achieving and maintaining body weight loss 
in individuals with obesity is crucial. Current standard of care consists of lifestyle counselling 
including reduced-calorie diets and increased physical activity. However, with this first line 
treatment for obesity only one in five individuals successfully achieves a significant long-term body 
weight loss25.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin and inhibitory effect on glucagon secretion from the pancreatic islets 26, 27. In 
subjects with T2D who have a decreased incretin effect28 the insulinotropic action of GLP-1 and 
thus, the ability to lower BG levels, is preserved when GLP-1 is administered at supraphysiological 
levels29. In addition, supraphysiological levels of GLP-1 induce reduction in body weight30. This 
makes GLP-1 an appropriate treatment for obesity in subjects with T2D. GLP-1 is a physiological 
regulator of appetite31 and GLP-1 receptors are present in several areas of the brain involved in 
appetite regulation. Semaglutide is a long-acting GLP-1 analogue with a half-life of 160 hours, 
making it suitable for once weekly dosing32.
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3.2
Background
3.2.1
Semaglutide
Semaglutide is the next generation glucagon-like-peptide (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 dosing33. GLP-1 is a physiological regulator of appetite and GLP-1
receptors are present in several areas of the brain involved in appetite regulation31.
A 52-week phase 2 dose-finding trial within weight management (NN9536-4153) has recently been 
completed. A total of 957 randomised subjects with obesity (without diabetes) were exposed to 
semaglutide (n=718), liraglutide 3.0 mg (n=103) or placebo (n=136). In this trial, an overall 
monotone dose-dependent weight loss was observed across the 5 semaglutide doses tested (0.05 to 
0.4 mg once-daily). The estimated weight loss at week 52 was 13.8 % at the highest dose tested (0.4 
mg once-daily) compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone43.
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 HbA1c of up to 1.85 percentage-point) 
after 30 weeks with a safety and tolerability profile comparable to other GLP-1 RA34, 36, 37, 44, 45. 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.
Clinical33-38 and non-clinical data46 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)43 and any updates hereof.
3.2.2
Trial population 
The trial population will consist of subjects with obesity or with overweight and weight-related 
comorbidities. In addition, a group of subjects with obesity or overweight, and T2D will be 
included. The group of subjects with T2D will be allowed to be on 0-3 OADs, but not on insulin 
treatment. In total, these subjects represent a clinically relevant population for pharmacotherapeutic 
weight management, and are likely to benefit from weight reduction. Inclusion of subjects with T2D 
allows for bridging to the dedicated trial for subjects with T2D in the global phase 3a programme 
(NN9536-4374).
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First line treatment in weight management should always be lifestyle modification through a 
healthier nutrition and increased physical activity. Thus, only subjects who have tried but failed a 
dietary weight loss intervention will be included in accordance with regulatory guidelines47,48.
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 loss was 
accompanied by a consistent improvement in the weight-related comorbidities, indicated by 
cardiovascular risk factors, lipid profile and glycaemic factors, as well as improvements in clinical 
outcome assessments.
In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site and counselling by a dietician or a similar qualified healthcare professional, all of 
which will most likely result in intensified weight management.
3.3.2
Risks and precautions
The sections below describe identified and potential risks associated with semaglutide treatment. 
For classification and further details of the risks, please refer to the current version of the IB43 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.
x
Gastrointestinal adverse events
o
Consistent with findings with other GLP-1 RAs, the most frequently reported 
adverse events (AE) in clinical trials with semaglutide were gastrointestinal (GI) 
AEs. A low starting dose and dose escalation steps will be implemented in the trial to 
mitigate the risk of gastrointestinal AEs.
x
Cholelithiasis
o
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. 
x
Acute pancreatitis
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o
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.
x
Hypoglycaemia (in combination with SU and/or insulin) (identified for T2D patients) 
o
There is a low risk of hypoglycaemic episodes when semaglutide is used as 
monotherapy. Subjects treated with semaglutide in combination with a SU or insulin 
has an increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered 
by reducing the dose of SU when initiating treatment with semaglutide (or insulin if 
subjects have been allowed to use insulin as rescue therapy).
x
Diabetic retinopathy complication (identified for T2D patients)
o
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 randomisation 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).
x
Medullary thyroid cancer (MTC) (based on non-clinical data)
o
Expected proliferative thyroid C-cell changes were seen in the mouse and rat 
carcinogenicity studies after daily exposure to semaglutide for 2 years. No 
hyperplasia was observed in monkeys after 52 weeks exposure up to 13-fold above 
the clinical plasma exposure at 2.4 mg/week. In clinical trials with semaglutide, there 
have been no clinically relevant changes in calcitonin levels. The C-cell changes in 
rodents are mediated by the GLP-1 receptor, which is not expressed in the normal 
human thyroid. Accordingly, the risk of GLP-1 receptor-mediated C-cell changes in 
humans is considered to be low. However, as a precaution, 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. 
x
Pancreatic cancer 
o
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 (EMA). As a precaution, subjects with a history of 
malignant neoplasms within the past 5 years prior to screening will be excluded from 
the trial. 
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x
Allergic reactions
o
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. 
x
Pregnancy and fertility (based on non-clinical data)
o
Studies in animals have shown reproductive toxicity. There are limited data from the 
use of semaglutide in pregnant women. Therefore, semaglutide should not be used 
during pregnancy. Exclusion and discontinuation criteria related to pregnancy have 
been implemented in the trial.
3.3.3
Conclusion on benefit-risk profile
Necessary precautions have been implemented in the design and planned conduct of the trial in 
order to minimise the risks and inconveniences of participation in the trial. The safety profile for 
semaglutide generated from the clinical and non-clinical development programme has not revealed 
any safety issues that would prohibit administration of semaglutide s.c. 2.4 mg once-weekly. The 
results of the phase 2 trial (NN9536-4153) indicate that semaglutide will provide a clinically 
meaningful weight loss.
In conclusion, the potential risk to the subjects in this trial is considered low and outweighed by the 
anticipated benefits that semaglutide would provide subjects included in the trial. 
More detailed information about the known and expected benefits and risks and expected AEs of 
semaglutide s.c. may be found in the IB43 and any updates hereof.
4
Objectives and endpoints
4.1
Primary and secondary objective(s)
4.1.1
Primary objective
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and with or without 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 as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity and with or without T2D on:
x
Cardiovascular risk factors 
x
Clinical Outcome Assessments (COAs)
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x
Glucose metabolism
x
Glycaemic status
x
Use of medication for hypertension and dyslipidaemia
x
Use of oral antidiabetic medication (apply to subjects with T2D at screening)
x
Liver indices
x
Treatment discontinuation
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo as an adjunct to a reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity and with or without T2D.
Primary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 44 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) (“treatment policy” estimand). The 
estimand will cover all effect-related objectives.
Secondary estimand
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 44 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) (“hypothetical” estimand). The estimand will cover the primary objective.
4.2
Primary and secondary endpoints 
4.2.1
Primary endpoint
The primary endpoints addressing the primary objective:
x
Change from baseline at week 0 to week 44 in body weight (%)
x
Subjects who after 44 weeks achieve (yes/no):
o
Body weight reduction ≥ 5% from baseline at 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
x
Subjects who after 44 weeks achieve (yes/no): 
o
Body weight reduction ≥ 10% from baseline at week 0
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o
Body weight reduction ≥ 15% from baseline at week 0
x
Change from baseline at week 0 to week 44 in:
o
Waist circumference (cm)
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
Effect endpoints
The supportive secondary endpoints are used to compare effect of semaglutide s.c. 2.4 mg once 
weekly versus semaglutide placebo.
x
Change from baseline at week 0 to week 44 in:
o
Body weight (kg)
o
BMI (kg/m2)
o
HbA1c (%, mmol /mol)
o
Fasting plasma glucose (FPG) (mg/dL)
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
Short Form-36 (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
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o
IWQoL-Lite for CT 

pain/discomfort domain score 

psychosocial domain score 

total score
x
Subjects who after 44 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 
x
Change from baseline at week 0 to week 44 in:
o
Glycaemic category (normo-glycaemia, pre-diabetes, T2D)
o
Antihypertensive medication (decrease, no change, increase) 
o
Lipid-lowering medication (decrease, no change, increase)
o
Concomitant oral antidiabetic medication (decrease, no change, increase) (only apply 
to subjects with T2D at week 0)
o
Fatty liver index (FLI) score category (<30, ≥30 and <60, ≥60)
x
Subjects who from randomisation at week 0 to week 44 have permanently discontinued 
randomised trial product (yes/no)
x
Time to permanent discontinuation of randomised trial product (weeks)
Safety endpoints
x
Number of treatment emergent adverse events (TEAEs) from week 0 to week 51
x
Number of serious adverse events (SAEs) from week 0 to week 51
x
Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemia episodes (yes/no) from week 0 to week 51 (only applies to subjects with 
T2D at week 0)
x
Change from baseline at week 0 to week 44 in:
o
Pulse (bpm)
o
Amylase (U/L) 
o
Lipase (U/L) 
o
Calcitonin (ng/L) 
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5
Trial design
5.1
Overall design
This is a 44-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre, multiregional clinical trial (MRCT) comparing semaglutide s.c. 2.4 mg once-weekly with 
semaglutide placebo in subjects with obesity or with overweight and weight-related comorbidities.
The trial includes a screening visit to assess the subject’s eligibility followed by visits/phone 
contacts every 2nd week during dose escalation. From week 20, visits/phone contacts will take place 
every 4th week for the remaining maintenance period until end of treatment (week 44). A follow-up
visit (‘End of trial’) for safety assessments is scheduled 7 weeks after end of treatment, to account 
for the exposure to the long half-life of semaglutide
The trial design is outlined in Figure 5-1.
Figure 5-1
A schematic diagram of the trial design, with the duration of the trial periods 
including follow-up period.
Eligible subjects fulfilling all randomisation criteria at visit 2 will be randomised in a 2:1 manner to 
receive either semaglutide s.c. 2.4 mg once-weekly or semaglutide placebo as an adjunct to a 
reduced-calorie diet and increased physical activity.
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At the time of randomisation subjects will be stratified according to the following categories:
x
Subjects without T2D or
x
Subjects with T2D 
To mitigate SU or glinide induced hypoglycaemia, subjects treated with SU or glinide (either alone 
or in combination with other OADs) will be asked to reduce the SU or glinide dose by 
approximately 50% at the discretion of the investigator, from randomisation. 
5.2
Subject and trial completion
Approximately 625 subjects will be screened to achieve 375 subjects randomly assigned to trial 
product.
Planned number of subjects to be randomised in Region China is 300.
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 44 weeks with an additional 7 weeks follow-up (without trial 
product). The 7 weeks follow-up period is included to account for the exposure and long half-life of 
semaglutide. A 44-week treatment duration (including 28 weeks on target dose) is considered 
sufficient to assess weight loss, safety and tolerability in the phase 3 weight management 
development programme.
A randomised, double-blind, placebo-controlled, multi-centre trial design is chosen to minimise bias 
in the assessment of the effect and safety of semaglutide 2.4 mg once-weekly versus semaglutide 
placebo, as an adjunct to a reduced calorie diet and increased physical activity.
5.5
Justification for dose
Results from the phase 2 dose-finding trial (NN9536-4153) showed that the semaglutide s.c. 0.4 mg 
once-daily dose was most effective in terms of weight loss while displaying an acceptable 
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tolerability profile. Using population pharmacokinetic (Pop-PK) modelling, it was estimated that a 
once-weekly maintenance dose of 2.4 mg semaglutide s.c. will result in similar Cmax at steady-state 
as that obtained by the once-daily 0.4 mg semaglutide s.c. dose in trial NN9536-4153.
A maintenance dose of 2.4 mg semaglutide s.c. once-weekly has been chosen for the phase 3 weight 
management development programme. The once-weekly dosing is anticipated to ease the burden of 
drug administration in clinical practice. Subjects will be initiated at a once-weekly dose of 0.25 mg 
and follow a fixed-dose escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 
1.7 and 2.4 mg/week), until the target dose is reached after 16 weeks.
It is well known that to mitigate gastrointestinal (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 was 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:
For subjects without T2D at screening, the following four inclusion criteria apply:
1. Informed consent obtained before any trial-related activities. Trial-related activities are 
any procedures that are carried out as part of the trial, including activities to determine 
suitability for the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent 
3. Body mass index (BMI) of
a.
≥ 30 kg/m2
b. ≥ 27 kg/m2 with the presence of at least one of the following weight-related 
comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive 
sleep apnoea or cardiovascular disease
4. History of at least one self-reported unsuccessful dietary effort to lose body weight
For subjects with T2D at screening, the following five inclusion criteria apply:
1. Informed consent obtained before any trial-related activities. Trial-related activities are 
any procedures that are carried out as part of the trial, including activities to determine 
suitability for the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent 
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3. BMI ≥ 27 kg/m2
4. T2D diagnosis including:
x
Diagnosed with T2D ≥ 180 days prior to the day of screening
x
Treated with either:
o
diet and exercise alone or 
o
stable treatment (same drug(s), dose and dosing frequency) for at least 60 days 
prior to the day of screening with up to 3 oral antidiabetic medications alone or 
in any combination (metformin, α-glucosidase (AGI), SU, glinides, SGLT2i or 
glitazones) according to local label
x
HbA1c 7.0-10.0% (53-86 mmol/mol) (both inclusive) as measured by the central 
laboratory at screening 
5. History of at least one self-reported unsuccessful dietary effort to lose body weight
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
For country specific requirements, see Appendix 10.
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:
Glycaemia related:
For subjects without T2D, the following four exclusion criteria apply:
1. HbA1c ≥ 6.5% (48 mmol/mol) as measured by the central laboratory at screening 
2. History of type 1 or type 2 diabetes mellitus 
3. Treatment with glucose-lowering agent(s) within 90 days before screening
4. Treatment with a GLP-1 receptor agonist within 180 days before screening
For subjects with T2D, the following five exclusion criteria apply:
5. Treatment with any medication for the indication of diabetes other than stated in the 
inclusion criteria within the past 60 days prior to the day of screening
6. 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
7. Treatment with a GLP-1 receptor agonist within 180 days prior to screening
8. Renal impairment measured as 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 201239 by the central laboratory at 
screening
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9. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
fundus examination performed within the past 90 days prior to screening or in the period 
between screening and randomisation. Pharmacological pupil-dilation is a requirement 
unless using a digital fundus photography camera specified for non-dilated examination. 
The following criteria apply to all subjects.
Obesity related:
10. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
11. Treatment with any medication for the indication of obesity within the past 90 days 
before screening
12. 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
13. 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:
14. History of major depressive disorder within 2 years before screening 
15. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder)
16. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15 at screening 
17. A lifetime history of a suicidal attempt
18. Suicidal behaviour within 30 days before screening 
19. 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:
20. Presence of acute pancreatitis within the past 180 days prior to the day of screening
21. History or presence of chronic pancreatitis
22. Calcitonin ≥ 100 ng/L as measured by the central laboratory at screening
23. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma
24. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of  < 
15 ml/min/1.73 m2 as defined by KDIGO 201239 by the central laboratory at screening 
(only subjects without T2D at screening)
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25. 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
26. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina 
or transient ischaemic attack within the past 60 days prior to screening
27. Subject presently classified as being in New York Heart Association (NYHA) Class IV
28. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in 
the opinion of the investigator 
29. Known or suspected abuse of alcohol or recreational drugs
30. Known or suspected hypersensitivity to trial product(s) or related products
31. Previous participation in this trial. Participation is defined as signed informed consent 
32. Participation in another clinical trial within 90 days before screening
33. Other subject(s) from the same household participating in any semaglutide trial
34. 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. 
35. 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.
6.3
Randomisation criteria
Subjects are eligible to be randomised in the trial only if all of the following criteria apply:
1. PHQ-9 score of < 15 at randomisation.
2. No suicidal behaviour in the period between screening and randomisation.
3. 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.
Subjects 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
x
Subjects must attend the visits fasting according to the flowchart.
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x
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. 
x
For China: At the ‘end of trial’ visit only 2 hours of fasting is required prior to the anti-
semaglutide antibody sampling.
x
If the subject is not fasting as required, the subject should be called in for a new visit within 
the visit window to have the fasting procedures done. Procedures requiring subject to fast 
include blood sampling of FPG, fasting serum insulin and lipids.
6.4.2
Caffeine and tobacco
x
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 
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
x
All trial products listed in Table 7-1 are considered investigational medicinal products 
(IMP).
x
Trial product must only be used, if it appears clear and colourless.
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Table 7-1
Trial products provided by Novo Nordisk A/S
x
Dose escalation of semaglutide/semaglutide placebo should take place during the first 16 
weeks after randomisation as described in Table 7-2. All subjects should aim at reaching the 
recommended target dose of semaglutide 2.4 mg once-weekly or the corresponding volume 
of semaglutide placebo. 
x
If a subject does not tolerate the designated target dose (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 trail product, as per the investigator’s discretion. It is recommended that the 
subject makes at least one attempt to re-escalate to the designated target dose, as per the 
investigator’s discretion. 
x
It is recommended that the investigator consults Novo Nordisk in case of persistent 
deviations from the planned escalation and maintenance regimen. 
x
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.
Trial product name
Dosage form
Delivery device
Dosing 
instructions
Route of 
administration
Semaglutide B 0.68 mg/mL 
PDS290  
Solution for 
injection
1.5 mL PDS290
pre-filled pen-injector
Once-
weekly
s.c.
Semaglutide B 1.34 mg/mL 
PDS290  
Semaglutide placebo 
PDS290
Semaglutide B 1.34 mg/mL 
PDS290  
3 mL PDS290 
pre-filled pen-injector
Semaglutide B 2.27 mg/mL 
PDS290 
Semaglutide B 3.2 mg/mL 
PDS290
Semaglutide Placebo 
PDS290
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Training in the PDS290 pen-injector
The investigator must document that training in the DFU has been given to the subjects orally and 
in writing at the first dispensing visit. Training must be repeated, during the trial at regular intervals 
in order to ensure correct use of the medical device. Training is the responsibility of the investigator 
or a delegate.
Table 7-3
Auxiliary supplies provided by Novo Nordisk A/S
Auxiliary supply
Details
Needles
Needles for pre-filled pen system. Details provided in the TMM.
Only needles provided and approved by Novo Nordisk must be used for administration 
of trial product.
Direction for use (DFU)
DFU for 3 mL PDS290 pre-filled pen injector
Not included in the dispensing unit and to be handed out separately. 
DFU for 1.5 mL PDS290 pre-filled pen injector
Not included in the dispensing unit and to be handed out separately.
BG meters 
BG meter includes lancets, test strips, control solutions and instructions. Details are 
provided in the BG meter manual.
Only subjects with T2D at screening
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 using the stairs) 
taking subject’s diabetes into account. Counselling should be done by a dietician or a similar 
qualified healthcare professional every 4th week except between V10 and V12 (every 2 weeks) 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 subjects should be encouraged to keep diary of their food intake and physical activity 
on a daily basis. 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) (see Table 7-4)
with a Physical Activity Level value of 1.349.
 ൌ ൈͳǤ͵
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Table 7-4
Equation for estimated BMR
Sex
Age
BMR (kcal/day)
Men
18-30 years
31-60 years
> 60 years
15.057 × weight at 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 ≤ 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
x
Not applicable for this trial. Please refer to Section 7.1 for description of missed dose(s). 
7.3
Method of treatment assignment
All subjects will be centrally randomised using IWRS and assigned to the next available treatment 
according to randomisation schedule. 20%-30% of trial population will be subjects with T2D at 
randomisation. Trial product will be dispensed at the trial visits summarised in the flowchart.
Randomisation will be stratified according to:
x
Subjects with T2D at randomisation
x
Subjects without T2D at randomisation
7.4
Blinding
The active drug and placebo are visually identical for the following trial products:
x
Semaglutide B 0.68 mg/mL PDS290 / Semaglutide placebo (1.5 mL pre-filled pen injector) 
x
Semaglutide B 1.34 mg/mL PDS290 / Semaglutide placebo (1.5 mL pre-filled pen-injector)
x
Semaglutide B 1.34 mg/mL PDS290 / Semaglutide placebo (3 mL pre-filled pen-injector)
x
Semaglutide B 2.27 mg/mL PDS290 / Semaglutide placebo (3 mL pre-filled pen-injector)
x
Semaglutide B 3.2 mg/mL PDS290 / Semaglutide placebo (3 mL pre-filled pen-injector) 
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the subjects’ medical record.
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Whenever the blind is broken, the person breaking the blind must print the "code break 
confirmation" notification generated by the IWRS, and sign and date the document. 
When the blind is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of blind break, the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.
7.5
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product.
Table 7-5
Trial product storage conditions
Trial product name
Storage conditions
(not-in-use)
In-use conditions
In-use time
Semaglutide B 0.68 mg/mL PDS290
Storage conditions are 
available on the trial 
product label and are 
also provided in the 
Trial Materials Manual 
(TMM). 
In-use conditions will 
be available on the trial 
product label
In-use time will be 
available on the trial 
product label
Semaglutide B 1.34 mg/mL PDS290
Semaglutide placebo PDS290
Semaglutide B 1.34 mg/mL PDS290
Semaglutide B 2.27 mg/mL PDS290 
Semaglutide B 3.2 mg/mL PDS290
Semaglutide placebo PDS290
x
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.
x
The investigator must confirm that appropriate temperature conditions have been maintained 
during transit for all trial products received (see Table 7-5) and any discrepancies are 
reported and resolved before use of the trial products.
x
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.
x
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. 
x
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.
x
The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records).
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x
Drug accountability should be performed on a pen level and must be documented in the 
IWRS.
x
The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator.
x
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. 
x
Destruction of trial products must be documented in the IWRS. 
x
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.
x
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 pharmacokinetic (PK) dosing diaries. Information about compliance and missed 
doses should be described in the subject’s medical record.
7.7
Concomitant medication
7.7.1
Rescue criteria
For subject with T2D at screening: 
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 local guidelines50
(excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues).
For a description of rescue medication, please refer to Section 7.7.2.
7.7.2
Rescue medication
For subject with T2D at screening:
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Glycaemic rescue medication, i.e. intensification of background OAD treatment or addition of new 
OADs or insulin treatment, should be implemented at the discretion of the investigator in case of 
persistent hyperglycaemia as described in Section 7.7.1.
The following guidelines should be used:
1. Rescue medication according to American Diabetes Association (ADA)/European 
Association for the Study of Diabetes (EASD)50 or local guidelines (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/EASD50 or local guideline 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 the subject is 
participating in the trial, if required according to local regulations Appendix 10.
7.7.3
Concomitant medication criteria
For all subjects:
Any medication (including over-the-counter or prescription medicines) other than the trial product 
that the subject is receiving at the time of the first visit or receives during the trial must be recorded 
along with:
x
Trade name or generic name
x
Indication
x
Dates of administration including start and stop dates
x
Dose (only to be recorded for anti-hypertensive and lipid-lowering medication)
During the trial subjects should not initiate any anti-obesity treatment (e.g. medication) which is not 
part of the trial procedures. If such treatment is initiated, the subject should be instructed to stop the 
anti-obesity treatment.
Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 9.2.
For subject with T2D at screening:
If the subject receives OADs or insulin as rescue medication, the dose must be recorded in the 
concomitant medication form.
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To mitigate SU or glinide induced hypoglycaemia, subjects treated with SU or glinide (either alone 
or in combination with other OADs) will be asked to reduce the SU or glinide dose by 
approximately 50% at the discretion of the investigator, from randomisation. 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 (270 mg/dL), the subject should intensify treatment according to the 
(ADA/EASD51 or local guidelines (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.
7.8
Treatment after the end of the trial
After the end of the trial the subject should be treated at the discretion of the investigator.
8
Discontinuation/Withdrawal criteria 
The subject may be discontinued at any time during the trial at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons.
Efforts must be made to have the subjects, who discontinue trial product, to continue in the trial.
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial.
8.1
Discontinuation of trial treatment
x
Discontinuation of trial treatment can be decided by either the investigator or the subject.
x
Subjects who discontinue trial product should continue with the scheduled visits and 
assessments to ensure continued counselling and data collection.
x
If the subject does not wish to attend the scheduled clinic visits efforts should be made to 
have the visits converted to phone contacts. However all efforts should be made to have the 
subject attend at least the ‘end of treatment’ clinic visit containing the final data collection 
of primary and confirmatory secondary efficacy endpoints, and the ‘end of trial’ visit.
x
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. Safety concern as judged by the investigator
2. Calcitonin ≥ 100 ng/L (see Appendix 9)
3. Suspicion of pancreatitis
4. Pregnancy
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5. Intention of becoming pregnant
6. 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. 3 are allowed to resume trial product 
if the Atlanta criteria52 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. 1, 4, and 5 are allowed to resume trial 
product, if the criteria are no longer met (see Section 8.1.1).
The primary reason for discontinuation of trial product must be specified in the source data at the 
time of discontinuation, and subject should continue to follow the visit and assessment schedule. A 
change in ‘treatment status’ must be made in IWRS to discontinue trial product. If subject is not 
allowed to resume trial product, then the reason for discontinuation will be recorded in the ‘end of 
treatment’ form in the 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 discontinue trial product on their own initiative should be encouraged 
to resume trial product (Section 7.1).
Each missed dose should be recorded in the CRF, as per subject’s recollection. If a ‘treatment 
status’ session previously has been made in IWRS, to indicate discontinuation of trial product, a 
new ‘treatment status’ session must be made to resume trial product.
8.2
Withdrawal from the trial
A subject may withdraw consent at any time at his/her own request.
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to the ‘end of treatment’ visit. See the flowchart 
for data to be collected. 
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. 
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If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record.
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent.
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF.
8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
8.3
Lost to follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the trial site for a required visit:
x
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
trial.
x
Before a subject is deemed lost to follow-up, the investigator must make every effort to 
regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). 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.
x
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of lost to 'follow-up'. 
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9
Trial assessments and procedures
x
Trial procedures and their timing are summarised in the flowchart. 
x
Informed consent must be obtained before any trial related activity, see Appendix 3.
x
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
x
The investigator will maintain a screening log to record details of all subjects screened and 
to confirm eligibility or record reason for screen failure, as applicable.
x
At screening, subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant trial site staff. 
x
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
x
Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit the bias between 
assessments. The suggested order of the assessments:
1. Electrocardiogram (ECGs) and vital signs
2. Blood samples
3. Patient reported outcomes (see Section 9.1.2) and mental health assessment instruments 
(Section 9.4.1)
4. Other assessments
x
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, electrocardiogram (ECG), diary 
recordings and clinical outcome assessments. 
x
Subjects must receive training in how to collect dosing information prior to PK sampling in 
a designated paper diary. 
x
Only the subject can make entries and corrections in the diaries, unless the section is 
specified for site staff.
x
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.
x
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.
x
Subject’s weight history must be recorded in the subject’s medical record.
x
Review of diaries, mental health assessment instruments, ECG, and laboratory reports must 
be documented either on the documents or in the subject's source documents. If clarification 
of entries or discrepancies in 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.
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x
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.
x
For subjects receiving antihypertensive or lipid-lowering or OAD treatment, the investigator 
should evaluate changes in the subjects’ treatment intensity within each therapeutic area. 
The evaluation should be based on whether an overall change from randomisation until the 
time of the evaluation has occurred (i.e., either increase, decrease or no change) after 
reviewing all available relevant information e.g., changes in drug dose, drug class, number 
of drugs or a combination of these.
x
Only for subjects without T2D: 
The investigator will evaluate the subject’s glycaemic status periodically during the trial as 
detailed in the flowchart based on all available relevant information e.g. medical records, 
concomitant medication, BG parameters (HbA1c, FPG) and AEs. The subject’s glycaemic 
status will be categorised as normo-glycaemia, prediabetes or diagnosed with T2D 
according to the American Diabetes Association’s definitions51.
9.1
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the flowchart.
9.1.1
Body measurements
x
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.
x
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.
x
Waist circumference is defined as:
o
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
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The following patient reported outcome questionnaires will be used:
x
Short Form 36 v2.0 acute (SF-36)
o
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 scores53.
x
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 life54
9.1.3
Self-measured plasma glucose
For subjects with T2D at screening:
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
x
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
9.2
Adverse events
The definitions of AEs and SAEs can be found in Appendix 4.
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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 are listed in Figure 9-1.
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1 and the 
reporting timelines in Figure 9-1.
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9.2.1.1
Event for adjudication
Event adjudication will be performed for adverse events in randomised subjects. These events are 
reviewed by an independent external event adjudication committee (EAC) in a blinded manner, 
refer to Appendix 3 for further details
There are four ways to identify events relevant for adjudication as described below:
x
Investigator-reported events for adjudication: When reporting AEs, the investigator must 
select the appropriate AE category based on pre-defined criteria (see Table 9-1 and 
Appendix 4)
x
Death
x
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.
x
EAC-identified events: When reviewing source documents provided for another event for 
adjudication, the EAC can identify additional events in scope for adjudication that were not 
initially reported by the investigator. In these instances, the investigator will be notified of 
the newly identified event and has the option to report the EAC-identified event. Regardless 
of whether the investigator decides to report the event, it will undergo adjudication. 
Occasionally, EAC-identified events may require the investigator to collect additional 
source documents, which should be provided by uploading to the event adjudication system 
(EAS). 
With the exception of EAC-identified events, an event-specific adjudication form for the event in 
question should be completed in the CRF within 14 calendar days of the investigator's first 
knowledge of the event. 
Copies of collected source documents should be labelled with trial ID, subject and AE number, 
redacted (anonymised of personal identifiers) and uploaded to the EAS within 4 weeks according to 
instructions outlined in the event adjudication site manual. If no, or insufficient source documents 
are provided to the adjudication supplier, the investigator can be asked to complete a clinical 
narrative to be uploaded to the EAS. 
If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS
9.2.2
Method of detecting AEs and SAEs
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non 
leading verbal questioning of the subject is the preferred method to inquire about events.
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9.2.3
Follow-up on AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, or if the event 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Novo Nordisk policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5
Cardiovascular and death events
Cardiovascular and death events will be handled and reported according to AE/SAEs description in 
Section 9.2.1.
9.2.6
Hypoglycaemic episodes
For subjects without T2D at screening.
Hypoglyceamic episodes must be reported as an AE in accordance with section 9.2 and Appendix 4.
For hypoglycaemic episodes in subjects with T2D, see section 9.2.7.
9.2.7
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE
For subject with T2D at screening:
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The following Disease-Related Events are common in subjects with T2D and can be serious/life 
threatening:
x
Hypoglycaemic episodes
Definitions, classification and reporting requirements are described in Appendix 8.
Hypoglycaemia
Non-serious hypoglycaemia must be reported on a hypoglycaemic episode form only.
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.
9.2.8
Pregnancies and associated adverse events
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until the ‘end of trial’ visit.
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in 
Figure 9-2 and Appendix 5.
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
Maternal form 1b 
≤ 14 calendar days after birth
Maternal form 1a
≤ 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤ 14 calendar days
Paternal form*1 ≤ 14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy.
9.2.9
Medical device incidents (including malfunctions)
The section is not applicable for this trial. Refer to technical complaints in Section 9.2.10.
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For more information on overdose, also consult the current version of the IB43 and any updates 
hereof.
9.4
Safety assessments
Planned time points for all safety assessments are provided in the flowchart.
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit) or 
found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product. 
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be recorded. Findings of specific 
medical history should de described in designated forms.
As part of the medical history information related to history of gallbladder disease, breast neoplasm, 
colon neoplasm, skin cancer, and psychiatric disorder will be recorded. Follow-up questions will be 
asked at the end of trial related to the breast neoplasm and colon neoplasm.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix 4) during the trial and any clinically significant 
worsening from baseline must be reported as an AE (see Section 9.2).
9.4.1
Mental health assessment instruments
x
PHQ-955 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. 
x
C-SSRS56 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.
x
Prior to administering the C-SSRS questionnaire, the investigator or qualified delegate must 
complete sufficient training.
If a subject has a PHQ-9 score of 10-14 both inclusive the subject should be referred to a mental 
health professional (MHP) if judged relevant by the investigator. If referral is not deemed relevant 
this, along with the reason why, must be documented in the subject’s medical records.
A subject must be referred to a MHP if:
x
the subject has a PHQ-9 score ≥15 or
x
the subject has any suicidal behaviour or
x
the subject has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment or
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x
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
x
A physical examination will include assessments of the general appearance, thyroid gland, 
breast (females) and abdomen, as well as the cardiovascular and respiratory system.
Subject with T2D at screening: Physical examination will include central and peripheral nervous 
systems.
x
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.3
Vital signs
x
The method for measuring systolic and diastolic blood pressure needs to follow the standard 
clinical practice at site.
x
Blood pressure (diastolic and systolic) and pulse measurements should be preceded by at 
least 5 minutes of rest for the subject in a quiet setting without distractions (e.g. television, 
cell phones).
x
Blood pressure and pulse measurements will be assessed in a sitting position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
9.4.4
Electrocardiograms
x
12-lead ECG will be obtained as outlined in the flowchart using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS and QT intervals.
9.4.5
Eye examination
For subject with T2D at screening:
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Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist or another suitably qualified 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). Pharmacological pupil-
dilation is a requirement unless using a digital fundus photography camera specified for non-dilated 
examination.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the subject has experienced worsening of visual function since 
the last examination. If the applicable eye examination was performed before the subject signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial.
After randomisation an eye examination performed according to 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.
x
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.
x
Urine pregnancy tests provided by central laboratory must be performed for women of 
childbearing potential at screening and as specified in the flowchart. Urine pregnancy test 
must be repeated at any time during the trial if pregnancy is suspected. Further instructions 
can be found in the laboratory manual.
9.4.7
Immunogenicity assessments
Blood samples for determination of serum antibodies against semaglutide, including cross reactivity 
to endogenous GLP-1, will be taken during the trial at visits specified in the flowchart. Antibody 
samples are only collected in China and not in other participating countries. The results of the 
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analysis will only be disclosed after completion of the clinical trial report (CTR) if required by local 
regulation. 
9.5
Pharmacokinetics
x
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.
x
Subject must be instructed to withhold their trial product dose in the morning of the clinic 
visit until blood sampling has been performed.
x
The PK dosing information should be transcribed into the CRF for the last 2 doses of trial 
product.
x
The exact timing of obtaining the PK sample must be recorded on the laboratory form.
x
The dual purpose of measuring plasma semaglutide levels is to perform population 
pharmacokinetic (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 PK of semaglutide. Each plasma sample will be divided into 2 
aliquots (e.g. one for PK and a backup,) and may also be used to evaluate safety or efficacy aspects 
that address concerns arising during or after the trial. PK samples are only collected in China and 
not in other participating countries.
9.6
Pharmacodynamics
Not applicable for this trial.
9.7
Genetics
Not applicable for this trial.
9.8
Biomarkers
Not applicable for this trial. 
9.9
Severe hypersensitivity
In the event of a severe immediate hypersensitivity reaction to trial product, it is recommended to 
test locally 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 after 1-2 weeks of trial product wash-out.
10 Statistical considerations 
Taxonomy of week 44 assessments
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For each subject a given assessment at week 44 may be available or missing and Table 10-1
describes the taxonomy for this. Note, this is done per assessment and per subject; subjects may be 
a different type for different assessments (a subject may have “available on randomised treatment 
(AT)” for body weight but “missing on randomised treatment (MT)” for waist circumference).
Table 10-1
Taxonomy for subjects based on week 44 assessments
Assessment
at week 44
Subjects on 
randomised 
treatment at 
week 44
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised treatment with an assessment at week 44: 
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 44. 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 44: 
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 44. These are also called non-retrieved subjects
MD
10.1
Sample size determination 
The tests of superiority of semaglutide 2.4 mg to semaglutide placebo for the primary and 
confirmatory secondary endpoints are performed using the fixed-sequence statistical strategy. This 
strategy tests the endpoints using a predefined hierarchical order, all at the significance level of 5%, 
moving to test the next endpoint only after a statistically significant superiority result (p-value < 
5%) on the previous endpoint. The test hierarchy is given in Table 10-2 with underlying 
assumptions, marginal power and effective power. The effective power is calculated under the 
assumption of independence of endpoints by multiplying the respective marginal powers 
successively. As the two primary endpoints are included in the statistical testing hierarchy, 
significant superiority of semaglutide 2.4 mg vs. semaglutide placebo must be demonstrated for 
each of the primary endpoints.
In the analysis approach addressing the primary estimand, week 44 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 44 for 
non-retrieved subjects (MD). The imputation is done separately within each treatment arm (see 
description below). However, for the power calculations missing values (MT and MD), regardless 
of treatment arm, are assumed to be similar to semaglutide placebo subjects. These assumptions are 
likely conservative with respect to the power, and correspond to the jump to reference sensitivity 
analysis planned below.
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Assumptions
The common assumptions for the power calculations are
x
The significance level is 5%
x
The randomisation ratio is 2:1
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
70% of subjects are assumed to be treatment completers, i.e. on randomised treatment (AT) 
at week 44 
x
Thus 30% of subjects discontinue trial product permanently and
x
≥ 50% of these are retrieved (AD) at week 44 
x
30% of the subjects have T2D
x
All subjects in the semaglutide placebo arm are assumed to have same effect as subjects 
who complete the trial on semaglutide placebo (AT)
x
Retrieved subjects (AD) in the semaglutide arm are assumed to have an effect corresponding 
to half the treatment difference (compared to semaglutide placebo) of subjects who complete 
the trial on semaglutide (AT)
x
Non-retrieved subjects (MD) in the semaglutide arm are assumed to have an effect 
corresponding to the semaglutide placebo arm
x
80% of the total trial population are Chinese subjects
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. Furthermore, the sample size for this trial was determined to reach 
approximately 95% effective power (corresponding to approximately 90% effective power for the 
Chinese subpopulation) for the body weight related endpoints in the statistical hierarchy, i.e. body 
weight change, 5%, 10% and 15% responders and waist circumference change.
Given these assumptions, the sample size of 375 subjects (250 in the s.c. semaglutide 2.4 mg once 
weekly and 125 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 25% for the  last endpoint in the hierarchical testing procedure, i.e. IWQoL-Lite 
physical function domain score change. 
Table 10-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 375 randomised 
subjects
Order
Endpoint
Assumed mean or 
proportion for completers
Expected mean (±SD) or 
proportion
Marginal 
power 
(%)
Effective 
power 
(%)
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[non-T2D][T2D] (±SD)
Expected 
difference 
or 
proportion 
ratio
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
Semaglutide 
placebo
1
% weight 
change #
[12.6] [10.4] 
(±10)
[3] [1.7] 
(±10)
9.8 (±11)
2.6 (±11)
7.2%-
points
> 99
99
2
5% responders
[78%] [71%]
[42%] [37%]
68%
41%
1.7
> 99
99
3
10% 
responders
[60%] [52%]
[24%] [20%]
50%
23%
2.2
> 99
99
4
15% 
responders
[41%] [32%]
[12%] [9%]
31%
11%
2.8
99
99
5
WC change 
(cm) #
[9.9] [8.2] 
(±10)
[4] [2.8] 
(±10)
8.1 (±11)
3.6 (±11)
4.5 cm
96
95
6
sBP change 
(mmHg) #
[5.6] [4.6] 
(±13)
[1.5] [0.4] 
(±13)
4.4 (±14)
1.2 (±14)
3.2 mmHg
55
52
7
SF-36 PF score 
change
[5.4] [5.4] 
(±10)
[2] [2] (±10)
4.6 (±11)
2 (±11)
2.6 score-
points
59
31
IWQoL-Lite 
PFD score 
change
[21.6] [21.6] 
(±20)
[13] [13] 
(±20)
19.7 (±21)
13 (±21)
6.7 score-
points
82
25
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 
All tests in the hierarchy are based on the primary estimand
10.2
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.
x
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:
x
In-trial: The in-trial period is defined as the uninterrupted time interval from date of 
randomisation to date of last contact with trial site.
x
On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose 
of trial product has been administered within the prior 2 weeks (14 days). The on-treatment 
period is defined as all times which are considered on-treatment.
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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. 
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 44 in body weight (%) is defined as
% weight change= (body weight at week ͶͶ – body weight at baseline)
body weight at baseline
 ×100.
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Definition of primary endpoint: 5% responders
A body weight reduction of at least 5% from baseline (week 0) to week 44 is defined as 
5% responder = ൜1 if  % weight change ≤ Ȃ 5%
0 if  % weight change > Ȃ 5%.
Analyses addressing the primary estimand
The following statistical analyses and imputation methods are designed to address the primary 
estimand, i.e. to assess the effectiveness of semaglutide 2.4 mg. 
The analysis model for % weight change is a linear regression (ANCOVA) of % weight change 
with randomised treatment and stratification groups as factors and baseline body weight (kg) as 
covariate. The stratification group is defined by T2D status stratification category. The estimated 
treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% confidence interval (CI) and corresponding p-value.
The 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 T2D status stratification category. The estimated odds ratio (OR) 
between semaglutide 2.4 mg and semaglutide placebo will be reported together with the associated 
two-sided 95% CI and corresponding p-value.
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows 
for the two analysis models.
Let μsemaglutide and μsemaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo group, respectively. The null and alternative hypotheses tested are
ܪǣߤ௦௘௠௔௚௟௨௧௜ௗ௘൒ߤ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢ݒݏ
ܪ஺ǣ ߤ௦௘௠௔௚௟௨௧௜ௗ௘൏ߤ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢Ǥ
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Let ORsemaglutide/semaglutide placebo denote the true odds ratio between semaglutide 2.4 mg and 
semaglutide placebo. The null and alternative hypotheses tested are
ܪǣܱܴ௦௘௠௔௚௟௨௧௜ௗ௘Ȁ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢൑ͳݒݏ
ܪ஺ǣ ܱܴ௦௘௠௔௚௟௨௧௜ௗ௘Ȁ௦௘௠௔௚௟௨௧௜ௗ௘௣௟௔௖௘௕௢൐ͳǤ
The hypothesis will be rejected and superiority claimed, if the lower limit of the estimated two-
sided 95% CI is above 1.
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Handling of missing week 44 values for the primary estimand
All available data at week 44 (AT and AD) are used and missing values (MT and MD) at week 44 
will be imputed and the endpoints will be derived from the imputed values. Several approaches for 
imputation will be applied. First, a description of the primary imputation approach to address the 
primary estimand for the primary endpoints is given followed by a description of the sensitivity 
analyses used to assess the robustness of the primary analysis results. The sensitivity analyses 
investigate how assumptions on body weight development after discontinuation of randomised 
treatment impact the estimated treatment contrasts between semaglutide 2.4 mg and semaglutide 
placebo. An illustration of all imputation approaches for the primary estimand is given in Figure 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 McEvoy57.
Missing body weight measurement at week 44 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. 
Missing body weight measurements at week 44 for subjects on randomised treatment (MT) are 
imputed by sampling from available measurements at week 44 from subjects on randomised 
treatment (AT) in the relevant randomised treatment arm. The multiple imputation approach is done 
in three steps:
5. 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-OT of 
body weight. The model will be a linear regression of body weight (kg) at week 44 with 
gender (male/female), baseline BMI (kg/m2) (in categories 27-<35,35-<40, ≥40) and 
stratification groups (defined by stratification categories for T2D status) 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 11 weeks). If timing by quarters is too restrictive, halves (intervals of 22 weeks) or 
excluding timing will be used. If any subjects are MT, an imputation model for missing 
body weight measurements at week 44 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 44 body weight values for each randomised treatment arm. This will be 
done 1,000 times and results in 1,000 complete data sets.
6. 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.
7. Pooling: Integrates the 1,000 times 2 estimation results into two final results using 
Rubin’s formula.
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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 95364379 as seed number.
Sensitivity analyses
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
44 (MT and MD) for both the semaglutide 2.4 mg and semaglutide placebo group are imputed by 
sampling among all available assessments at week 44 in the semaglutide placebo group (AT and 
AD). This approach makes the assumption that subjects instantly after discontinuation lose any 
effect of randomised treatment beyond what can be expected from semaglutide placebo treatment as 
adjunct to reduced-calorie diet and increased physical activity58. The multiple imputation approach 
is done as above with the first step replaced by
x
1. Imputation: Defines an imputation model using semaglutide placebo subjects from FAS 
with a week 44 measurement (AT and AD). The model will be a linear regression of body 
weight (kg) at week 44 with gender (male/female), BMI (kg/m2) (in categories 27-<35, 35-
<40, ≥40) and stratification groups (defined by stratification categories for T2D status) 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 44 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 Sacks59 (S1-SI and S2-SI): Missing weight measurements 
at week 44 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 44. The weight regain imputation will be done for both randomised arms 
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo arm uses last available observation (corresponding to a weight regain rate 
of 0 kg/month) will be performed (S2-SI). For both versions, missing weight measurements at week 
44 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 44. 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 
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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 44 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.
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 primary 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 44 assessments for retrieved drop-outs (AD) are 
not used in this analysis. The MMRM for efficacy will use assessments only from subjects who are 
taking the randomised treatment until end of treatment or until first discontinuing of randomised 
treatment. The derived date of the second consecutive missed dose will be used as the latest date for 
using assessments in this MMRM. The assessment closest in time and before the derived date of the 
second consecutive missed dose will be used as last assessment on randomised treatment. For 
subjects who initiate rescue interventions before completion or first discontinuing of randomised 
treatment, the date of starting weight management drugs or undergoing bariatric surgery will be 
used as latest date for using assessments in this MMRM. Similarly, the assessment closest in time 
and before the date of starting weight management drugs or undergoing bariatric surgery will be 
used as last assessment on randomised treatment. The MMRM for efficacy will be fitted using % 
weight change and the same 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 44 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 primary and secondary 
estimands for the primary endpoints is given in Table 10-3.
10.3.2
Secondary endpoints
10.3.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in section 4.2.2.1 and are all included in the fixed-
sequence statistical strategy, see above. All tests are tests of superiority of semaglutide 2.4 mg to 
semaglutide placebo.
Analyses addressing the primary estimand
All confirmatory secondary endpoints will be analysed using the same imputation approach as used 
for the primary endpoints and to address the primary estimand. The imputation model is the same as 
for the primary endpoints with body weight replaced by assessments of the endpoint to be analysed. 
The statistical model for continuous endpoints will be ANCOVA with 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 
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 primary and secondary 
estimands for confirmatory secondary endpoints is given in Table 10-3.
Table 10-3
Analysis and imputation methods to address the primary and secondary 
estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy
Objective
Endpoint
Test 
order
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Primary endpoints
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS 
MMRM
-
-
Primary
5% responders
2
Binary
Primary
FAS 
LR
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Non-
responder
Secondary
FAS 
LR
MMRM
-
Confirmatory secondary endpoints
Primary
10% responders
3
Binary
Primary
FAS 
LR 
RD-MI
Non-
responders
Secondary
FAS 
LR 
MMRM
-
Primary
15% responders
4
Binary
Primary
FAS 
LR 
RD-MI
Non-
responders
Secondary
FAS 
LR 
MMRM
-
Primary
WC change (cm)
5
Continuous
Primary
FAS 
ANCOVA
RD-MI
J2R-MI
Secondary
FAS 
MMRM
-
-
Secondary
sBP change (mmHg)
6
Continuous
Primary
FAS 
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
7
Continuous
Primary
FAS 
ANCOVA 
RD-MI
J2R-MI
Secondary
IWQoL-Lite PFD score 
change
8
Continuous
Primary
FAS 
ANCOVA 
RD-MI
J2R-MI
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
J2R-MI = jump to reference multiple imputation; S1-SI and S2-SI = single imputation as done by Sacks; TP-MI = 
tipping point multiple imputation; MMRM = mixed model for repeated measurements; LR = logistic regression; WC = 
waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = physical functioning; 
IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = physical function domain
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10.3.2.2
Supportive secondary endpoints
Supportive secondary endpoints are listed in Section 4. All tests are tests of superiority of 
semaglutide 2.4 mg to semaglutide placebo. 
Analyses addressing the primary estimand
The effect-related supportive secondary endpoints will be analysed using the same imputation 
approach as used for the primary endpoints and to address the primary estimand. The imputation 
model is the same as for the primary endpoints with body weight replaced by assessments of the 
endpoint to be analysed. The statistical model for continuous endpoints will be ANCOVA with 
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 responder endpoints relating to COAs will be logistic regression with 
randomised treatment and stratification groups (defined by stratification categories for T2D status) 
as factors and the baseline assessment of the endpoint to be analysed as covariate. 
For lipids 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.
For glycaemic status, antihypertensive medication, lipid-lowering medication, concomitant oral 
antidiabetic medication, fatty liver index score category and treatment discontinuation no analysis 
will be performed. Observed data will be summarised by descriptive statistics. 
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 
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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 primary and secondary 
estimands for supportive secondary endpoints is given in Table 10-4.
Table 10-4
Analysis and imputation methods to address the primary and secondary 
estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (effect related)
Primary
Weight change (kg)
Continuous
Primary 
FAS
ANCOVA
RD-MI
- 
Secondary
FAS 
MMRM
-
-
Primary
BMI change (kg/m2)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
FAS 
MMRM
-
- 
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
FPG change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
Fasting serum insulin change 
(mIU/L)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
dBP change (mmHg)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
Total cholesterol change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
HDL change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
LDL change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
VLDL change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
FFA change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
Triglycerides change (mg/dL)
Continuous
Primary 
FAS 
ANCOVA
RD-MI
- 
Secondary
SF-36 PF score responders #
Binary
Primary
FAS
LR
RD-MI
-
Secondary
SF-36 RP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 BP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 GH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 VT score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 SF score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 RE score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 PCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary 
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
Glycaemic category change
Categorical
Primary
FAS
Descriptive 
statistics
-
-
Secondary
Antihypertensive medication change
Categorical
Primary
FAS
Descriptive 
statistics
-
-
Secondary
Lipid-lowering medication change
Categorical
Primary
FAS
Descriptive 
statistics
-
-
Secondary
Concomitant OAD change
Categorical
Primary
FAS
Descriptive 
statistics
-
-
Secondary
FLI score category change
Categorical
Primary
FAS
Descriptive 
statistics
-
-
Secondary
Subjects who have permanently 
discontinued randomised trial 
product
Binary
Primary
FAS
Descriptive 
statistics
-
-
Secondary
Time to permanent discontinuation 
of randomised trial product
Continuous
Primary
FAS
Descriptive 
statistics
-
-
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
-
- 
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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 = Glycated Haemoglobin A1c; 
FPG = fasting plasma glucose; dBP = diastolic blood pressure; HDL = high density lipoprotein; LDL = low density 
lipoprotein; VLDL = very low density lipoprotein; FFA = free fatty acids; LR = logistic regression; SF-36 = Short Form 
36 v2.0 acute; PF= Physical Functioning; RP = Role-Physical; BP = Bodily Pain; GH = General Health; VT = Vitality; 
SF = Social Functioning; RE = Role-Emotional; MH = Mental Health; PCS = Physical component summary; MCS = 
Mental component summary; IWQoL-Lite = Impact of Weight on Quality of Life-Lite for Clinical Trials; PFD = 
physical function domain; PDD = pain/discomfort domain; PSD = psychosocial domain; OAD = oral antidiabetic drug; 
FLI = fatty liver index; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; # responder value 
= 4.3; ## responder value = 20
10.3.3
Explorative statistical analysis for pharmacogenetics and biomarkers
Not applicable for this trial. 
10.3.4
Other analyses
All collected data that were not defined as endpoints will be summarised by descriptive statistics.
10.4
Pharmacokinetic and/or pharmacodynamic modelling
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
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
COA
Clinical Outcome Assessments 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTR
clinical trial report
DFU
direction for use 
DUN
dispensing unit number
EAC
event adjudication committee 
EAS
event adjudication system 
EASD
European Association for the Study of Diabetes 
ECG
electrocardiogram
eGFR 
estimated glomerular filtration rate 
EMA
European Medicines Agency 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
FDA Amendments Act
FPG
fasting plasma glucose
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FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GI
Gastrointestinal
GLP-1
glucagon-like peptide-1
HbA1c
glycated haemoglobin
HDL
high density lipoprotein 
HRT
hormone replacement therapy
IB
investigator’s brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IWQoL-Lite for CT
Impact of Weight on Quality of Life-Lite for Clinical Trials 
IWRS
interactive web response system
KDIGO
kidney disease improving global outcome
LAO-OT
last available observation on treatment
LDL
low-density lipoprotein
MD
missing and discontinued
MEN2
multiple endocrine neoplasia type 2 
MHP
mental health professional 
MMRM 
mixed model for repeated measurements
MT
missing on treatment
MTC
medullary thyroid cancer 
OAD
oral antidiabetic drug 
OR
odds ratio
PCD
primary completion date
PG
plasma glucose
PHQ-9
Patient Health Questionnaire -9
PK
Pharmacokinetic
Pop
population 
PYO
patient years of observation
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PYE
patient years of exposure
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set 
sBP
systolic blood pressure 
s.c.
Subcutaneus
SD
standard deviation 
SF-36
Short Form-36 v2.0 acute
SGLT2i
sodium–glucose co-transporter 2 inhibitor 
SMPG
self-measured plasma glucose
SU
Sulphonylurea
T2D
type 2 diabetes 
TEE
total energy expenditure 
TEAE
treatment emergent adverse event 
TMM
trial materials manual
TSH
thyroid stimulating hormone 
UNL
upper normal limit 
WC
waist circumference
WOCBP
woman of child bearing potential
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Clinical laboratory tests
x
The tests detailed in Table 11-1 and Table 11-2 will be performed by the central laboratory.
x
Laboratory samples specified in the protocol should be sent to the central laboratory for 
analysis.
x
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. 
x
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the trial 
database, but the values will be reported to the investigator. 
x
The investigator must review all laboratory results for concomitant illnesses and AEs.
x
Laboratory samples will be destroyed no later than at finalisation of the CTR except, 
antibody samples which will be stored until marketing authorisation or destroyed at the 
latest 15 years from end of trial.
x
For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept according to local regulations. 
Table 11-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism /
Glycaemic control
x Fasting plasma glucose1
x HbA1c
x Fasting serum insulin
Lipids
x Cholesterol
x High density lipoprotein (HDL) cholesterol
x Low density lipoprotein (LDL) cholesterol
x Triglycerides
x Very-low-density lipoprotein (VLDL) cholesterol
x Free fatty acids
NOTES :
1A FPG result ≤3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the discretion of the investigator 
(Appendix 4).
For subjects with T2D at screening:
A FPG result >16.7 mmol/L (300 mg/dL) should not be reported as a hyperglycaemic episode but 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
x Basophils
x Eosinophils
x Erythrocytes
x Haematocrit
x Haemoglobin
x Leucocytes
x Lymphocytes
x Monocytes
x Neutrophils
x Thrombocytes
Biochemistry1
x Alanine Aminotransferase (ALT)2
x Albumin
x Albumin corrected calcium
x Alkaline phosphatase
x Amylase
x Aspartate Aminotransferase (AST)2
x Bicarbonate (only subjects with T2D at screening)
x Calcitonin
x Creatine kinase
x Creatinine
x Gamma Glutamyl Transferase (GGT) 
x Lipase
x Potassium
x Sodium
x Thyroid stimulating hormone (TSH)/Thyrotropin3
x Total Bilirubin
x Urea
Pregnancy Testing
x Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)4
Other tests
x Anti-semaglutide antibodies
x Semaglutide plasma concentration
x eGFR calculated according to CKD-EPI creatinine equation as defined by KDIGO 
201239 by the central laboratory at screening
x (Tryptase in case of severe hypersensitivity, see Section 9.9)
Notes :
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 4 (Hy’s Law) and Section 8.1.
2If ALT or AST >3 upper normal limit (UNL) additional blood samples should be taken from subjects to analyse, 
international normalised ratio (INR) by central laboratory (except at screening visit). Repeat testing of the abnormal 
lab assessments should be performed via central lab. for the subject until abnormalities return to normal or baseline 
state.
3If TSH level is out of normal range, additional testing will be performed by central lab: total and free T3 and T4 
except at screening visit
4Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC
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x
Anti-semaglutide antibodies and semaglutide plasma concentration will be performed at a 
specialised laboratory.
x
Laboratory results that could unblind the trial (e.g. antibodies) will only be disclosed after 
completion of the CTR if required by local regulation.
x
Laboratory outlier: If the following laboratory parameters are above/below the cut-off 
values in Table 11-3 they are considered to be laboratory outliers and should be reported by 
completing a laboratory outlier form in the CRF:
Table 11-3
Criteria for laboratory outliers
Cut-off
Haematology
Leucocytes
< 1 × 109/L
Lymphocytes
< 0.2 × 109/L
Thrombocytes
< 25 × 109/L
Biochemistry
Albumin corrected calcium
< 1.50 mmol/L or > 3.4 mmol/L
Alkaline phosphatase
> 20 × UNL
Calcitonin
> 100 ng/L
Creatinine
> 6 × UNL
Creatine kinase
> 10 × UNL
Potassium
< 2.50 mmol/L or > 7.0 mmol/L
Sodium
< 120 mmol/L or > 160 mmol/L
x
Hepatic laboratory outlier: If the following hepatic laboratory parameters are above the cut-
off values in Table 11-4, it is considered to be a hepatic laboratory outlier and should be 
reported by completing a hepatic event form in the CRF. It is at the investigator’s discretion 
to determine whether it should also be reported as an adverse event (see Appendix 4).
Table 11-4
Criteria for hepatic laboratory outliers
Cut-off
Alkaline phosphatase
>20 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
1) Regulatory and ethical considerations
x
This trial will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki60 and applicable ICH Good Clinical Practice (GCP) 
Guideline61
o
Applicable laws and regulations
x
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.
x
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements.
x
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial subjects.
x
Before a trial site is allowed to start screening subjects, written notification from Novo 
Nordisk must be received.
x
The investigator will be responsible for:
o
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities
o
notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
providing oversight of the conduct of the trial at the site and adherence to 
requirements of  ICH guidelines, the IRB/IEC, and all other applicable local 
regulations
o
ensuring submission of the CTR 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.
3) Informed consent process
x
The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial. 
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x
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
x
Subjects must be informed that their participation is voluntary.
x
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines61, Declaration of Helsinki60 and the 
IRB/IEC or trial site.
x
The medical record must include a statement that written informed consent was obtained 
before any trial related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial related activity.
x
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in 
accordance with local requirements.
x
Subjects must be re-consented to the most current version of the informed consent form(s)
during their participation in the trial.
x
A copy of the informed consent form(s) must be provided to the subject.
4) Information to subjects during trial
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. 
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
x
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records 
or datasets that are transferred to Novo Nordisk will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.
x
The subject and any biological material obtained from the subject will be identified by 
subject number, visit number and trial ID. Appropriate measures such as encryption or 
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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. 
x
The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also 
be explained to the subject. 
x
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities.
6) Committee structure
Novo Nordisk safety committee
Novo Nordisk will constitute an internal Semaglutide s.c. safety committee to perform ongoing 
safety surveillance. The Semaglutide s.c. safety committee may recommend unblinding of any data 
for further analysis, and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel.
Event adjudication committee
An independent external EAC is established to perform ongoing blinded adjudication of selected 
types of events and deaths (see Table 9-1 and Appendix 4). The EAC will evaluate events sent for 
adjudication using pre-defined definitions and guidelines in accordance with the EAC Charter. The 
evaluation is based on review of pre-defined clinical data collected by the trial sites. 
The EAC is composed of permanent members covering all required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. The EAC will have no authorisations to impact on trial conduct, trial protocol or 
amendments.
The assessment made by both the EAC and the investigator will be presented in the CTR. 
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 obesity62. 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 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information.
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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 CTR for this trial.
One (or two) investigator(s) will be appointed by Novo Nordisk to review and sign the CTR 
(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 publications63.
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 CTR 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 Editors63 .
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 research subjects' data, and will be provided with the 
randomisation code after results are available.
8) Dissemination of clinical trial data
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn 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)64, the Food and Drug 
Administration  Amendment Act (FDAAA)65, European Commission Requirements66, 67 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 + 44 weeks corresponding to V18 (‘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)
x
Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data.
x
All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
x
For some data both electronic and paper CRFs are used.
x
The following will be provided as paper CRFs:
o
Pregnancy forms
x
The following will be provided as paper CRFs to be used when access to the electronic CRF 
is revoked or temporarily unavailable: 
o
AE forms 
o
Safety information forms
o
Technical complaint forms (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation)
x
Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the 
old and the new data, identification of the person entering the data, date and time of the 
entry and reason for the correction. If corrections are made by the investigator’s delegated 
staff after the date when the investigator signed the CRF, the CRF must be signed and dated 
again by the investigator.
x
The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to 
Novo Nordisk for data verification and validation purposes
Monitoring
x
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents (original 
documents, data and records). Direct access includes permission to examine, analyse, verify 
and reproduce any record(s) and report(s) that are important to the evaluation of the trial. If 
the electronic medical record does not have a visible audit trail, the investigator must 
provide the monitor with signed and dated printouts. In addition the relevant trial site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone). 
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x
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements.
x
Monitoring will be conducted using a risk based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites. 
x
Monitors will review the subject’s medical records and other source data e.g. the diaries and 
mental health assessment instruments, to ensure consistency and/or identify omissions 
compared to the CRF. 
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.
10) Source documents
x
All data entered in the CRF must be verifiable in source documentation other than the CRF.
x
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. 
x
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site.
x
Data reported 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. 
x
It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record. 
x
Subjects completing electronic patient reported outcome instruments are the data 
originators. Data will be transmitted to a technology service provider database, thus the 
service provider database is the source.
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x
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who was contacted.
x
Definition of what constitutes source data can be found in a source document agreement at 
each trial site. There will only be one source document defined at any time for any data 
element.
11) Retention of clinical trial documentation
x
Records and documents, including signed informed consent forms, pertaining to the conduct 
of this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No 
records may be transferred to another location or party without written notification to Novo 
Nordisk. 
x
The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF and other subject data will be provided in 
an electronic readable format to the investigator before access is revoked to the systems 
and/or electronic devices supplied by Novo Nordisk. Site-specific CRFs and other subject 
data (in an electronic readable format or as paper copies or prints) must be retained by the 
trial site. If the provided electronic data (e.g. the CD-ROM) is not readable during the entire 
storage period, the investigator can request a new copy. A copy of all data will be stored by 
Novo Nordisk.
x
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice
12) Trial and site closure
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation.
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed.
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to:
x
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines
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x
inadequate recruitment of subjects by the investigator
x
discontinuation of further trial product development.
13) Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects. 
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions. 
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
14) Indemnity statement 
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence. 
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the site or investigator are responsible. 
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Novo Nordisk may pay additional costs incurred in relation to assessments relevant for following 
the safety of the subject. Investigator must contact Novo Nordisk on a case by case basis for 
whether the costs will be covered.
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Adverse events: definitions and procedures for 
recording, evaluation, follow-up, and reporting
AE definition
x An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
x An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or 
disease (new or exacerbated) temporally associated with the use of a medicinal product.
Events meeting the AE definition
x Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator.
x A 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.
x Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition.
x Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction.
x Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent.
x A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition.
Events NOT meeting the AE definition 
x Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product. 
Note: pre-existing conditions should be recorded as medical history/concomitant illness.
x Pre-planned procedures, unless the condition for which the procedure was planned has worsened from the first 
trial related activity after the subject has signed the informed consent.
Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
x Results in death
x Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death 
at the time of the event. It does not refer to an event which hypothetically might have caused death, if it were more 
severe.
x Requires inpatient hospitalisation or prolongation of existing hospitalisation
x Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
x Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
Note:
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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.
x Results in persistent or significant disability/incapacity
x The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
x This definition is not intended to include experience of relatively minor medical significance such as
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
x Is a congenital anomaly/birth defect
x Important medical event:
x Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations. This includes important medical events that may not be immediately life-threatening or result in 
death or hospitalisation, but may jeopardise the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion.
x The following adverse events must always be reported as SAEs using the important medical event criterion, if 
no other seriousness criteria are applicable:

suspicion of transmission of infectious agents via the trial product. 

risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x 
UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law).
Description of AEs requiring additional data collection (via specific event form) and events for adjudication.
AEs requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the evaluation of the safety of 
the trial product (see Table 9-1). The selection of these events is based on the non-clinical and clinical data with 
semaglutide, knowledge from the GLP-1 RA drug class as well as regulatory requirements. 
Event type
Description
Acute gallbladder disease
Events of symptomatic acute gallbladder disease (including gallstones and 
cholecystitis)
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following three 
features:
(1) abdominal pain consistent with acute pancreatitis (acute onset of a 
persistent, severe, epigastric pain often radiating to the back)
(2) serum lipase activity (and/or amylase activity) at least three times 
greater than the upper limit of normal
(3) characteristic findings of acute pancreatitis on imaging.
Malignant neoplasm
Malignant neoplasm by histopathology or other substantial clinical 
evidence
Hepatic event
Hepatic event defined as:
x
Disorders of the liver including cholestatic conditions and liver 
related signs and symptoms
x
ALT or AST > 3x UNL and total bilirubin > 2x UNL or INR > 
1.5*
x
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:
x
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.
x
Wrong route of administration, such as intramuscular instead of 
subcutaneous. 
x
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.
Misuse or abuse of trial 
product2
Misuse is when the trial product is intentionally and inappropriately used. 
Abuse of trial product is persistent or sporadic, intentional excessive use, 
which is accompanied by harmful physical or psychological effects (e.g. 
overdose with the intention to cause harm).
              2Additional data for misuse or abuse of trial product is reported on the medication error event form.
Events for adjudication
Event type
Description
Adjudication outcome
Death
All-cause death
x
Cardiovascular death 
(including undetermined 
cause of death)
x
Non-Cardiovascular death
Acute Coronary Syndrome
Acute Coronary Syndrome 
conditions include all types of acute 
myocardial infarction and 
hospitalisation for unstable angina 
pectoris
x
Acute myocardial 
infarction (including 
subgroup classifications)
x
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
x
Ischaemic stroke
x
Haemorrhagic stroke
x
Undetermined stroke
x
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
x
Coronary 
revascularisation 
procedure
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Heart failure
Presentation of the patient for an 
urgent, unscheduled 
clinic/office/emergency department 
visit or hospital admission, with a 
primary diagnosis of heart failure 
(new episode or worsening of 
existing heart failure)
x
Heart failure 
hospitalisation
x
Urgent heart failure visit
Acute pancreatitis
The diagnosis of acute pancreatitis 
requires two of the following three 
features:
(1) abdominal pain consistent with 
acute pancreatitis (acute onset of 
a persistent, severe, epigastric 
pain often radiating to the back)
(2) serum lipase activity (and/or 
amylase activity) at least three 
times greater than the upper limit 
of normal
(3) characteristic findings of acute 
pancreatitis on imaging
x
Acute pancreatitis
x
Mild
x
Moderately severe 
x
Severe
AE and SAE recording
x The investigator will record all relevant AE/SAE information in the CRF.
x The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.
x When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event.
x There may be instances when copies of source documents (e.g. medical records) for certain cases are requested by 
Novo Nordisk. In such cases, all subject identifiers, with the exception of the subject number, will be redacted on 
the copies of the source documents before submission to Novo Nordisk.
x For all non-serious AEs the applicable forms should be signed when the event is resolved or at the end of the trial 
at the latest. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this section.
x Novo Nordisk products used as concomitant medication if an AE is considered to have a causal relationship with a 
Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the suspected 
relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
Assessment of severity
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories: 
x Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities.
x Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
x Severe: An event that prevents normal everyday activities. 
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe.
Assessment of causality
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The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as: 
x Probable - Good reason and sufficient documentation to assume a causal relationship.
x Possible - A causal relationship is conceivable and cannot be dismissed.
x Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated.
The investigator should use the 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:
x Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial-related activity after the subject signed the informed consent.
x Recovering/resolving: The condition is improving and the subject is expected to recover from the event. This 
term is only applicable if the subject has completed the trial or has died from another AE.
x Recovered/resolved with sequelae: The subject has recovered from the condition, but with lasting effect due to a 
disease, injury, treatment or procedure. If a sequelae meets an SAE criterion, the AE must be reported as an SAE.
x Not recovered/not resolved: The condition of the subject has not improved and the symptoms are unchanged or 
the outcome is not known.
x Fatal: This term is only applicable if the subject died from a condition related to the reported AE. Outcomes of 
other reported AEs in a subject before he/she died should be assessed as “recovered/resolved”, 
“recovering/resolving”, “recovered/resolved with sequelae” or “not recovered/not resolved”. An AE with a fatal 
outcome must be reported as an SAE.
x Unknown: This term is only applicable if the subject is lost to follow-up.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations 
as medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as 
fully as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick 
test) or investigations, histopathological examinations, or consultation with other health care professionals.
If a subject dies during participation in the trial or during a recognised follow-up period, the investigator should 
provide Novo Nordisk with a copy of autopsy report including histopathology.
New or updated information will be recorded in the CRF.
SAE reporting via electronic CRF
x Relevant forms (AE and safety information form) must be completed in the CRF. 
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x For reporting and sign-off timelines, see box below. 
x If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
unavailable for more than 5 calendar days then the site will use the safety information form (see box below).
x The site will enter the SAE data into the CRF as soon as it becomes available, see 9.2.1.
x After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a 
previously reported SAE after CRF decommission, then the site can report this information on a paper AE and 
safety information form (see box below) or to Novo Nordisk by telephone.
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SAE reporting via paper CRF
x Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail 
or courier.
x Initial notification via telephone is acceptable, although it does not replace the need for the investigator to 
complete the AE and safety information form within the designated reporting time frames (as illustrated in 
Figure 9-1):
x AE form within 24 hours.
x Safety information form within 5 calendar days. 
x Both forms must be signed within 7 calendar days.
Contact details for SAE reporting can be found in the investigator trial master file.
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Contraceptive guidance and collection of pregnancy 
information
It must be recorded in the CRF whether female subjects are of childbearing potential. 
Definitions
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered.
Females in the following categories are not considered WOCBP
1. Premenarcheal
2. Females with one or more of the following:
x
Documented total hysterectomy
x
Documented bilateral salpingectomy
x
Documented bilateral oophorectomy
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment.
3. Postmenopausal female:
x
A postmenopausal state is defined as amenorrhoea for 12 months without an alternative 
medical cause.
x
Females ≥ 50 years of age can be considered postmenopausal (irrespective of treatment with 
a hormonal contraception or hormone replacement therapy (HRT)) if they have both:
x
Amenorrhoea and
x
Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
postmenopausal range and one of these was observed ≥1 year prior to screening.
x
Females ≥ 60 years of age can be considered postmenopausal.
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use one of the highly effective/acceptable contraception methods.
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s
medical records, medical examination or medical history interview.
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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. Such methods include:
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 b
x oral 
x intravaginal 
x transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
x oral 
x injectable 
Highly effective methods that are user independent b
x Implantable progestogen only hormonal contraception associated with inhibition of ovulation
x Intrauterine Device (IUD)
x Intrauterine hormone-releasing System (IUS)
x Bilateral tubal occlusion
Vasectomised partner
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.
Sexual abstinenceb
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
Notes: 
a Failure rates may differ from 1% per year, if not used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
b Contraception should be utilised during the treatment period and for at least 49 days after the last dose of trial product
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with:
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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/her knowledge about the female’s obesity history, concomitant illness, 
concomitant medication and observed AEs. The justification must be stated in the medical records.
Pregnancy testing
x
WOCBP should only be included after a negative highly sensitive urine pregnancy test.
x
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.
x
Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period, if required locally (Appendix 10).
x
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 
x
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this trial.
x
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 
14 calendar days of learning of a subject's pregnancy.
x
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the 
delivery date.
x
Any termination of pregnancy will be reported, regardless of foetal status (presence or 
absence of anomalies) or indication for procedure.
x
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
x
A spontaneous abortion is always considered to be an SAE and will be reported as such.
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x
Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the trial product by the investigator will be reported to Novo 
Nordisk as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former subjects, he or she may learn of an SAE through spontaneous 
reporting. 
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product. 
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Technical complaints: Definition and procedures for 
recording, evaluation, follow-up and reporting
Technical complaint definition 
x A technical complaint is any written, electronic or oral communication that alleges product (medicine or device) 
defects. The technical complaint may be associated with an AE, but does not concern the AE itself.
Examples of technical complaints:
x
Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination).
x
Problems with packaging material including labelling.
x
Problems related to medical devices (e.g. to the injection mechanism).
Time period for detecting technical complaints 
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last
usage of the product, must be collected for products predefined on the technical complaint form. 
Reporting of technical complaints to Novo Nordisk
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I
Technical complaints must be reported on a separate technical complaint form:
1.
One technical complaint form must be completed for each affected DUN
2.
If DUN is not available, a technical complaint form for each batch, code or lot number must be completed
Timelines for reporting of technical complaints to Novo Nordisk
The investigator must complete the technical complaint form in the CRF within the timelines specified in Figure 9-3.
If the CRF is unavailable or when reporting a technical complaint that is not subject related, the information must be 
provided on a paper form by fax, e-mail or courier to Customer Complaint Center, Novo Nordisk, within the same 
timelines as stated above. When the CRF becomes available again, the investigator must enter the information on the 
technical complaint form in the CRF.
Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the originally 
completed form
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and all associated parts that were packed in the same 
DUN and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all 
associated parts must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy 
of the completed technical complaint form. The technical complaint sample should contain the batch, code or lot 
number and, if available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on 
the technical complaint form. If several samples are shipped in one shipment, the sample and the corresponding 
technical complaint form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
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Retention of human biosamples
Antibody samples
x
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 reasons1.
x
Only Novo Nordisk staff and personnel from the specialised laboratory will have access to 
the stored specimens1.
x
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, or 
according to local regulation, but no longer than 15 years from end of trial after which they 
will be destroyed1.
x
Samples might be transferred to other countries, if not prohibited by local regulations. 
x
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 relatives1.
Subjects can contact the investigator if they wish to be informed about results derived from stored 
biosamples obtained from their own body1.
For country specific requirements, see Appendix 10.
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Hypoglycaemic episodes
For subject with T2D at screening
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)68. 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 
classification69:
1. Severe hypoglycaemia according to the ADA classification69.
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:
x
A hypoglycaemic episode with missing information on symptoms will be classified as 
without symptoms. 
x
A hypoglycaemic episode with missing information on being able to self-treat will be 
regarded as an episode where the subject was able to self-treat and classified in accordance 
with the able to self-treat classifications.
Episodes that cannot be classified according to the above, are included in one of the following 
categories:
x
‘Novo Nordisk unclassifiable’ includes episodes where subjects were able to self-treat and 
with PG ≥ 3.1 mmol/L (56 mg/dL) and hypoglycaemic episodes for a subject able to self-
treat with missing PG as it is to be treated as an episode with PG > 3.9 mmol/L (70 mg/dL).
x
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able to 
self-treat but neither of the following conditions were reported: PG ≤ 3.9 mmol/L (70 
mg/dL), alleviation of symptoms, seizure, unconscious/comatose or fatal.
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Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
2. Symptomatic 
BG confirmed 
hypoglycaemia
3. Asymptomatic 
BG confirmed 
hypoglycaemia
Yes
No
5. Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
4. BG confirmed 
hypoglycaemia
6. Severe or 
BG confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
1.Severe 
hypoglycaemia 
(ADA 2013)
Figure 11-1
Novo Nordisk classification of hypoglycaemia
ADA classification 69 of hypoglycaemia
x
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration.
x
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
x
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 
mg/dL).
x
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.
x
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
For hypoglycaemic episodes reported with missing information related to the classification, the 
following applies when classifying the episode according to the ADA classification:
x
A hypoglycaemic episode with missing information on symptoms will be classified as 
without symptoms. 
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x
A hypoglycaemic episode with missing information on being able to self-treat will be 
regarded as an episode where the subject was able to self-treat and classified in accordance 
with the able to self-treat classifications
Episodes that cannot be classified according to the above, are included in one of the following 
categories
x
‘ADA unclassifiable’ includes episodes where subjects were able to self-treat and with PG > 
3.9 mmol/L (70 mg/dL) or missing PG, and with no information on symptoms.
x
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able 
to self-treat but neither of the following conditions were reported: PG  ≤ 3.9 mmol/L (70 
mg/dL), alleviation of symptoms, seizure, unconscious/comatose or fatal
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Figure 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 hypoglycaemia69.
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Reporting of hypoglycaemic episodes:
PG should always be measured and recorded when a hypoglycaemic episode is suspected. 
All PG values:
≤ 3.9 mmol/L (70 mg/dL) or 
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms should be 
reported as a hypoglycaemic episode according to the flowchart and instructions below. When 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 guidelines69.
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 data70, 71.
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.
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.:
x
renal dysfunction
x
tobacco use
x
autoimmune thyroiditis
x
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various comorbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L, the algorithm outlined in Figure 11-3 and 
described below should be followed. The algorithm applies for all calcitonin values in the trial.
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Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease72. 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: 
x
thyroid ultrasound examination 
x
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. 
x
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery.
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin
according to the protocol.
If the subject is a screen failure, or if the value is from the last sample taken in the trial, the subject 
should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20–50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease72. 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.72 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 conclusions73, 74.
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Country-specific requirements 
The below list is not an exhausted list of country specific requirements. The list will only be 
updated in case of a global protocol amendment.
Section 5.2 Subject and trial completion
For China: Planned number of subjects to be randomised in China and Hong Kong is 300.
Section 6.2 Exclusion criteria
For Brazil:
32: Participation in other trials within one year prior to screening visit unless there is a direct benefit 
to the subject at the investigator’s discretion.
Section 7.5 Preparation/Handling/Storage/Accountability
For South Korea: In-use storage conditions:
Storage conditions:
x
Store in refrigerator (2°C-8°C)
x
Do not freeze
x
Protect from light
In-use conditions:
x
Store at 8-30°C
x
Do not refrigerate
x
Use within 8 weeks
x
Protect from light
Section 7.8 Treatment after the end of the trial
For Brazil: After the end of the trial the subject should be treated at the discretion of the 
investigator. Or the recommended treatment will be made available according to local regulations.
Appendix 2 Clinical laboratory results
For Brazil: All laboratory results will be communicated to the investigators.
Appendix 3, Section 1
1) Regulatory and ethical considerations
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x
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements. For China, an 
international cooperative relevant report of related China’s Human Genetic Resources will 
be submitted based on local regulation requirement.
Appendix 3, Section 8
For China: Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com.
For South Korea: Rescue medication will not be reimbursed in South Korea.
Appendix 5 Contraceptive guidance and collection of pregnancy information 
For Brazil: For women who expressively declare free of the risk pregnancy, either by not engaging 
in sexual activity or by having sexual activity with no birth potential risk (e.g. sex with a same sex 
partner), use of contraceptive method will not be mandatory. 
Appendix 7 Retention of human biosamples
For China: the laboratory samples for Chinese subjects will be destroyed at the latest at the 
completion of the CTR, including samples for anti-semaglutide antibody analysis. All laboratory 
samples will be destroyed according to local regulatory requirement.
For Brazil: Biological samples from Brazil will not be stored but destroyed after completion of the 
trial. 
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Protocol amendment history
Protocol version 5.0 (17 February 2020)
Overall rationale for preparing protocol, version 5.0:
To ensure that pregnancy test is performed “For all female subjects” before randomisation at visit 2.
Section # and name
Description of change
Brief rationale
Section 2 Flowchart
In the flowchart at Pregnancy test 
(9.4.6, Appendix 5) add “Pregnancy 
testb”and ”X” at Randomisation, V2
“b” after pregnancy test and ”X” are 
missing in protocol version 4.0. To 
ensure pregnancy test is performed 
for all female subjects before 
randomisation. 
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