Effect and Safety of Subcutaneous Semaglutide 2.4 mg Once Weekly Compared to Liraglutide 3.0 mg Once Daily on Weight Management in Subjects With Overweight or Obesity
Phase: PHASE3
Conditions: Overweight, Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04074161 
Sponsor trial ID: 
NN9536-4576  
Official title of study: 
Effect and safety of subcutaneous semaglutide 2.4 mg once 
weekly compared to liraglutide 3.0 mg once daily on weight 
management in subjects with overweight or obesity
Document date*: 
25 November 2020 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content.

Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Log of Protocols..................................................................................................................................
Attachment I and II............................................................................................................................
CONFIDENTIAL
Date:
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Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4576 (STEP 8)
Clinical Trial Report
Appendix 16.1.1
08 July 2021
1.0
Final
16.1.1 Protocol and protocol amendments
.
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 
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Protocol 
Protocol title: 
Effect and safety of subcutaneous semaglutide 2.4 mg once weekly compared to liraglutide 3.0 
mg once daily on weight management in subjects with overweight or obesity 
Substance names: semaglutide and liraglutide 
Universal Trial Number: U1111-1233-0977 
EUdraCT Number: N/A 
Trial phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
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.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Trial ID: NN9536-4576 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 4.0 
25 November 2020 
US 
Protocol version 3.0 
15 April 2020 
US 
Protocol version 2.0 
17 March 2020 
US 
Original protocol version 1.0 
 08 July 2019 
US 
Protocol version 4.0 (01 December 2020) 
This amendment is considered to be substantial. 
Overall rationale for preparing protocol, version 4.0: 
Co-participation in other clinical trials is generally not allowed while participating in a Novo 
Nordisk trial. However, given the large societal impact of the COVID-19 pandemic, Novo Nordisk 
will allow for co-participation in trials with the primary objective of evaluating an approved or 
non-approved investigational medicinal product for prevention or treatment of COVID-19 disease 
or postinfectious conditions. For the current trial it has been evaluated that the safety profiles of 
liraglutide and semaglutide are well established and based on current knowledge it is expected that 
co-participation in COVID-19 trials will not lead to unreasonable unforeseen risks for trial subjects. 
Discontinuation criterion 6 regarding simultaneous participation in other trials has thus been 
amended. 
Section # and name 
Description of change 
Brief rationale 
Section 8.1 
Amending the discontinuation 
criterion 6, so that subjects are 
allowed to continue in the trial, while 
also participating in a COVID-19 
trial. 
To allow for simultaneous 
participation in current trial and a 
COVID-19 trial.  
Overall rationale for preparing protocol, version 2.0 and 3.0: 
To improve ease of use and convenience for subjects, Novo Nordisk is developing a single dose 
pen-injector with an integrated prefilled syringe for semaglutide s.c. referred to as DV3396 pen-
injector. In order to generate clinical trial data with the DV3396 pen-injector, all 
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semaglutide/semaglutide placebo subjects will switch device from PDS290 to DV3396 at week 44 
(visit 18).  
Further, a new questionnaire (Injection Device Experience and Acceptance (IDEA) Questionnaire) 
will be introduced for subjects switching device. The questionnaire has a total of 21 questions and 
will be completed one time at the end of treatment visit (week 68). 
In Protocol version 2.0 there was a mistake in the summary of changes table, which is updated and 
therefore version 3.0. 
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Section # and name 
Description of change 
Brief rationale 
Section 1 Synopsis 
Adding information about the 
different doses provide in DV3396 
pen-injector. 
Adding new device. 
Section 2 Flowchart 
Adding information about trial 
product handling regarding DV3396 
pen-injector, IDEA questionnaire 
and Injection Device Experience and 
Acceptance Questionnaire.  
To ensure correct handling of trial 
product and correct collection of 
data. 
Section 3 Introduction. Section 3.3.2 
Risk and precautions 
Adding information about rationale 
and risk of the DV3396. 
To clarify the reason for the new 
device in this protocol. 
Section 7 
Adding information about the new 
device DV3396. 
To explain the new device, doses, 
trial product handling and ensure 
alignment. 
Section 9 Trial assessment and 
procedures 
Adding information about the new 
device, total drug accountability for 
the PDS290 pen-injectors and 
questionnaire to site staff about 
training of subjects in the DV3396. 
Adding new section 9.10: Pen-
injector use error for DV3396 pen-
injector. 
Adding missing information about 
how to evaluate subject’s glycaemic 
status and ADA guidance. 
To ensure alignment if definitions 
and provide guidance. 
Section 9.3 Treatment of overdose 
Adding safety information about 
liraglutide and hypoglycaemia.  
Adding new information on 
liraglutide. 
References added: 
• Novo Nordisk A/S. Investigator's Brochure, Semaglutide subcutaneous administration, 
Project NN9536 and NN9931, (edition 5). 20 Sep 2019. 
• Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care. 
2017;40(Suppl 1):S4-S5 
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Table of Contents 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 5 
1 
Synopsis ...................................................................................................................................................... 8 
2 
Flowchart ................................................................................................................................................. 12 
3 
Introduction ............................................................................................................................................. 14 
3.1 
Background .................................................................................................................................... 14 
3.2 
Trial rationale ................................................................................................................................. 15 
3.3 
Benefit-risk assessment .................................................................................................................. 16 
3.3.1 
Benefits ............................................................................................................................ 16 
3.3.2 
Risks and precautions ...................................................................................................... 17 
3.3.3 
Conclusion on benefit-risk profile ................................................................................... 19 
4 
Objectives and endpoints ........................................................................................................................ 19 
4.1 
Primary and secondary objectives ................................................................................................. 19 
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 ..................................................................... 21 
5 
Trial design .............................................................................................................................................. 22 
5.1 
Overall design ................................................................................................................................ 22 
5.2 
Subject and trial completion .......................................................................................................... 23 
5.3 
End of trial definition ..................................................................................................................... 23 
5.4 
Scientific rationale for trial design ................................................................................................. 23 
5.5 
Justification for dose ...................................................................................................................... 24 
6 
Trial population ....................................................................................................................................... 25 
6.1 
Inclusion criteria ............................................................................................................................ 25 
6.2 
Exclusion criteria ........................................................................................................................... 25 
6.3 
Lifestyle restrictions....................................................................................................................... 27 
6.3.1 
Meals and dietary restrictions .......................................................................................... 27 
6.3.2 
Caffeine and tobacco ....................................................................................................... 27 
6.4 
Screen failures ................................................................................................................................ 27 
7 
Treatments ............................................................................................................................................... 28 
7.1 
Treatments administered ................................................................................................................ 28 
7.1.1 
Semaglutide ..................................................................................................................... 29 
7.1.2 
Liraglutide ....................................................................................................................... 30 
7.1.3 
Auxiliary supplies ............................................................................................................ 31 
7.2 
Medical devices ............................................................................................................................. 32 
7.2.1 
Diet and physical activity counselling ............................................................................. 32 
7.3 
Dose modification .......................................................................................................................... 33 
7.4 
Method of treatment assignment .................................................................................................... 33 
7.5 
Shipment of trial product to subject’s home .................................................................................. 33 
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7.6 
Blinding ......................................................................................................................................... 34 
7.7 
Preparation/Handling/Storage/Accountability ............................................................................... 34 
7.8 
Treatment compliance .................................................................................................................... 35 
7.9 
Concomitant medication ................................................................................................................ 35 
7.10 
Treatment after the end of the trial................................................................................................. 36 
8 
Discontinuation/Withdrawal criteria .................................................................................................... 36 
8.1 
Discontinuation of trial treatment .................................................................................................. 36 
8.1.1 
Temporary discontinuation of trial treatment .................................................................. 37 
8.2 
Withdrawal from the trial ............................................................................................................... 37 
8.2.1 
Replacement of subjects .................................................................................................. 38 
8.3 
Lost to follow-up ........................................................................................................................... 38 
9 
Trial assessments and procedures ......................................................................................................... 38 
9.1 
Efficacy assessments ...................................................................................................................... 40 
9.1.1 
Body measurements ......................................................................................................... 40 
9.1.2 
Clinical efficacy laboratory assessments ......................................................................... 40 
9.2 
Adverse events ............................................................................................................................... 41 
9.2.1 
Time period and frequency for collecting AE and SAE information .............................. 41 
9.2.2 
Method of detecting AEs and SAEs ................................................................................ 43 
9.2.3 
Follow-up on AEs and SAEs ........................................................................................... 43 
9.2.4 
Regulatory reporting requirements for SAEs .................................................................. 43 
9.2.5 
Hypoglycaemic, Cardiovascular and death events .......................................................... 43 
9.2.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE ................................................................................................................................. 43 
9.2.7 
Pregnancies and associated adverse events ..................................................................... 44 
9.2.8 
Medical device incidents (including malfunctions) ......................................................... 44 
9.2.9 
Technical complaints ....................................................................................................... 44 
9.3 
Treatment of overdose ................................................................................................................... 45 
9.4 
Safety assessments ......................................................................................................................... 46 
9.4.1 
Mental health assessment instruments ............................................................................. 46 
9.4.2 
Physical examinations ..................................................................................................... 47 
9.4.3 
Vital signs ........................................................................................................................ 47 
9.4.4 
Electrocardiograms .......................................................................................................... 47 
9.4.5 
Clinical safety laboratory assessments ............................................................................ 47 
9.5 
Pharmacokinetics ........................................................................................................................... 47 
9.6 
Pharmacodynamics ........................................................................................................................ 47 
9.7 
Genetics ......................................................................................................................................... 48 
9.8 
Biomarkers ..................................................................................................................................... 48 
9.9 
Severe hypersensitivity .................................................................................................................. 48 
9.10 
Pen-injector use error for DV3396 pen-injector ............................................................................ 48 
10 Statistical considerations ........................................................................................................................ 48 
10.1 
Sample size determination ............................................................................................................. 49 
10.2 
Definition of analysis sets .............................................................................................................. 50 
10.3 
Statistical analyses ......................................................................................................................... 51 
10.3.1 
Primary endpoint ............................................................................................................. 51 
10.3.2 
Secondary endpoints ........................................................................................................ 53 
10.3.2.1 Confirmatory secondary endpoints ................................................................. 53 
10.3.2.2 Supportive secondary endpoints ..................................................................... 53 
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10.4 
Interim analysis .............................................................................................................................. 53 
11 Appendices ............................................................................................................................................... 54 
Appendix A 
Abbreviations and Trademarks .......................................................................................... 55 
Appendix B 
Clinical laboratory tests ....................................................................................................... 57 
Appendix C 
Trial governance considerations ......................................................................................... 60 
Appendix D 
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
and reporting ........................................................................................................................................... 69 
Appendix E 
Contraceptive guidance and collection of pregnancy information ................................... 75 
Appendix F 
Technical complaints: Definition and procedures for recording, evaluation, follow-
up and reporting ...................................................................................................................................... 78 
Appendix G 
Monitoring of calcitonin ....................................................................................................... 80 
12 References ................................................................................................................................................ 83 
Attachment I Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country 
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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 
extensive, and obesity is one of the most significant public health challenges worldwide1-7. 
Obesity is associated with an increased risk of a variety of comorbidities including hyperglycaemia, 
type 2 diabetes (T2D), dyslipidaemia, hypertension, cardiovascular disease, obstructive sleep 
apnoea, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), urinary 
incontinence, several types of cancers, and increased mortality8-22. 
The risk of obesity-related 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 on many 
obesity related comorbidities as well as physical symptoms and quality of life23. 
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss24-32. 
The present trial will compare the effect on body weight and safety of semaglutide s.c. 2.4 mg once 
weekly versus liraglutide s.c. 3.0 mg once daily as an adjunct to a reduced-calorie diet and 
increased physical activity in subjects with overweight or obesity. The 68 weeks duration of the trial 
ensures a treatment period of 52 weeks at the maintenance dose of semaglutide. This will make it 
possible to compare the effect and safety of once weekly semaglutide for weight management after 
52 weeks of maintenance dose with the already marketed anti-obesity medication liraglutide s.c. 3.0 
mg once daily. 
Objectives and endpoints 
Primary objective 
To show the superiority of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 mg once daily 
both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity or 
with overweight and at least one weight related comorbidity on body weight. 
Secondary objectives 
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 
mg once daily both as adjuncts to reduced-calorie diet and increased physical activity in subjects 
with obesity or with overweight and at least one weight related comorbidity. 
To compare the effect of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 mg once daily 
both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity or 
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with overweight and at least one weight related comorbidity on cardiovascular risk factors and 
glucose metabolism.  
To show the superiority of semaglutide s.c. 2.4 mg once weekly versus placebo both as adjuncts to a 
reduced-calorie diet and increased physical activity in subjects with obesity or with overweight and 
at least one weight related comorbidity on body weight. 
To show the superiority of liraglutide s.c. 3.0 mg once daily versus placebo both as adjuncts to a 
reduced-calorie diet and increased physical activity in subjects with obesity or with overweight and 
at least one weight related comorbidity on body weight. 
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to liraglutide after 
68 weeks, as adjuncts 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. 
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of semaglutide s.c. 2.4 mg relative to placebo 
after 68 weeks, as an adjunct to reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of starting rescue 
interventions. 
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of liraglutide s.c. 3.0 mg relative to placebo after 
68 weeks, as an adjunct to reduced-calorie diet and increased physical activity, in all randomised 
subjects regardless of adherence to treatment and regardless of starting rescue interventions. 
Secondary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to liraglutide after 
68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all randomised 
subjects had they remained on their randomised treatment for the entire planned duration of the trial 
and not started any rescue intervention (weight management drugs or bariatric surgery) 
(“hypothetical” estimand). The estimand will cover the primary objective. 
Primary endpoint 
• Change from baseline (week 0) to week 68 in body weight (%) 
Confirmatory secondary endpoints 
• Subject who from baseline (week 0) to week 68 achieve (yes/no): 
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o Body weight reduction ≥10% 
o Body weight reduction ≥15% 
o Body weight reduction ≥20% 
Overall design: 
This is a 68-week, randomised, open label, pairwise placebo-controlled, multi-centre, US only 
clinical trial comparing semaglutide s.c. 2.4 mg once weekly with liraglutide s.c. 3.0 mg once daily 
in subjects with overweight or obesity. Semaglutide once weekly vs liraglutide once daily treatment 
will be open label, but each of the two active treatment arms will be double blinded against placebo 
administered at the same dosing frequency. 
Key Inclusion criteria 
1. Male or female, age ≥ 18 years at the time of signing informed consent 
2. Body mass index (BMI) ≥ 30.0 kg/m2 or ≥ 27.0 kg/m2 with the presence of at least one of 
the following weight-related comorbidities (treated or untreated): hypertension, 
dyslipidaemia, obstructive sleep apnoea or cardiovascular disease 
3. History of at least one self-reported unsuccessful dietary effort to lose body weight 
Key exclusion criteria 
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening 
2. History of type 1 or type 2 diabetes mellitus 
3. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records 
Number of subjects: 
Approximately 396 subjects will be screened to achieve 336 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
Eligible subjects will be randomised in a 3:1:3:1 manner to receive either semaglutide s.c. 2.4 mg 
once weekly, semaglutide placebo, liraglutide s.c. 3.0 mg once daily or liraglutide placebo. 
The total trial duration for the individual subject will be approximately 76 weeks, including a one 
week screening period to assess the subject´s eligibility, a 68 week treatment period, and a follow 
up period of 7 weeks. The treatment period will include 16 weeks of dose escalation in the 
semaglutide/semaglutide placebo arms, and 4 weeks of dose escalation in the liraglutide/liraglutide 
placebo arms. The follow up period of 7 weeks is included to account for the long half-life of 
semaglutide. 
The following trial products will be supplied by Novo Nordisk A/S: 
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• Semaglutide B 3.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector. 
• Liraglutide 6.0 mg/mL PDS290 and liraglutide placebo, solution for injection, 3 mL 
PDS290 pre-filled pen-injector. 
At week 44 (visit 18) all subjects treated with semaglutide/semaglutide placebo will switch from the 
PDS290 pen-injector to DV3396 pen-injector. 
From week 44: 
• Semaglutide D 0.5 mg/mL DV3396 or semaglutide placebo Ia, solution for injection, 0.5 
mL DV3396 pen-injector. 
• Semaglutide D 1.0 mg/mL DV3396 or semaglutide placebo Ia, solution for injection, 0.5 
mL DV3396 pen-injector. 
• Semaglutide D 2.0 mg/mL DV3396 or semaglutide placebo Ia, solution for injection, 0.5 
mL DV3396 pen-injector. 
• Semaglutide D 2.27 mg/mL DV3396 or semaglutide placebo Ia, solution for injection, 0.75 
mL DV3396 pen-injector. 
• Semaglutide D 3.2 mg/mL DV3396 or semaglutide placebo Ib, solution for injection, 0.75 
mL DV3396 pen-injector. 
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2 
Flowchart 
 
Screening Randomisation 
Treatment period 
End of 
treatment 
End of 
trial 
Visit 
V1 
V2 
V3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 V19 V20 V21 
V22 
V23 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 12 14 
16 
18 
20 
24 
28 
32 
36 
40 
44 
50 
56 
62 
68 
75 
Visit Window (Days) 
-7 to 0 
0 
±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
Informed consent and Demographya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria (6.1 and 6.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS and PHQ-9 (9.4.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Barriers and motivation interview (9) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection Device Experience and Acceptance Questionnaire b  
(7.9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Medical History/Concomitant Illness (9.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight history (9) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Usec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication  (7.9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Trial product compliance (7.1) (7.8) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body measurements (9.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Body Weight 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
    Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Waist Circumference 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Attend visit fasting (6.3.1) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Laboratory Assessment (Appendix B) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Vital Signs (9.4.3) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination (9.4.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test (9.4.5) (Appendix E) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
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Screening Randomisation 
Treatment period 
End of 
treatment 
End of 
trial 
Visit 
V1 
V2 
V3 V4 P5 V6 P7 V8 P9 V10 P11 V12 P13 V14 P15 V16 P17 V18 V19 V20 V21 
V22 
V23 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 12 14 
16 
18 
20 
24 
28 
32 
36 
40 
44 
50 
56 
62 
68 
75 
Visit Window (Days) 
-7 to 0 
0 
±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
Pen-injector use error (9.10) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
ECG (9.4.4) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Adverse event (9.2) (Appendix D) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of lipid-lowering treatment (9) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Evaluation of antihypertensive treatment (9) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Evaluation of glycaemic status (9) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Breast Neoplasms Follow-up 9.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Colon Neoplasms Follow-up (9.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug dispensing (7) 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Diet and physical activity counselling (7.2.1) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Training in devices (7.1) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
a Demography consists of date of birth, sex, ethnicity and race. 
b Applies only for subjects receiving semaglutide/semaglutide placebo. 
c Smoking is defined as smoking at least one cigarette or equivalent daily. 
 
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3 
Introduction 
3.1 
Background 
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 
extensive and obesity is one of the most significant public health challenges worldwide1-7. 
Obesity is associated with an increased risk of a variety of comorbidities including hyperglycaemia, 
type 2 diabetes (T2D), dyslipidaemia, hypertension, cardiovascular disease, obstructive sleep 
apnoea, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), urinary 
incontinence, several types of cancers, and increased mortality8-22. 
The risk of obesity-related 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 on many 
obesity related comorbidities as well as physical symptoms and quality of life23. 
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss24-32. 
Glucagon-like-peptide (GLP-1) is a physiological regulator of appetite and postprandial GLP-1 
response is present in several areas of the brain involved in appetite regulation33. 
Semaglutide is the next generation GLP-1 receptor agonist (RA) currently under development by 
Novo Nordisk for the treatment of weight management. Semaglutide has a half-life of 
approximately 160 hours, making it suitable for once-weekly dosing34. 
Clinical35 and non-clinical36 data indicate that the body weight reducing effect of semaglutide is 
mainly mediated by a reduced energy intake. 
The GLP-1 receptor agonist liraglutide 3.0 mg is approved for weight management with once daily 
dosing and is launched under the brand name Saxenda®. In the development programme, treatment 
with liraglutide 3.0 mg as adjunct to diet and exercise resulted in significantly greater weight loss 
than diet and exercise alone in subjects with obesity or overweight with at least one weight-related 
comorbidity37. 
A 52-week phase 2 dose-finding trial in weight management with semaglutide (NN9536-4153) has 
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). An overall 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) 
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compared to the weight loss of  7.8% with liraglutide and of 2.3% achieved by diet, exercise and 
placebo alone38. 
No unexpected safety findings were identified, and the tolerability and the safety profile were 
overall consistent with previous findings in the T2D development programme for semaglutide and 
with the GLP-1 RA class in general38. 
The phase 3a programme for semaglutide for weight management is currently ongoing. 
A comprehensive review of results from the non-clinical and clinical studies of semaglutide and 
liraglutide can be found in the current edition of the investigator’s brochures (IB)39, 40 and any 
updates hereof. 
3.2 
Trial rationale 
In the phase 2 trial with semaglutide for weight management, semaglutide was administered once 
daily, while the dose for semaglutide in the phase 3 programme is 2.4 mg once weekly. The 
decision to dose once weekly in phase 3a and in this trial is that the pharmacokinetic properties and 
the efficacy and tolerability data obtained with semaglutide allow patients to get the benefit of more 
convenient once weekly injections.  
The phase 2 trial had a total duration of 52 weeks, and the mean weight loss with the highest dose 
of semaglutide appeared to continue at week 5241. 
The present trial will compare the effect on body weight and safety of semaglutide s.c. 2.4 mg once 
weekly versus liraglutide s.c. 3.0 mg once daily as an adjunct to a reduced-calorie diet and 
increased physical activity in subjects with overweight or obesity. The duration of the trial is 68 
weeks which ensures a treatment period of 52 weeks at the maintenance dose of semaglutide s.c. of 
2.4 mg.  
To further improve ease of use and convenience for subjects, Novo Nordisk is developing a single 
dose pen-injector with an integrated prefilled syringe for semaglutide s.c. referred to as DV3396 
pen-injector. In order to generate clinical trial data with the DV3396 pen-injector, this pen-injector 
will be included in the trial from week 44 (visit 18). The DV3396 pen-injector will be similar for all 
doses, however, with a dose volume of 0.5 mL for the three lower doses (0.25 mg, 0.5 mg and 1 
mg) and 0.75 mL for the two higher doses (1.7 mg and 2.4 mg). In order to administer the five 
doses with the DV3396 pen-injector, the semaglutide drug product (semaglutide D) will be 
available in five concentrations: 0.5 mg/mL, 1.0 mg/mL, 2.0 mg/mL, 2.27 mg/mL and 3.2 mg/mL. 
The drug product formulation (semaglutide D) is similar to the current phase 3a drug product 
formulation for semaglutide 1.0 mg/mL and 3.0 mg/mL solution for injection (semaglutide B); 
except that the solutions do not contain phenol (preservative), as the DV3396 pen-injector is 
intended for single use.  
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Data obtained in this study will allow direct comparison of the effect and safety of once weekly 
semaglutide for weight management after 52 weeks of maintenance dose with the already marketed 
anti-obesity medication liraglutide s.c. 3.0 mg once daily. 
The trial population will consist of subjects with obesity (BMI ≥ 30.0 kg/m2) or overweight (BMI ≥ 
27.0 kg/m2) and at least one weight-related comorbidity. These subjects represent a clinically 
relevant population for pharmacotherapeutic weight management as they are at significant risk for 
weight related morbidities and mortality and are likely to benefit from weight reduction. 
Information about weight-related comorbidities, including hypertension, dyslipidaemia, obstructive 
sleep apnoea or cardiovascular disease, will be collected systematically at screening by the 
investigators as part of the medical history.  
Subjects with T2D are excluded from the trial. Treatment with semaglutide for weight management 
in subjects with overweight or obesity and T2D is being addressed in a dedicated phase 3a trial 
(NN9536-4374).  
First line treatment in weight management should always be lifestyle modification through a 
reduced-calorie diet and increased physical activity. Only subjects who have tried but failed a 
dietary weight loss intervention will be included in this trial in accordance with regulatory 
guidelines42, 43. 
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 profile41.  
Results from the clinical development programme for liraglutide for weight loss demonstrated that 
liraglutide 3.0 mg, as an adjunct to a reduced calorie diet and increased physical activity, was 
effective for weight loss in subjects with overweight or obesity while displaying a satisfactory 
tolerability profile44. 
Weight loss with either semaglutide or liraglutide in clinical trials 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 assessments41, 44. 
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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 and precautions associated with 
semaglutide and liraglutide treatment. For classification and further details, please refer to the 
current version of the IBs or any updates hereof39, 40. The identified/potential risks are based on 
findings in non-clinical studies and clinical trials with semaglutide, liraglutide as well as other GLP-
1 RAs. For each of these risks and precautions, mitigating actions have been implemented to 
minimise the risks for subjects enrolled in this trial. 
Semaglutide 
When used in accordance with the directions for use, the risk associated with the semaglutide 
formulations to be used in the DV3396 pen-injector are considered to be similar to the risk 
associated with the semaglutide formulation used in the PDS290 pen-injector. Local reactions at the 
injection site may be seen; these include pain, redness, warmth, hives, swelling, itching and bruising 
and are usually of short duration. 
Gastrointestinal adverse events 
• Consistent with findings with other GLP-1 RAs, the most frequently reported adverse events 
(AE) in clinical trials with semaglutide were gastrointestinal AEs. A low starting dose and 
dose escalation steps will be implemented in the trial to mitigate the risk of gastrointestinal 
AEs. 
Cholelithiasis 
• Events of cholelithiasis were the most frequently reported gallbladder events in the phase 2 
weight management trial (NN9536-4153) and were in a few instances co-reported with the 
event adjudication committee (EAC) confirmed acute pancreatitis. As a precaution, if 
cholelithiasis is suspected, appropriate clinical follow-up is to be initiated at the 
investigator’s discretion. 
Acute pancreatitis 
• Acute pancreatitis has been observed with the use of GLP-1 RA drug class. As a precaution, 
subjects with a history of chronic pancreatitis or recent acute pancreatitis will not be 
enrolled in the trial. In addition, trial product should be discontinued in case of suspicion of 
acute pancreatitis in accordance to section 8.1. 
Medullary thyroid cancer (MTC) (based on non-clinical data) 
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• 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. 
Pancreatic cancer 
• There is currently no support from non-clinical studies, clinical trials or post-marketing data 
that GLP-1 RA based therapies increase the risk of pancreatic cancer, but pancreatic cancer 
has been classified as a potential class risk of GLP-1 RAs by European Medicines Agency. 
As a precaution, subjects with a history of malignant neoplasms within the past 5 years prior 
to screening will be excluded from the trial. 
Allergic reactions 
• As is the case with all protein-based pharmaceuticals, subjects treated with semaglutide are 
at risk of developing immunogenic and allergic reactions. As a precaution, subjects with 
known or suspected hypersensitivity to semaglutide or related products will not be enrolled 
in this trial. 
Pregnancy and fertility (based on non-clinical data) 
• Studies in animals have shown reproductive toxicity. There are limited data from the use of 
semaglutide in pregnant women. Therefore, semaglutide should not be used during 
pregnancy. Exclusion and discontinuation criteria related to pregnancy have been 
implemented in the trial. 
Liraglutide 
Liraglutide shares the same risks as presented for semaglutide. In addition to the above, the 
following risks have also been associated with liraglutide treatment. 
Altered renal function 
• During post-marketing surveillance of spontaneous reports from marketed use of liraglutide 
for T2D (Victoza®), Novo Nordisk A/S identified reports of acute renal failure. These 
events mainly occurred in relation to dehydration as the result of gastrointestinal adverse 
events, and the majority were reported in patients with pre-existing renal impairment. 
Patients should be advised of the potential risk of dehydration in relation to gastrointestinal 
side effects and take precautions to avoid fluid depletion. 
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Acute gallstone disease 
• Events of acute gallstone disease including cholelithiasis and cholecystitis were reported 
more commonly in subjects treated with liraglutide 3.0 mg compared to placebo during the 
development programme for liraglutide for weight management. From literature it is well 
known that obesity carries an increased risk of cholelithiasis and that an association between 
rapid and marked weight loss and the development of cholelithiasis is present. Both 
cholelithiasis and cholecystitis have possible clinical implications for the patients as the 
events might lead to hospitalization and cholecystectomy.  
Neoplasms (including melanoma) 
• Patients with overweight or obesity have an increased risk of certain types of cancer. In the 
liraglutide weight management programme, the reporting rate of neoplasm events confirmed 
by event adjudication was similar with liraglutide and placebo. A limited number of reports 
in the weight management programme identified a numerical imbalance in events of 
malignant melanoma, breast neoplasms in females and colorectal adenomas in males. 
3.3.3 
Conclusion on benefit-risk profile 
Necessary precautions have been implemented in the design and planned conduct of the trial to 
minimise the risks and inconveniences of participation in the trial. The safety profiles for 
semaglutide and liraglutide generated from the clinical and non-clinical development programmes 
have not revealed any safety issues that would prohibit administration of semaglutide s.c. 2.4 mg 
once-weekly or liraglutide 3.0 mg once-daily, and both products can 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 would be provided to subjects included in the trial.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of semaglutide and liraglutide may be found in the investigator´s 
brochures39, 40. 
4 
Objectives and endpoints 
4.1 
Primary and secondary objectives 
Primary objective 
To show the superiority of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 mg once daily 
both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity or 
with overweight and at least one weight related comorbidity on body weight. 
Secondary objectives 
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To compare the safety and tolerability of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 
mg once daily both as adjuncts to reduced-calorie diet and increased physical activity in subjects 
with obesity or with overweight and at least one weight related comorbidity. 
To compare the effect of semaglutide s.c. 2.4 mg once weekly versus liraglutide 3.0 mg once daily 
both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity or 
with overweight and at least one weight related comorbidity on cardiovascular risk factors and 
glucose metabolism 
To show the superiority of semaglutide s.c. 2.4 mg once weekly versus placebo both as adjuncts to a 
reduced-calorie diet and increased physical activity in subjects with obesity or with overweight and 
at least one weight related comorbidity on body weight. 
To show the superiority of liraglutide s.c. 3.0 mg once daily versus placebo both as adjuncts to a 
reduced-calorie diet and increased physical activity in subjects with obesity or with overweight and 
at least one weight related comorbidity on body weight. 
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to liraglutide after 
68 weeks, as adjuncts 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. 
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of semaglutide s.c. 2.4 mg relative to placebo 
after 68 weeks, as an adjunct to reduced-calorie diet and increased physical activity, in all 
randomised subjects regardless of adherence to treatment and regardless of starting rescue 
interventions. 
The following expansion of the primary estimand will cover objectives related to weight. The 
estimand will quantify the average treatment effect of liraglutide s.c. 3.0 mg relative to placebo after 
68 weeks, as an adjunct to reduced-calorie diet and increased physical activity, in all randomised 
subjects regardless of adherence to treatment and regardless of starting rescue interventions. 
Secondary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to liraglutide after 
68 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in all randomised 
subjects had they remained on their randomised treatment for the entire planned duration of the trial 
and not started any rescue intervention (weight management drugs or bariatric surgery) 
(“hypothetical” estimand). The estimand will cover the primary objective. 
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The handling of intercurrent events with respect to data collection and analysis is specified in 
Table 4-1 for the primary endpoint. Apart from the listed intercurrent events, missing data will 
occur due to death, or if subjects withdraw consent, become lost to follow-up, or continue to be 
followed without being ascertained for the endpoint. 
Table 4-1 
Handling of intercurrent events for the primary endpoint 
Intercurrent event 
Data collection  
Data analysis 
Premature treatment discontinuation 
Subjects will be followed and data 
collected after intercurrent events 
Primary estimand: data collected 
after intercurrent events used in 
analysis in line with a treatment-
policy strategy 
 
Secondary estimand: data 
collected after intercurrent events 
treated as missing in line with a 
hypothetical strategy 
Initiation of other weight management 
drugs or bariatric surgery  
4.2 
Primary and secondary endpoints 
4.2.1 
Primary endpoint 
• Change from baseline (week 0) to week 68 in body weight (%) 
4.2.2 
Secondary endpoints 
4.2.2.1 
Confirmatory secondary endpoints 
• Subject who from baseline (week 0) to week 68 achieve (yes/no): 
o Body weight reduction ≥10% 
o Body weight reduction ≥15% 
o Body weight reduction ≥20% 
4.2.2.2 
Supportive secondary endpoints 
The supportive secondary endpoints are used to compare the effect of semaglutide s.c. 2.4 mg once-
weekly versus liraglutide 3.0 mg once-daily unless otherwise stated: 
• Change from baseline (week 0) to week 68 in waist circumference (cm) 
• Change from baseline (week 0) to week 68 in body weight (%) (semaglutide s.c. 2.4 mg 
once-weekly versus placebo and liraglutide s.c. 3.0 mg once-daily versus placebo) 
• Change from baseline (week 0) to week 68 in: 
o systolic blood pressure (mmHg) 
o lipids (mg/dL) 
▪ Total cholesterol 
▪ High density lipoprotein (HDL) cholesterol 
▪ Low density lipoprotein (LDL) cholesterol 
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▪ Very low density lipoprotein (VLDL) cholesterol 
▪ Free fatty acids (FFA) 
▪ Triglycerides 
o hsCRP (mg/L) 
o HbA1c (%) 
o fasting plasma glucose (mg/dL) 
o glycaemic category (normo-glycaemia, pre-diabetes, T2D) 
• Subjects who from baseline (week 0) to week 68 have permanently discontinued randomised 
trial product (yes/no) 
• Number of treatment emergent adverse events (TEAEs) from baseline (week 0) to week 75 
• Number of serious adverse events (SAEs) from baseline (week 0) to week 75 
5 
Trial design 
5.1 
Overall design 
This is a 68-week, randomised, open label, pairwise placebo-controlled, multi-centre, US only 
clinical trial comparing semaglutide s.c. 2.4 mg once weekly with liraglutide s.c. 3.0 mg once daily 
in subjects with overweight or obesity. Semaglutide once weekly vs liraglutide once daily treatment 
will be open label, but each of the two active treatment arms will be double blinded against placebo 
administered at the same dosing frequency. 
The trial includes a screening visit to assess the subject’s eligibility followed by visits/phone 
contacts every 2nd week until week 20. From week 20, visits/phone contacts will take place every 
4th week until week 44 and then every 6 weeks until end of treatment (week 68). A follow-up visit 
(‘End of trial’) for safety assessments is scheduled 7 weeks after end of treatment to account for the 
long half-life of semaglutide. 
Eligible subjects will be randomised in a 3:1:3:1 manner to receive either semaglutide s.c. 2.4 mg 
once weekly or semaglutide placebo once weekly or liraglutide s.c. 3.0 mg once daily or liraglutide 
placebo once daily as an adjunct to a reduced-calorie diet and increased physical activity. 
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Figure 5-1
A schematic diagram of the trial design
5.2
Subject and trial completion
Approximately 396 subjects will be screened to achieve 336 subjects randomly assigned to trial
product.
Trial period completion for a subject:
Trial period completion is defined as when the randomised subject has completed the final 
scheduled visit ('end of trial' according to the flowchart).
'Date of trial completion' is the date the subject completed the final scheduled visit.
Treatment period completion for a subject: 
Treatment period completion is defined as when the randomised subject 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 trial population will consist of subjects with obesity (BMI ≥ 30.0 kg/m2) or with overweight 
(BMI ≥ 27.0 kg/m2) and at least one weight-related comorbidity. These subjects represent a 
clinically relevant population for pharmacotherapeutic weight management as they are at significant 
risk for weight related comorbidities and mortality and are likely to benefit from weight reduction. 
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The treatment length will be 68 weeks to allow for 52 weeks at maintenance dose of semaglutide 
after 16 weeks of dose escalation.  
The follow up period of 7 weeks is included to account for the long half-life of semaglutide. 
To mitigate potential bias, the trial is randomised and both active treatment arms are controlled 
against placebo in a double blinded design.  
We know that some patients treated with placebo and lifestyle intervention have a considerate 
weight loss. We include a double blinded placebo arm matching each of the active treatment arms 
so that both the investigator and the subjects will be unaware if they are on active treatment or not.  
The comparison between semaglutide s.c. once weekly vs liraglutide s.c. once daily is open label 
due to the differences in the length of the titration periods and differences in the treatment policies. 
The treatment of subjects who do not tolerate the maximum dose of trial product is different in the 
two arms, as it for semaglutide is aligned with the method used in the 3a programme for 
semaglutide for the treatment of obesity, while it is aligned with the approved label for Saxenda in 
the liraglutide arm.  
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 
tolerability profile. Using population pharmacokinetic (Pop-PK) modelling, it was estimated that a 
once-weekly maintenance dose of semaglutide s.c. 2.4 mg will result in similar Cmax at steady-state 
as that obtained by the once-daily 0.4 mg semaglutide dose in trial NN9536-4153. 
A maintenance dose of semaglutide s.c. 2.4 mg 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 0.24 mg 
and follow a fixed-dose escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 
1.7 and 2.4 mg/week), until the target dose is reached after 16 weeks. 
It is well known that to mitigate gastrointestinal side effects with GLP-1 RA treatment, dose 
escalation to the target dose is required.  
For semaglutide, based on experience from the semaglutide T2D development programme, a fixed-
dose escalation regimen was selected, with dose escalation every 4 weeks until the target dose is 
reached. 
For liraglutide, clinical trials in adults with or without obesity and with or without T2D have 
demonstrated that liraglutide should be initiated at a daily dose of 0.6 mg, with subsequent dose 
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escalation in 0.6 mg weekly increments until reaching the maintenance dose. The dose of liraglutide 
s.c. 3.0 mg once daily has been tested in the clinical development programme for liraglutide for 
weight management. 
Please refer to section 7 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 the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial 
2. Male or female, age ≥ 18 years at the time of signing informed consent 
3. Body mass index (BMI) ≥ 30.0 kg/m2 or ≥ 27.0 kg/m2 with the presence of at least one of the 
following weight-related comorbidities (treated or untreated): hypertension, dyslipidaemia, 
obstructive sleep apnea or cardiovascular disease 
4. History of at least one self-reported unsuccessful dietary effort to lose body weight 
 
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
6.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
 
Glyceamia related: 
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening 
2. History of type 1 or type 2 diabetes mellitus 
3. Treatment with glucose-lowering agent(s) within 90 days before screening 
Obesity related: 
4. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records 
5. Treatment with any medication for the indication of obesity within the past 90 days before 
screening 
6. Previous or planned (during the trial period) obesity treatment with surgery or a weight loss 
device. However, the following are allowed: (1) liposuction and/or abdominoplasty, if 
performed > 1 year before screening, (2) lap banding, if the band has been removed > 1 year 
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before screening, (3) intragastric balloon, if the balloon has been removed > 1 year before 
screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before 
screening 
7. Uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 
0.35 mIU/L as measured by the central laboratory at screening 
Mental health: 
8. History of major depressive disorder within 2 years before screening 
9. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder) 
10. A Patient Health Questionnaire-9 (PHQ-9) score ≥ 15 at screening 
11. A lifetime history of suicidal attempt 
12. Suicidal behaviour within 30 days before screening 
13. Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) within the past 30 days before screening 
General Safety: 
14. Presence of acute pancreatitis within the past 180 days prior to the day of screening 
15. History or presence of chronic pancreatitis 
16. Calcitonin ≥ 100 ng/L as measured by the central laboratory at screening 
17. Personal or first-degree relative history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma 
18. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR <15 
ml/min/1.73 m2 as defined by KDIGO 201245 by the central laboratory at screening 
19. History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous 
cell skin cancer and any carcinoma in-situ are allowed 
20. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening. 
21. Subject presently classified as being in New York Heart Association (NYHA) Class IV 
22. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator 
23. Known or suspected abuse of alcohol or recreational drugs 
24. Known or suspected hypersensitivity to trial product(s) or related products.  
25. Previous participation in this trial. Participation is defined as signed informed consent. 
26. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening. 
27. Other subject(s) from the same household participating in any semaglutide or liraglutide trial 
28. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method 
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29. 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. 
6.3 
Lifestyle restrictions 
To ensure alignment regarding performance of assessments across subjects and trial sites, the below 
restrictions apply. 
6.3.1 
Meals and dietary restrictions 
• Subjects must attend visits fasting according to the flowchart. 
• Fasting is defined as at least 8 hours before the visit without food or liquids, except for water. 
Trial product and any medication which should be taken with or after a meal should be withheld 
on the day of the visit until blood samples have been obtained. 
• If the subject is not fasting as required, the subject should be called in for a new visit within the 
visit window to have the fasting procedures done. Procedures requiring the subject to fast 
include blood sampling of FPG, fasting serum insulin and free fatty acids. 
6.3.2 
Caffeine and tobacco 
Subjects should avoid caffeine and smoking at least 30 minutes prior to measuring blood pressure. 
6.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes date of informed consent, 
date of visit, demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters.  
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7 
Treatments 
7.1 
Treatments administered 
• All trial products listed in  Table 7-1 and Table 7-2 are considered investigational medicinal 
products (IMP). 
• Total drug accountability for the PDS290 pen-injectors for semaglutide/semaglutide placebo 
must be performed at visit 18. 
• The investigator must document that directions for use are given to the subject orally and in 
writing at the first dispensing visit as specified in the flowchart. 
• It is recommended that the investigator consults Novo Nordisk in case of persistent deviations 
from the planned escalation regimen. 
• A dose reminder card will be handed out to the subjects at each site visit during the escalation 
period. This is to remind the subjects of the dose to be taken until next site visit and provide a 
conversion of the dose to value shown in the dose counter. Once the target dose has been 
reached, the dose reminder card is only handed out as needed. 
Table 7-1 
Trial products provided by Novo Nordisk A/S 
Trial product name: 
 
Liraglutide 6.0 mg/mL or Liraglutide 
placebo 
Semaglutide B 3.0 mg/mL or 
Semaglutide placebo  
Dosage form: 
 
Solution for injection 
Solution for injection 
Route of administration:  
 
Subcutaneous 
Subcutaneous 
Dosing instructions: 
 
Once-daily  
Once-weekly 
Delivery device 
 
3 mL PDS290 pre-filled pen-injector 
3 mL PDS290 pre-filled pen-injector 
At visit 18 (week 44) all semaglutide/semaglutide placebo subjects will switch from the PDS290 
pen-injector to the DV3396 pen-injector. 
Table 7-2 
 Semaglitide/semaglutide placebo trial products from visit 18/week 44 
Trial product name 
Dose 
Dosage 
form 
Route 
Dosage 
instructions 
Delivery device  
Semaglutide D 0.5 mg/mL 
DV3396  
0.25 mg 
Solution for 
injection 
s.c. 
Once-
weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 1.0 mg/mL 
DV3396  
0.5 mg 
Solution for 
injection 
s.c. 
Once-
weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 2.0 mg/mL 
DV3396  
1.0 mg 
Solution for 
injection 
s.c. 
Once-
weekly 
0.5 mL DV3396 
pen-injector 
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Semaglutide placebo Ia 
NA 
Solution for 
injection 
s.c 
Once-
weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 2.27 mg/mL 
DV3396  
1.7 mg 
Solution for 
injection 
s.c. 
Once-
weekly 
0.75 mL DV3396 
pen-injector 
Semaglutide D 3.2 mg/mL 
DV3396  
2.4 mg 
Solution for 
injection 
s.c. 
Once-
weekly 
0.75 mL DV3396 
pen-injector 
Semaglutide placebo Ib 
NA 
Solution for 
injection 
s.c. 
Once-
weekly 
0.75 mL DV3396 
pen-injector 
7.1.1 
Semaglutide 
• Dose escalation of semaglutide/semaglutide placebo should take place during the first 16 weeks 
after randomisation as described in Table 7-3. All subjects should aim at reaching the 
recommended target dose of semaglutide 2.4 mg once-weekly or the corresponding volume of 
semaglutide placebo. 
Table 7-3 
Dose escalation and maintenance of semaglutide 2.4 mg once-
weekly/semaglutide placebo  
Trial product name 
Dose 
Value shown in dose counter 
Duration 
Dose escalation period 
Semaglutide B 3.0 mg/mL PDS290/ 
semaglutide placebo 
0.24 mg 
8 
4 weeks 
Semaglutide B 3.0 mg/mL PDS290/ 
semaglutide placebo 
0.5 mg 
17 
4 weeks 
Semaglutide B 3.0 mg/mL PDS290/ 
semaglutide placebo 
1.0 mg 
34 
4 weeks 
Semaglutide B 3.0 mg/mL PDS290/ 
semaglutide placebo 
1.7 mg 
57 
4 weeks 
Maintenance period 
Semaglutide B 3.0 mg/mL PDS290/ 
semaglutide placebo 
2.4 mg 
80 
28 weeks 
Table 7-4 
Maintenance of semaglutide /semaglutide placebo Ib from V18 to V22 (DV3396) 
Trial product name 
Dose 
Volume 
Duration 
Maintenance period 
Semaglutide D 3.2 mg/mL DV3396 
or semaglutide placebo Ib 
2.4 mg* 
0.75 mL 
24 weeks 
*applicable for subjects who are on the maintenance dose of 2.4 mg once-weekly at V18. For subjects on a different 
dose level, please contact Novo Nordisk for further guidance. 
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• Subjects will be instructed to inject semaglutide/semaglutide placebo once-weekly at the same 
day of the week (to the extent possible) throughout the trial. 
• Injections may be administered in the thigh, abdomen or upper arm, at any time of day 
irrespective of meals.  
• If a single dose of trial product is missed, it should be administered as soon as noticed, provided 
the time to the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next 
scheduled dose is less than 2 days (48 hours) away, the subject should not administer a dose 
until the next scheduled dose. A missed dose should not affect the scheduled dosing day of the 
week. 
• If ≥ 2 consecutive doses of trial product are missed, the subject should be encouraged to re-
commence the treatment if considered safe as per the investigator’s discretion and if the subject 
does not meet any of the discontinuation criteria (section 8).The starting dose for re-initiation of 
trial product is at the investigator’s discretion. In case of questions related to re-initiation of trial 
product, the investigator should consult Novo Nordisk medical experts. 
• If a subject does not tolerate the recommended target dose of 2.4 mg once-weekly, the subject 
may stay at the lower dose level of 1.7 mg once-weekly. This should only be allowed if the 
subject would otherwise discontinue trial product completely and if considered safe to continue 
on trial product, as per the investigator’s discretion. It is recommended that the subject makes at 
least one attempt to re-escalate to the recommended target dose of 2.4 mg once-weekly, as per 
the investigator’s discretion. 
7.1.2 
Liraglutide 
• Dose escalation of liraglutide/liraglutide placebo should take place during the first 4 weeks after 
randomisation as described in Table 7-5. If the subject does not tolerate an increased dose 
during the dose escalation window, the investigator can delay the dose escalation by 
maintaining the subject at the current dosage step for approximately one additional week. After 
reaching the maintenance dose (3.0 mg), the dose and dosing frequency should not be changed.  
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Table 7-5 
Dose escalation and maintenance of liraglutide 3.0 once-daily/liraglutide placebo  
Trial product name 
Dose 
Duration 
Dose escalation period 
Liraglutide 6.0 mg/mL PDS290/ liraglutide 
placebo 
0.6 mg 
1 week 
liraglutide 6.0 mg/mL PDS290/ Liraglutide 
placebo 
1.2 mg 
1 week 
Liraglutide 6.0 mg/mL PDS290/ liraglutide 
placebo 
1.8  mg 
1 week 
Liraglutide 6.0 mg/mL PDS290/ liraglutide 
placebo 
2.4 mg 
1 week 
Maintenance period 
Liraglutide 6.0 mg/mL PDS290/ liraglutide 
placebo 
3.0 mg 
64 weeks  
• Injections may be administrated in the abdomen, thigh, or upper arm, at any time of day, 
irrespective of timing of meals. 
• The injection site and timing can be changed without dose adjustment. 
• If a single dose is missed, the once-daily regimen should be resumed as prescribed at the next 
scheduled dose. 
•  If more than 3 consecutive days have elapsed since the last dose, subject should reinitiate dose 
escalation, (e.g. restart the dosing at 0.6 mg and follow the dose escalation schedule again) if 
considered safe as per the investigator’s discretion and if the subject does not meet any of the 
discontinuation criteria. In case of questions related to re-initiation of trial product, the 
investigator should consult Novo Nordisk medical experts.  
• If a subject cannot tolerate the 3.0 mg dose, or if any of the other treatment discontinuation 
criteria are met, then treatment with trial product must be discontinued. In case this happens, it 
is acceptable to restart trial product (at the discretion of investigator); the dose must be escalated 
according to the algorithm above. 
7.1.3 
Auxiliary supplies 
Auxiliary supplies will be provided in accordance with the trial materials manual (TMM) and  
Table 7-6. 
Table 7-6 
Auxiliary supplies provided by Novo Nordisk A/S 
Auxiliary supply 
Details 
Needles 
Needles for pre-filled pen system. Details provided in the TMM. 
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Auxiliary supply 
Details 
Only needles provided and approved by Novo Nordisk must be used for administration 
of trial product.  
The DV3396 pen-injector comes with an integrated and hidden needle of 6 mm in 
length (29G), therefore no needles are required to be used with this pen-injector 
Direction for use (DFU) 
DFUs for 3 mL PDS290 pre-filled pen-injectors 
Not included in the dispensing unit and to be handed out separately. 
DFU for DV3396 pen-injector  
Not included in the dispensing unit and is to be handed out separately 
7.2 
Medical devices 
Information about the use of the pre-filled PDS290 pen-injector for semaglutide 3.0 mg/mL and 
semaglutide placebo can be found in the DFU. 
Information about the DV3396 pen-injector can be found in the investigator’s brochure (IB) edition 
546 and any updates hereof. Information about the use of the DV3396 pen-injector can be found in 
the DFU.  
Information about the use of the pre-filled PDS290 pen-injector for liraglutide 6.0 mg/mL 
liraglutide placebo can be found in the DFU. 
7.2.1 
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 (minimum 150 min of physical activity per week is encouraged, e.g. walking or use the 
stairs). Counselling should be done by a dietician or a similar qualified healthcare professional 
every 4th to 6th week via visits/phone contacts. 
Calculation of estimated TEE 
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (Table 7-7 with a 
Physical Activity Level value of 1.347. 
TEE = BMR × 1.3 
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Table 7-7 
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. 
7.3 
Dose modification 
Not applicable for this trial. Please refer to 7.1.1 and 7.1.2 for description of missed dose(s). 
7.4 
Method of treatment assignment 
All subjects will be centrally randomised using IWRS and assigned to the next available treatment 
according to randomisation schedule. Trial product will be dispensed at the trial visits summarised 
in the flowchart. 
7.5 
Shipment of trial product to subject’s home 
If permitted by local regulations, the investigator may offer to send trial product and auxiliaries 
from the trial site or pharmacy to the subject’s home by courier service.  
The process for sending trial product from the trial site or pharmacy to a subject’s home is 
described in the “Trial site/pharmacy instruction for shipment of trial product to subject’s homes” 
document. This document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
subject. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document. 
Investigators, trial site/pharmacy staff and subjects who will be involved in shipment of trial 
product to the subject’s home will be adequately trained in this process. 
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7.6 
Blinding 
Semaglutide once weekly vs liraglutide once daily treatment will be open label, but each of the two 
active treatment arms will be double blinded against placebo.  
The active drugs and placebo are shown in Table 7-1 For the semaglutide/semaglutide placebo trial 
products from week 44/visit 18, please refer to Table 7-2.  
• The active drug and matching placebo are visually identical. 
• The specific treatment for a subject will be assigned using an IWRS. The site will access the 
IWRS before the start of trial product administration for each subject. 
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the subject’s medical record. 
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.  
7.7 
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.  
Storage- and in-use conditions will be available on the trial product label and in the TMM. 
• Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to screening 
and randomisation. 
• The investigator must confirm that appropriate temperature conditions have been maintained 
during transit for all trial products received and any discrepancies are reported and resolved 
before use of the trial products. 
• All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
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• The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. Additional details regarding handling of temperature deviations 
can be found in the TMM.  
• Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. 
• Subjects must return all used, partly used and unused trial products as instructed by the 
investigator. 
• The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records).  
• Drug accountability must be performed in the IWRS by registering pen-injectors as used/partly 
used, unused or lost.  
• Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor.  
• Destruction of trial products must be documented in the IWRS.  
• All returned, expired or damaged trial products (for technical complaint samples see Appendix 
F) must be stored separately from non-allocated trial products. No temperature monitoring is 
required. 
• Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site.  
7.8 
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 the subject about missed doses 
and current treatment dose at every visit. Information on treatment dose and periods >14 days 
without treatment will be recorded in the CRF.  
7.9 
Concomitant medication 
Any medication (including over-the-counter or prescription medicines) other than the trial product 
that the subject is receiving at the time of the first visit or receives during the trial must be recorded 
along with: 
• Trade name or generic name 
• Indication 
• Dates of administration including start and stop dates 
• Dose (only to be recorded for anti-hypertensive and lipid-lowering medication) 
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During the trial, subjects should not initiate any anti-obesity treatment (e.g. medication) which is 
not part of the trial procedures. If such treatment is initiated, the subject should be instructed to stop 
the anti-obesity treatment. 
Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to section 9.2.  
7.10 
Treatment after the end of the trial 
After the end of the trial, the subject should be treated at the discretion of the investigator. 
8 
Discontinuation/Withdrawal criteria  
The subject may be discontinued at any time during the trial at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the subjects, who discontinue trial product, to continue in the trial. 
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial. 
8.1 
Discontinuation of trial treatment 
• Discontinuation of trial product can be decided by either the investigator or the subject. 
• Subjects who discontinue trial product should continue with the scheduled visits and 
assessments to ensure continued counselling and data collection. 
o If the subject does not wish to attend the scheduled clinic visits, efforts should be made 
to have the visits converted to phone contacts. However, all efforts should be made to 
have the subject attend at least the ‘end of treatment’ clinic visit containing the final data 
collection of primary and confirmatory secondary efficacy endpoints, and the ‘end of 
trial’ visit. 
• The ‘end of trial’ visit is scheduled approximately 7 weeks after the final data collection, to 
ensure the safety of the subject.  If the subject has discontinued trial product >7 weeks prior to 
the ‘end of treatment’ visit, and the requirements for the follow-up period prior to the ‘end of 
trial’ visit is fulfilled, then the ‘end of trial’ visit can be performed in combination with ‘end of 
treatment’ visit.  
o If the subject refuses to attend the ‘end of treatment’ and/or ‘end of trial’ visit, 
information about the attempts to follow up with the subject must be documented in the 
subject’s medical record. 
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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 (Appendix G) 
3. Suspicion of pancreatitis 
4. Pregnancy 
5. Intention of becoming pregnant 
6. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal producta. 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed at the investigator’s discretion without discontinuing trial product. 
If acute pancreatitis is suspected, appropriate actions should be initiated, including local 
measurement of amylase and lipase (see Appendix D for reporting). 
Subjects meeting discontinuation of trial product criterion no. 3 can resume trial product if the 
Atlanta criteria48 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 (8.1.1). 
The primary reason for discontinuation of trial product must be specified in the source data at the 
time of discontinuation, and the subject should continue to follow the visit and assessment schedule. 
A change in ‘treatment status’ must be made in the IWRS to discontinue trial product. If the 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 a temporary safety concern and can resume, the 
subject should follow the guide for missed doses (7.1). Similarly, subjects who discontinue trial 
product on their own initiative should be encouraged to resume trial product (7.1). 
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. 
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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. Refer to the 
flowchart for data to be collected.  
Final drug accountability must be performed even if the subject is not able to come to the trial site. 
The investigator must make a ‘treatment status’ session in IWRS to discontinue trial product. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF. 
8.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
8.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site.  
The following actions must be taken if a subject fails to return to the trial site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the subject (where possible, at least three telephone calls and, if necessary, a 
certified letter to the subject's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject's source document. Should the subject 
continue to be unreachable at the ‘end of treatment’ visit, he/she will be considered to have 
withdrawn from the trial with a primary reason of lost to 'follow-up'.  
9 
Trial assessments and procedures 
• Trial procedures and their timing are summarised in the flowchart. 
• Informed consent must be obtained before any trial related activity (Appendix C). 
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• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
• The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
• At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant trial site staff. 
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
• Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit the bias between 
assessments. The suggested order of the assessments:  
1. Electrocardiogram (ECGs) and vital signs 
2. Blood samples 
3. Mental health assessment instruments (9.4) 
4. Other assessments 
• Source data of clinical assessments performed and recorded in the CRF must be available and 
will usually be the subject’s medical records. Additional recording to be considered source data 
includes, but is not limited to laboratory reports, ECG and Mental Health assessments. 
• The barriers and motivation interview identify barriers to and motivation for lifestyle change 
and compliance with the protocol. The interview must be conducted at screening to assist in 
identifying subjects who are unable or unwilling to comply with protocol procedures as per the 
exclusion criteria. In addition, the interview will ensure that any minor barriers are addressed 
during lifestyle counselling. 
o The results of the interview will not be entered in the CRF. It will be at the investigator’s 
discretion to evaluate the motivation of the subject and related eligibility. 
• 
After the final injection, semaglutide/semaglutide placebo subjects will rate ease-of-use and 
user experience using an instrument Injection Device Experience and Acceptance (IDEA) 
developed by Novo Nordisk.  
o The results of the questionnaire must be entered in the CRF. 
• After training the semaglutide/semaglutide placebo subject in the new DV3396, there will be a 
questionnaire to site staff: “How difficult or easy was it for site staff to train the subject?”, 
answered on a 5-point scale (very difficult-very easy).  
• The results must be entered in the CRF.Subject’s weight history must be recorded in the 
subject’s medical record. 
• Review of mental health assessment instruments, ECG and laboratory reports must be 
documented either on the documents or in the subject's source documents.  
• Repeat laboratory samples may be taken for technical issues. Please refer to Appendix B for 
further details on laboratory samples. 
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• For subjects receiving antihypertensive or lipid-lowering treatment, the investigator should 
evaluate changes in the 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. 
• Investigator will evaluate the subject’s glycaemic status periodically during the trial as detailed 
in the flowchart based on all available relevant information e.g. medical records, concomitant 
medication, blood glucose parameters (HbA1c, FPG) and AEs. The subject’s glycaemic status 
will be categorised as normo-glycaemia, prediabetes or diagnosed with type 2 diabetes 
accordingly to the American Diabetes Association’s definitions49. 
• If a pen-injector use error (see Section 9.10) occurs subject is instructed to contact the trial site 
or report it at the next scheduled visit. The pen-injector use error form must be completed by the 
site staff 
9.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart. 
9.1.1 
Body measurements 
Body weight should be measured at all site visits without shoes, on an empty bladder and only 
wearing light clothing. It should be measured on a digital scale and recorded in kilograms or pounds 
(one decimal) using the same scale throughout the trial. The scale must be calibrated yearly as a 
minimum. 
Height is measured without shoes in centimetres or inches (one decimal). BMI will be calculated 
from screening data and must agree with inclusion criterion no. 3. 
Waist circumference is defined as 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 efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix B, must be conducted in 
accordance with the flowchart and the laboratory manual. 
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9.2 
Adverse events 
The definitions of AEs and SAEs can be found in Appendix D. 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE. 
9.2.1 
Time period and frequency for collecting AE and SAE information 
All AEs will be collected from the first trial-related activity after obtaining informed consent and 
until the 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 D. 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 D. 
Timelines for reporting of AEs are listed in Figure 9-1. 
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1 and the 
reporting timelines in Figure 9-1. 
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AE identified
AE form    24 hours
SIF  5 calendar days
Sign off   7 calendar days
Is the AE serious or 
non-serious?
AE form
Is the AE listed as 
requiring a Specific Event 
Form to be completed?
Non-serious
Serious
No additional action
No
Specific event form
For SAE:
 14 calendar days
Yes
Timelines are from the awareness of an AE.
Queries and follow-up requests to be resolved  14 calendar days.
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
Table 9-1
AEs requiring additional data collection (via specific event form)
Event type
AE via specific event form
Medication error*
X
Misuse or abuse of trial product*
X
Cardiovascular events
Acute Coronary Syndrome
X
Cerebrovascular event
X
Heart failure
X
Coronary artery revascularisation
X
Acute pancreatitis
X
Acute gallbladder disease
X
Malignant neoplasms
X
Hepatic event
X
*Additional data for Misuse or abuse of trial product is reported on the medication error event form.
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9.2.2 
Method of detecting AEs and SAEs 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non- 
leading verbal questioning of the subject is the preferred method to inquire about events. 
9.2.3 
Follow-up on AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, or if the event 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in 
section 8.3). Further information on follow-up procedures is given in Appendix D. 
9.2.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for SUSARs (suspected unexpected serious adverse 
reaction) according to local regulatory requirements and Novo Nordisk policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
9.2.5 
Hypoglycaemic, Cardiovascular and death events 
Hypoglycaemic, cardiovascular and death events will be handled and reported according to 
AE/SAEs description in section 9.2.1. 
9.2.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE 
This section is not applicable for this trial. 
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9.2.7 
Pregnancies and associated adverse events 
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until ‘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 E.  
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
Maternal form 1b 
≤ 14 calendar days after birth
Maternal form 1a
≤ 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤ 14 calendar days
Paternal form*1 ≤ 14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 9-2 
Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
9.2.8 
Medical device incidents (including malfunctions) 
Section not applicable for this trial. Refer to technical complaints in section 9.2.9. 
9.2.9 
Technical complaints 
The investigator must assess whether a technical complaint is related to an AE. 
The definitions and reporting process for technical complaints can be found in Appendix F. 
Timelines for reporting technical complaints are listed in Figure 9-3. 
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Technical complaint form:   24 hours 
AE form:   24 hours 
SIF:   5 calendar days
Is it related  
to an SAE?
Technical complaint 
identified
Is it related
to an AE?
Yes
No
Technical complaint form
  5 calendar days
Technical complaint form: 
  5 calendar days
AE form:   5 calendar days
No
Yes
AE: Adverse Event, SAE: Serious Adverse Event,  SIF: Safety Information Form
Figure 9-3
Decision tree for determining the forms to complete with associated timelines 
for technical complaints.
9.3
Treatment of overdose
Overdoses of semaglutide s.c. up to 4 mg in a single dose, and up to semaglutide s.c 4 mg in a week 
have been reported in clinical trials. From clinical trials and marketed use of liraglutide, overdoses 
have been reported up to 24 times the recommended dose (72 mg). One case of a 6-fold overdose 
(18 mg daily) given for 7 months has been reported. 
The most commonly reported AE was nausea. All subjects recovered without complications. With 
liraglutide, very few post-marketing reports of severe hypoglycaemia have been observed in 
relation to overdose.
There is no specific antidote for overdose with semaglutide or liraglutide. In the event of an 
overdose, appropriate supportive treatment should be initiated according to the subject’s clinical 
signs and symptoms.
The overdose must be reported as a medication error (Appendix D), and for reporting times see 
section 9.2.1 and Figure 9-1. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities. A prolonged period of observation and treatment may be 
necessary, considering the long half-life of semaglutide of approximately one week.
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject.
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For more information on overdose, also consult the current version of the IB39, 40 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: 
• History of Gallbladder Disease 
• History of Breast Neoplasm 
• History of Colon Neoplasm 
• History of Skin Cancer 
• History of Psychiatric Disorder 
Follow-up questions will be asked at the end of trial related to the breast neoplasms and colon 
neoplasms. 
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (Appendix D) during the trial and any clinically significant worsening 
from baseline must be reported as an AE (9.2). 
9.4.1 
Mental health assessment instruments 
• PHQ-950 is a 9-item depression module of the patient health questionnaire, which is a self-
administered diagnostic tool used for assessment of mental disorders. The questionnaire will be 
available in a linguistically validated translated version. 
• C-SSRS51 is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation. 
The questionnaire will be administered as an interview by the investigator or a qualified 
delegate. The questionnaire (C-SSRS Baseline and C-SSRS Since Last Visit) will be available 
in a linguistically validated translated version. 
o Prior to administering the C-SSRS questionnaire, the investigator or qualified delegate 
must complete sufficient training. 
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A PHQ-9 score ≥15 or a suicidal ideation corresponding to type 4 or 5 on the C-SSRS within the 
past 30 days at screening excludes the subject from participation in the trial.  
The need to refer a subject to a mental health professional is at the discretion of the investigator. 
9.4.2 
Physical examinations 
A physical examination will include assessments of the general appearance, thyroid gland, breast 
(females) and abdomen, as well as the cardiovascular and respiratory system. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
9.4.3 
Vital signs 
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practice at site. 
However, as a minimum: 
• Blood pressure (diastolic and systolic) and pulse measurements should be preceded by at least 5 
minutes of rest for the subject in a quiet setting without distractions (e.g. television, cell 
phones). 
• Blood pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
9.4.4 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the flowchart using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS and QT intervals. 
9.4.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix B, must be conducted in 
accordance with the flowchart in section 2 and the laboratory manual. 
Urine pregnancy tests provided by the central laboratory must be performed for women of 
childbearing potential at screening and as specified in the flowchart. Urine pregnancy test must be 
repeated at any time during the trial if pregnancy is suspected. Further instructions can be found in 
the laboratory manual. 
9.5 
Pharmacokinetics 
Not applicable for this trial. 
9.6 
Pharmacodynamics 
Not applicable for this trial. 
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9.7 
Genetics 
Not applicable for this trial. 
9.8 
Biomarkers 
Collection of samples for biomarker research is part of this trial to support the effect objectives. The 
following samples must be conducted in accordance with the laboratory manual and the flowchart: 
Biomarkers linked to cardiovascular risk:  
• High sensitive C-reactive protein   
9.9 
Severe hypersensitivity 
This section is not applicable in this trial  
9.10 
Pen-injector use error for DV3396 pen-injector 
Pen-injector use errors are assessed for all injections with the DV3396 pen-injector according to the 
flowchart section 2. These are defined as user action or lack of user action during use of DV3396 
pen-injector leading to a different result than intended by the manufacturer or expected by the user. 
An example of a use error is that the user deviates from the instructions given in the DFU, e.g. if the 
user does not hold the pen-injector against the skin for as long as specified in the DFU. 
The pen-injector use error form is filled when a subject experience a pen-injection use error. The 
subjects can either contact site when the injection error occur or report it at the next visit. 
A pen-injector use error can be related to both a technical complaint or an adverse event. 
10 Statistical considerations  
General considerations  
A statistical analysis plan (SAP) will be written, including a more technical and detailed elaboration 
of the statistical analyses. The SAP will be finalized before breaking the blind to treatment 
assignment. 
The placebo arms will be pooled in the statistical analyses. 
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. 
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Results from statistical analyses will generally be accompanied by two-sided 95% confidence 
intervals and corresponding p-values. 
10.1 
Sample size determination 
The tests of superiority of semaglutide 2.4 mg to liraglutide 3.0 mg for the primary and 
confirmatory secondary endpoints are performed using the fixed-sequence statistical strategy. This 
strategy tests the endpoints using a predefined hierarchical order, all at the significance level of 5%, 
moving to test the next endpoint only after a statistically significant superiority result (p-value < 
5%) on the previous endpoint. The test hierarchy is given in Table 10-1 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. 
The trial is designed with an effective power of 92% to detect differences on all endpoints in the 
statistical test hierarchy at one-sided alpha of 0.025 (equivalent to a two-sided alpha of 0.05). 
Specifically, the trial tests the null hypothesis of equal % change in body weight (or equal 
proportions achieving body weight loss of 10%, 15%, and 20%) against the one-sided alternative of 
greater % body weight loss in the semaglutide 2.4 mg arm (or greater proportions achieving body 
weight loss of 10%, 15%, and 20%) compared to the liraglutide 3.0 mg arm. The calculations for 
the primary endpoint are based on a t test on the mean difference assuming equal variances, 
whereas those for the confirmatory secondary endpoints are based on the Pearson chi-square test for 
two independent proportions. Assumptions for these calculations are based on findings from 
NN8022 (SCALE) and trial NN9536-4153. These assumptions are further explored across a range 
of sample sizes in Table 10-2. Under these assumptions and a 3:1:3:1 randomisation ratio (section 
5), the desired power of more than 90% is obtained with 126 subjects randomized to each active 
drug arm and 42 subjects randomized to each placebo arm. 
Furthermore, a sample size of 84 subjects in the pooled placebo group (42 each in the semaglutide 
placebo and liraglutide placebo arms) gives a power of >99% for the comparison between 
semaglutide 2.4 mg once-weekly and pooled placebo on the primary endpoint, as well as a power of 
at least 80% for the comparison between liraglutide 3.0 mg once-daily and pooled placebo on the 
primary endpoint. 
Table 10-1 
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 336 randomised 
subjects 
Order 
Endpoint 
Expected mean (±SD) or 
proportion 
Expected difference or 
proportion ratio 
Marginal 
power (%) 
Effective 
power (%) 
Semaglutide 
2.4 mg 
Liraglutide 
3.0 mg 
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1 
% weight 
change # 
12.5 (±10) 
7.0 (±10) 
5.5%-points 
99 
99 
2 
10% 
responders 
61% 
37% 
1.6 
97 
96 
3 
15% 
responders 
39% 
18% 
2.2 
96 
93 
4 
20% 
responders 
27% 
6% 
4.5 
99 
92 
SD = standard deviation; # shown as a positive number  
All tests in the hierarchy are based on the primary estimand. Since all tests are tests of superiority of semaglutide 2.4 mg 
to liraglutide 3.0 mg, power is only shown for this comparison. 
Table 10-2 
Assumptions and effective power for the primary and confirmatory secondary 
endpoints across a range of number of randomised subjects 
Expected mean (±SD) 
Expected proportions of 
10%/15%/20% body weight 
loss responders 
N per active arm 
Total N 
randomised 
Effective 
power 
(%) 
Semaglutide 
2.4 mg 
Liraglutide 
3.0 mg 
Semaglutide 
2.4 mg 
Liraglutide 
3.0 mg 
12.5 (±10) 
7.0 (±10) 
61%/39%/27% 
37%/18%/6% 
99 
264 
81 
126 
336 
92 
150 
400 
97 
SD = standard deviation 
Mean weight change shown as a positive number. 
10.2 
Definition of analysis sets 
Two analysis sets are defined: 
The full analysis set (FAS) includes all randomised subjects according to the intention-to-treat 
principle. 
The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of 
randomised treatment. 
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided. 
Two observation periods are defined for each subject: 
In-trial: The in-trial period is defined as the uninterrupted time interval from date of randomisation 
to date of last contact with trial site. 
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On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose of trial 
product has been administered within the prior 2 weeks (14 days). The on-treatment period is 
defined as all times which are considered on-treatment. 
In general, the on-treatment period will therefore be from the date of first trial product 
administration to date of last trial product administration excluding potential off-treatment time 
intervals triggered by at least two consecutive missed doses. 
For the evaluation of AEs 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. 
Effect endpoints will be analysed using the FAS; safety endpoints will be analysed using the SAS. 
10.3 
Statistical analyses 
10.3.1 
Primary endpoint 
Definition of primary endpoint: % weight change 
Change from baseline (week 0) to week 68 in body weight (%) is defined as 
% weight change = (body weight at week 68 – body weight at baseline)
body weight at baseline
 ×100. 
Analyses addressing the primary estimand 
The following statistical analyses and imputation methods are designed to address the primary 
estimand.  
The analysis model for % weight change is a linear regression (ANCOVA) of % weight change 
with randomised treatment as a factor and baseline body weight (kg) as covariate. Randomised 
treatment will be coded in 3 levels: semaglutide 2.4 mg, liraglutide 3.0 mg, and pooled placebo. The 
estimated treatment difference between semaglutide 2.4 mg and liraglutide 3.0 mg will be reported 
together with the associated two-sided 95% confidence interval (CI) and corresponding p-value. 
Estimated treatment differences between semaglutide 2.4 mg and pooled placebo, as well as 
between liraglutide 3.0 mg and pooled placebo, will also be reported together with associated two-
sided 95% confidence intervals (CI). 
Handling of missing week 68 values for the primary estimand 
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All available data at week 68 are used and missing values at week 68 will be imputed and the 
endpoints will be derived from the imputed values. The imputation approach for the primary 
analysis is a multiple imputation similar to the one described by McEvoy52. For subjects in the 
semgalutide 2.4 mg, liraglutide 3.0 mg and pooled placebo groups, missing body weight 
measurements at week 68 for non-retrieved subjects are imputed using assessments from retrieved 
subjects in each treatment group. This will be done according to the timing of last available 
observation during the on-treatment period (LAO-OT) of body weight. Missing body weight 
measurements at week 68 for subjects on randomised treatment are imputed by sampling from 
available measurements at week 68 from subjects on randomised treatment in the relevant 
randomised treatment arm. Details of the multiple imputation approach are provided in the SAP. 
Sensitivity analyses 
Tipping-point multiple imputation analysis: First, missing data are imputed according to the primary 
multiple imputation approach. Then, a penalty is added to the imputed values at week 68. The 
approach is to explore a range of penalties for both the semaglutide 2.4 mg and liraglutide 3.0 mg 
arms, and the impact these would have on the study conclusions. The 2-dimensional space of 
penalties covering the range from -30% to 30% will be explored for both arms. Penalties for the 
pooled placebo group will not be considered, as this sensitivity analysis evaluates the robustness of 
the superiority conclusions to departures from the observed change in body weight in both active 
treatment groups. 
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 Mixed Model for Repeated Measurements (MMRM) approach. Week 68 
assessments for retrieved subjects are not used in this analysis. The MMRM will use assessments 
only from subjects who are taking the randomised treatment until end of treatment or until first 
discontinuation of 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. The MMRM will be fitted using % weight change and the same factor and covariate as for 
the primary analysis all nested within visit. An unstructured covariance matrix for measurements 
within the same subject will be employed, assuming that measurements for different subjects are 
independent. 
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10.3.2 
Secondary endpoints 
10.3.2.1 
Confirmatory secondary endpoints 
Confirmatory secondary endpoints are listed in section 2 and are all included in the fixed-sequence 
statistical strategy, see above. All tests are tests of superiority of semaglutide 2.4 mg to liraglutide 
3.0 mg.  
Analyses addressing the primary estimand 
All confirmatory secondary endpoints will be analysed using the primary imputation approach used 
for the primary endpoint and to address the primary estimand. The statistical model for body weight 
responder endpoints is a logistic regression using randomised treatment as a factor and baseline 
body weight (kg) as covariate. Randomised treatment will be coded in 3 levels: semaglutide 2.4 mg, 
liraglutide 3.0 mg, and pooled placebo. The estimated odds ratio (OR) between semaglutide 2.4 mg 
and liraglutide 3.0 mg will be reported together with the associated two-sided 95% confidence 
interval and corresponding p-value. Estimated odds ratios between semaglutide 2.4 mg and pooled 
placebo, as well as between liraglutide 3.0 mg and pooled placebo, will also be reported together 
with associated two-sided 95% confidence intervals. 
Analyses addressing the secondary estimand 
The confirmatory secondary endpoints will be analysed to address the secondary estimand using the 
same MMRM described for the primary endpoint. From the MMRM individually predicted values 
for % weight change at week 68 will be used to classify each subject as a responder or not. This 
classification will then be analysed using a logistic regression model with treatment as the only 
factor. 
Sensitivity analyses for confirmatory secondary endpoints 
For all confirmatory secondary endpoints a sensitivity analysis using non-retrieved subjects as non-
responders will be carried out. 
10.3.2.2 
Supportive secondary endpoints 
Analyses of supportive secondary endpoints will be described in the SAP. 
10.4 
Interim analysis 
This section is not applicable in this trial  
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11 Appendices 
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Appendix A 
Abbreviations and Trademarks 
AD 
available but discontinued  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AT 
available on randomised treatment  
BMI 
body mass index 
CLAE 
clinical laboratory adverse event 
CRF 
case report form 
DFU 
direction for use  
DUN 
dispensing unit number 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate  
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
glycated haemoglobin 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
IDEA  
injection device experience and acceptance questionnaire 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
KDIGO 
kidney disease improving global outcome 
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LAO 
last available observation  
LDL 
low-density lipoprotein 
MEN2 
multiple endocrine neoplasia type 2 
MD 
missing and discontinued 
MMRM 
mixed model for repeated measurements  
MT 
missing on randomised treatment  
MTC 
medullary thyroid cancer  
PCD 
primary completion date 
RD-MI 
multiple imputation using retrieved subjects 
SAS 
safety analysis set 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneus 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reactions  
TEAE 
treatment emergent adverse event 
TEE 
total energy expenditure  
TMM 
trial materials manual 
TSH 
thyroid stimulating hormone  
WC 
waist circumference 
WOCBP 
woman of child bearing potential 
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Appendix B 
Clinical laboratory tests 
• The tests detailed in Table 11-1 and Table 11-2 will be performed by the central laboratory. 
• Laboratory samples specified in the protocol should be sent to the central laboratory for 
analysis. 
• Additional tests may be performed at local laboratory any time during the trial as determined 
necessary by the investigator or required by local regulations.  
• The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
• The investigator must review all laboratory results for concomitant illnesses and AEs. 
• Laboratory samples will be destroyed no later than at finalisation of the clinical trial report.  
• For haematology samples (differential count) where the test result is not normal, then a part of 
the sample may be kept for up to two years or according to local regulations. 
Table 11-1 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
Fasting plasma glucose1 
HbA1c 
Fasting serum insulin 
Lipids 
Total Cholesterol 
High density lipoprotein (HDL) cholesterol 
Low density lipoprotein (LDL) cholesterol 
Triglycerides 
Very-low-density lipoprotein (VLDL) cholesterol 
Free fatty acids 
Biomarkers 
high sensitive C-reactive protein  
Notes: 
1 A FPG result ≤ 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode but as a CLAE at the discretion of the investigator, see Appendix D  
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Table 11-2 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
Erythrocytes 
Haematocrit 
Haemoglobin 
Leucocytes 
Thrombocytes 
Biochemistry1 
Alanine Aminotransferase (ALT)2  
Albumine 
Albumine corrected calcium 
Alkaline phosphatase 
Amylase 
Aspartate Aminotransferase (AST)2 
Calcitonin 
Creatine kinase 
Creatinine 
Lipase 
Potassium 
Sodium 
Thyroid stimulating hormone (TSH)3 
Total bilirubin 
Urea 
 
Pregnancy Testing 
Urine human chorionic gonadotropin (hCG) pregnancy test for women of childbearing 
potential 
Other tests 
eGFR calculated by the central laboratory based on the creatinine value using the CKD-
EPI equation as defined by KDIGO 201245 
Notes: 
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix D (Hy’s Law) and section 8.   
2If ALT or AST >3 upper normal limit (UNL), additional blood samples should be taken from the subject to analyse 
international normalised ratio (INR) by central laboratory (except at screening visit). Repeat testing of the abnormal 
labboratory assessments should be performed for the subject until abnormalities return to normal or baseline state.  
3If TSH level is out of normal range, additional testing will be performed by central lab: total and free T3 and T4 
except at screening visit. 
Hepatic laboratory outlier: if the following hepatic laboratory parameters are above the cut-offs 
values in Table 11-3, 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 D.  
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Table 11-3 
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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Appendix C 
Trial governance considerations 
1) Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki53  and applicable ICH Good Clinical Practice (GCP) Guideline54.  
o Applicable laws and regulations. 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements), must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the clinical trial report according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects. 
• Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations 
o ensuring submission of the clinical trial report synopsis to the IRB/IEC. 
2) Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest. 
3) Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial.  
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• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• Subjects must be informed that their participation is voluntary. 
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines54, Declaration of Helsinki53 and the IRB/IEC 
or trial site. 
• The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in accordance 
with local requirements. 
• Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
• A copy of the informed consent form(s) must be provided to the subject. 
4) Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator.  
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
Materials and items will be supplied if locally acceptable. The retention items will be relevant for 
the subjects’ participation in the trial and/or their obesity and will not exceed local fair market 
value. 
The initiatives for subject retention must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
5) Data protection 
• Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred. 
• The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
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certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
• The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject.  
• The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
6) Committee structure 
Novo Nordisk safety committee 
Novo Nordisk will constitute an internal semaglutide s.c. safety committee to perform ongoing 
safety surveillance. The semaglutide s.c. safety committee may recommend unblinding of any data 
for further analysis, and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel. 
7) Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial. 
 
One (or two) investigator(s) will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications55. 
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Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors55. 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
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is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own subjects' data and will be provided with the 
randomisation code after results are available. 
8) Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)56, the Food and Drug Administration Amendment 
Act (FDAAA)57, European Commission Requirements58, 59 and other relevant recommendations or 
regulations. If a subject request 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 affiliations57. 
 
The Primary Completion Date (PCD) is the last assessment of the primary endpoint and is for this 
trial Last Subject First Treatment LSFT + 68 weeks corresponding to visit 22 (´end of treatment´ 
visit). If the last subject is withdrawn early, the PCD is considered the date when the last subject 
would have completed visit 22 (´end of treatment´ visit). The PCD determines the deadline for 
results disclosure at clinicaltrials.gov according to FDAAA. 
9) Data quality assurance 
Case Report Forms (CRFs) 
• Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
• All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.  
• For some data both electronic and paper CRFs are used.  
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• The following will be provided as paper CRFs:  
o Pregnancy forms 
• The following will be provided as paper CRFs to be used when access to the electronic CRF is 
revoked or temporarily unavailable:  
o AE forms  
o Safety information forms  
o Technical complaint forms (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation)  
• Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the 
old and the new data, identification of the person entering the data, date and time of the 
entry and reason for the correction. If corrections are made by the investigator’s delegated 
staff after the date when the investigator signed the CRF, the CRF must be signed and dated 
again by the investigator. 
• The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to 
Novo Nordisk for data verification and validation purposes.  
 Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents (original 
documents, data and records). Direct access includes permission to examine, analyse, verify 
and reproduce any record(s) and report(s) that are important to the evaluation of the trial. If 
the electronic medical record does not have a visible audit trail, the investigator must 
provide the monitor with signed and dated printouts. In addition, the relevant trial site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone).  
• Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites.  
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• Monitors will review the subject’s medical records and other source data e.g. 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 
• All data entered in the CRF must be verifiable in source documentation other than the CRF. 
• The original of the completed Mental Health assessments must not be removed from the trial 
site. 
• If food/activity tracker is used it can be either paper based or electronic based on the decision of 
the subject.  
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site. 
• Data reported in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records. Also, current medical records must be 
available.  
• It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record  
• The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement at each 
trial site. There will only be one source document defined at any time for any data element. 
11) Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
• The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
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electronic readable format to the investigator before access is revoked to the systems 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. A copy of all data will be stored by 
Novo Nordisk. 
• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice 
12) Trial and site closure 
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation. 
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines. 
• inadequate recruitment of subjects by the investigator. 
• discontinuation of further trial product development. 
13) Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
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The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
14) Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the site or investigator are responsible.  
Novo Nordisk may pay additional costs incurred in relation to assessments relevant for following 
the safety of the subject. Investigator must contact Novo Nordisk on a case by case basis for 
whether the costs will be covered. 
 
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Appendix D 
Adverse events: definitions and procedures for recording, evaluation, 
follow-up, and reporting 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product. 
• 
An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or 
disease (new or exacerbated) temporally associated with the use of a medicinal product. 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the investigator. 
• 
A CLAE: a clinical abnormal laboratory finding which is clinically significant, i.e. an abnormality that suggests 
a disease and/or organ toxicity and is of a severity that requires active management. Active management 
includes active treatment or further investigations, for example change of medicine dose or more frequent 
follow-up due to the abnormality. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• 
Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent. 
• 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition. 
Events NOT meeting the AE definition  
• 
Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product.  
Note: pre-existing conditions should be recorded as medical history/concomitant illness. 
• 
Pre-planned procedures, unless the condition for which the procedure was planned has worsened from the first 
trial related activity after the subject has signed the informed consent. 
 
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Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
• 
Results in death 
• 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have caused death, if 
it were more severe. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
o 
Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalisation” occurred or was necessary, the AE should be considered serious. 
o 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
Note: 
▪ Hospitalisations for administrative, trial related and social purposes do not constitute AEs and 
should therefore not be reported as AEs or SAEs.  
▪ Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs 
or SAEs.  
• 
Results in persistent disability/incapacity 
o 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
o 
This definition is not intended to include experience of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained 
ankle), which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect 
• 
Important medical event: 
o 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations. This includes important medical events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the subject or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious and reported as SAEs using the important medical 
event criterion. 
o 
The following 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) >3x UNL and total bilirubin >2x UNL, where no alternative aetiology exists (Hy's law). 
 
 
Description of AEs requiring additional data collection (via specific event form)  
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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 products (Table 9-1). The selection of these events is based on the non-clinical and clinical data with 
semaglutide and liraglutide, knowledge from the GLP-1 RA drug class as well as regulatory requirements. 
Event type 
Description 
Acute gallbladder disease 
Events of symptomatic acute gallbladder disease (including 
gallstones and, cholecystitis) 
Acute pancreatitis 
The diagnosis of acute pancreatitis requires two of the following 
three features: 
(1) abdominal pain consistent with acute pancreatitis (acute onset 
of a persistent, severe, epigastric pain often radiating to the back) 
(2) serum lipase activity (and/or amylase activity) at least three 
times greater than the upper limit of normal 
(3) characteristic findings of acute pancreatitis on imaging. 
Malignant neoplasm 
Malignant neoplasm by histopathology or other substantial clinical 
evidence 
Hepatic event 
Hepatic event defined as: 
– Disorders of the liver including cholestatic conditions and liver 
related signs and symptoms 
– ALT or AST > 3x UNL and total bilirubin > 2x UNL or INR > 
1.5x* 
– ALT or AST > 3x UNL with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%). 
*Please note that in case of a hepatic event defined as ALT or AST 
> 3x UNL and total bilirubin > 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. 
Acute coronary syndrome 
Acute coronary syndrome conditions include all types of acute 
myocardial infarction and hospitalisation for unstable angina 
pectoris 
Cerebrovascular event 
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 
Coronary artery 
revascularisation 
Coronary revascularisation procedure is a catheter-based (PCI) or a 
surgical procedure (CABG) designed to improve myocardial blood 
flow.  
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) 
Medication error 
A medication error concerning trial products is defined as: 
- Administration of wrong drug. 
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- Note: Use of wrong dispensing unit number (DUN) is not 
considered a medication error unless it results in a confirmed 
administration of wrong drug. 
- Wrong route of administration, such as intramuscular instead of 
subcutaneous. 
- Accidental administration of more than 2.4 mg/week 
(semaglutide) or 3.0 mg/day (liraglutide) 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 product* 
Misuse is when the trial product is intentionally and inappropriately 
used. Abuse of trial product is persistent or sporadic, intentional 
excessive use, which is accompanied by harmful physical or 
psychological effects (e.g. overdose with the intention to cause 
harm). 
* Additional data for Misuse or abuse of trial product is reported on the medication error event form. 
 
AE and SAE recording 
• 
The investigator will record all relevant AE/SAE information in the CRF. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event. 
• 
For all non-serious AEs the applicable forms should be signed when the event is resolved or at the end of the 
trial at the latest. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this section. 
• 
Novo Nordisk products used as concomitant medication: if an AE is considered to have a causal relationship 
with a Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the 
suspected relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety 
information form. Novo Nordisk may need to report this 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:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities.  
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe. 
 
Assessment of causality 
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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:  
• 
Probable - Good reason and sufficient documentation to assume a causal relationship. 
• 
Possible - A causal relationship is conceivable and cannot be dismissed. 
• 
Unlikely - The event is most likely related to aetiology other than the trial product. 
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated. 
The investigator should use the investigator’s brochure for the assessment. For each AE/SAE, the investigator must 
document in the medical records that he/she has reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal information to include in 
the initial report. However, it is important that the investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data. 
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up 
report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Final outcome 
The investigator will select the most appropriate outcome: 
• 
Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial-related activity after the subject signed the informed consent. 
• 
Recovering/resolving: The condition is improving, and the subject is expected to recover from the event. This 
term is only applicable if the subject has completed the trial or has died from another AE. 
• 
Recovered/resolved with sequelae: The subject has recovered from the condition, but with lasting effect due to 
a disease, injury, treatment or procedure. If a sequelae meets an SAE criterion, the AE must be reported as an 
SAE. 
• 
Not recovered/not resolved: The condition of the subject has not improved, and the symptoms are unchanged 
or the outcome is not known. 
• 
Fatal: This term is only applicable if the subject died from a condition related to the reported AE. Outcomes of 
other reported AEs in a subject before he/she died should be assessed as “recovered/resolved”, 
“recovering/resolving”, “recovered/resolved with sequelae” or “not recovered/not resolved”. An AE with a fatal 
outcome must be reported as an SAE. 
• 
Unknown: This term is only applicable if the subject is lost to follow-up. 
 
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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 die during participation in the trial or during a recognised follow-up period, the investigator should 
provide Novo Nordisk with a copy of autopsy report including histopathology. 
New or updated information will be recorded in the CRF. 
 
 
SAE reporting via electronic CRF 
• 
Relevant forms (AE and safety information form) must be completed in the CRF.  
• 
For reporting and sign-off timelines, see box below.  
• 
If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
unavailable for more than 5 calendar days then the site will use the safety information form (see box below). 
• 
The site will enter the SAE data into the CRF as soon as it becomes available, see section 9.2.1. 
• 
After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a 
previously reported SAE after CRF decommission, then the site can report this information on a paper AE and 
safety information form (see box below) or to Novo Nordisk by telephone. 
 
 
SAE reporting via paper CRF 
• 
Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail 
or courier. 
• 
Initial notification via telephone is acceptable, although it does not replace the need for the investigator to 
complete the AE and safety information form within the designated reporting time frames (as illustrated in 
Figure 9-1 
o 
AE form within 24 hours. 
o 
Safety information form within 5 calendar days.  
o 
Both forms must be signed within 7 calendar days. 
Contact details for SAE reporting can be found in the investigator trial master file. 
 
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Appendix E 
Contraceptive guidance and collection of pregnancy information 
It must be recorded in the CRF whether female subjects are of childbearing potential.  
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
Women in the following categories are not considered WOCBP 
7. Premenarcheal  
8. Premenopausal female with one of the following: 
Documented hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
9. Postmenopausal female 
A postmenopausal state is defined as amenorrhoea for 12 months without an alternative medical 
cause.  
Females ≥ 50 years of age can be considered postmenopausal (irrespective of treatment with a 
hormonal contraception or hormone replacement therapy (HRT) if they have: 
o Amenorrhoea 
o Documentation of 2 high follicle stimulating hormone (FSH) measurements in 
the postmenopausal range and one of these was observed ≥1 year prior to 
screening. 
Females ≥ 60 years of age can be considered postmenopausal 
Females treated with HRT and whose menopausal status is uncertain are considered of childbearing 
potential and will be required to use one of the highly effective contraception methods.  
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely.  
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table below: 
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Table 11-4 
Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependent a and b 
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation b  
• 
oral  
• 
intravaginal  
• 
transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
oral  
• 
injectable  
Highly effective methods that are user independent b 
• 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation  
• 
Intrauterine Device  
• 
Intrauterine hormone-releasing System  
• 
Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
Sexual abstinenceb 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.  
Notes:  
aTypical use failure rates may differ from < 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.  
bContraception should be utilised during the treatment period and for at least 49 days after the last dose of trial product. 
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with: 
1) known intolerance to the highly effective methods mentioned in Table 11-4 - 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. 
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Pregnancy testing 
• WOCBP should only be included after a negative highly sensitive urine pregnancy test. 
• Additional urine pregnancy testing should be performed according to flowchart in WOCBP. 
• Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Female subjects who become pregnant  
• Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this trial. 
• Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy. 
• Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the delivery 
date. 
• Any termination of pregnancy will be reported regardless of foetal status (presence or absence 
of anomalies) or indication for procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial product by the investigator will be reported to Novo Nordisk as described in 
Appendix D. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.  
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Appendix F 
Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
Technical complaint definition  
A technical complaint is any written, electronic or oral communication that alleges product (medicine or device) 
defects. The technical complaint may be associated with an AE, but does not concern the AE itself. 
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination). 
• Problems with packaging material including labelling. 
• Problems related to medical devices (e.g. to the injection mechanism, dose setting 
mechanism, push button or interface between the pen-injector and the needle). 
Time period for detecting technical complaints 
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last 
usage of the product, must be collected for products predefined on the technical complaint form.  
 
Reporting of technical complaints to Novo Nordisk 
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must be completed 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within the timelines specified in 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. 
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Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product. 
 
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID. 
 
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Appendix G 
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.: 
• renal dysfunction 
• tobacco use 
• autoimmune thyroiditis 
• several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids) 
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various comorbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells. 
Calcitonin monitoring 
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. 
In case a subject has a calcitonin value ≥ 10 ng/L, the algorithm outlined in Figure 11-1 and 
described below should be followed. The algorithm applies for all calcitonin values in the trial. 
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Evaluation of 
calcitonin results
Calcitonin < 10 ng/L
  !"   	  	 
 

 10 ng/L and < 50 ng/L
  !"   	  	 
 

 50 ng/L and < 100 ng/L
  !"   	  	 
 

 100 ng/L 
  !"   	  	 
 

 10 ng/L and last 
measurmetn in the trial
No action
• 
Investigate potential confounding 
factors
• 
Continue sampling of calcitonin 
according to protocol
• 
Discontinue trial product
• 
Refer to thyroid specialist
• 
Refer to thyroid specialist
• 
Refer to thyroid specialist
Figure 11-1
Flow of calcitonin monitoring
Calcitonin ≥ 100 ng/L
Action: The subject (even if a screen failure) must immediately be referred to a thyroid specialist 
for further evaluation and the trial product must be discontinued (section 8). The subject should 
remain in the trial; however, all medications suspected to relate to this condition must be 
discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease60. All these patients were diagnosed with MTC, resulting in a positive predictive 
value of 100%.
Diagnostic evaluation should include:
•
thyroid ultrasound examination
•
fine needle aspiration of any nodules > 1 cm 
•
potentially, surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject (even if a screen failure) should be referred to a thyroid specialist for further 
evaluation. The subject should remain in the trial and can continue trial product.
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Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease60. Two of these subjects were diagnosed with MTC and two were diagnosed with C 
cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%. 
Diagnostic evaluation should include:  
• thyroid ultrasound examination  
• if available, and if there are no contraindications, a pentagastrin stimulation test should be 
done. For subjects with positive pentagastrin stimulation test, surgery should be considered.  
• if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery. 
Calcitonin ≥ 10 and < 50 ng/L 
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. 
If the subject is a screen failure, or if the value is from the last sample taken in the trial, the subject 
should be referred to a thyroid specialist for further evaluation. 
Background: Calcitonin values from 20–50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease60. 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.60 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 conclusions61, 62. 
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hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat 
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Version: 
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Log of Protocol Amendments 
Protocol 
amendment no 
Date 
Final, 
Version 
Country(ies) and/or trial 
site(s) affected 
Brief content 
Protocol amendment 1 
17 March 2020 
Protocol 
version 2.0 
US 
In order to generate clinical trial data with 
DV3396 pen-injector, all 
semaglutide/semaglutide placebo subjects will 
switch device from PDS290 to DV3396 at 
week 44 (visit 18) 
Further a new questionnaire (Injection Device 
Experience and Acceptance (IDEA) 
Questionnaire) will be introduced for subjects 
switching device.  
 
In protocol version 2.0 there was a mistake in 
summary of changes table, which is updated 
and therefore version 3.0 
Protocol amendment 2 
15 April 2020 
Protocol 
version 3.0 
US 
In order to generate clinical trial data with 
DV3396 pen-injector, all 
semaglutide/semaglutide placebo subjects will 
switch device from PDS290 to DV3396 at 
week 44 (visit 18) 
Further a new questionnaire (Injection Device 
Experience and Acceptance (IDEA) 
Questionnaire) will be introduced for subjects 
switching device.  
Protocol amendment 3 
25 November 2020 Protocol 
version 4.0 
US 
Amending the discontinuation criterion 6, so 
that subjects are allowed to continue in the 
trial, while also participating in a COVID-19 
trial. 
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Log of Protocol Amendments 
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Version: 
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16.1.01 
Statement Attachment I and II 
Attachments I and II (if applicable) to the protocol are located in the Trial Master File. 
Content: Global key staff and Country key staff. 
CONFIDENTIAL
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Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4576 (STEP 8)
Clinical Trial Report
Appendix 16.1.1
08 July 2021
1.0
Final
.
CONFIDENTIAL