Effect and Safety of Semaglutide 7.2 mg Once-weekly in Participants With Obesity
Phase: PHASE3
Conditions: Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05646706 
Sponsor trial ID: 
NN9536-4999 
Official title of study: 
Effect and safety of semaglutide 7.2 mg once-weekly in 
participants with obesity 
Document date: 
22 June 2023 

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
Status: 
Final 
Page: 
1 of 109 
Protocol
Protocol Title: Effect and safety of semaglutide 7.2 mg once-weekly in participants with 
obesity 
Substance name: semaglutide 
Universal Trial Number: U1111-1274-4259 
EudraCT Number: 2022-000790-94 
Study phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Redacted protocol 
Includes redaction of company confidential information 
only. 
. 

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
Status: 
Final 
Page: 
2 of 109 
 Protocol amendment summary of change table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or site(s) 
Protocol Version 5.0 
22 June 2023 
Global 
Protocol Version 4.0 
20 January 2023 
Global 
Protocol version 3.0 
28 September 2022 
Global 
Protocol version 2.0 
30 June 2022 
Global 
Original protocol version 1.0 
18 May 2022 
Internal 
Protocol version 5.0 (22 June 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.1  
Overall rationale for preparing protocol, version 5.0 
The primary reason for this protocol amendment was to include information about the new 
drug-device combination product, allowing for a single injection instead of 3 consecutive injections 
during the maintenance phase.  
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
Editorial changes e.g. spelling errors, 
punctuation or updates to more exact 
wording.   
To improve readability. 
Section 2.3.1, Table 2-1 
Removal of the potential risk of 
'Neoplasms’ (malignant and non-
malignant) from Table 2-1 
Risk removed in alignment with update 
of the investigator’s brochure (DLP 31 
May 2023).  
Sections 4.1 and 8.1.2 
The number of randomised participants in 
the MRI subgroup changed from 
approximately 210 to 50 participants 
To adjust the number of participants in 
the MRI subgroup based on the 
enrolled number of participants 
Table 6-1 and 6-2 and 
Sections 6.1 and 6.5 
Update of the dosage and administration 
of, and transition to, the new drug-device 
combination product during the 
maintenance phase. 
To update information about the 
introduction of the new drug-device 
combination product  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
3 of 109 
 
 
Table of Contents 
 
Page 
Protocol amendment summary of change table............................................................................................. 2 
Table of Contents.............................................................................................................................................. 3 
1 Protocol summary ....................................................................................................................................... 6 
1.1 
Synopsis .............................................................................................................................................. 6 
1.2 
Flowchart .......................................................................................................................................... 11 
2 Introduction ............................................................................................................................................... 15 
2.1 
Study rationale .................................................................................................................................. 15 
2.2 
Background ....................................................................................................................................... 16 
2.2.1 
Semaglutide ....................................................................................................................... 16 
2.2.2 
Study population ................................................................................................................ 16 
2.3 
Benefit-risk assessment ..................................................................................................................... 17 
2.3.1 
Risk assessment ................................................................................................................. 17 
2.3.2 
Benefit assessment ............................................................................................................. 20 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 20 
3 Objectives, endpoints and estimands ....................................................................................................... 21 
4 Study design ............................................................................................................................................... 26 
4.1 
Overall design ................................................................................................................................... 26 
4.2 
Scientific rationale for study design .................................................................................................. 26 
4.3 
Justification for dose ......................................................................................................................... 27 
4.4 
End of study definition ...................................................................................................................... 28 
5 Study population ....................................................................................................................................... 29 
5.1 
Inclusion criteria ............................................................................................................................... 29 
5.2 
Exclusion criteria .............................................................................................................................. 29 
5.3 
Lifestyle considerations .................................................................................................................... 30 
5.3.1 
Meals and dietary restrictions ............................................................................................ 31 
5.3.2 
Caffeine, alcohol and tobacco ........................................................................................... 31 
5.4 
Screen failures ................................................................................................................................... 31 
5.5 
Run-in criteria and randomisation criteria and dosing day criteria ................................................... 31 
6 Study intervention(s) and concomitant therapy ..................................................................................... 32 
6.1 
Study intervention(s) administered ................................................................................................... 32 
6.2 
Preparation, handling, storage and accountability ............................................................................ 35 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 37 
6.4 
Study intervention compliance.......................................................................................................... 37 
6.5 
Dose modification ............................................................................................................................. 38 
6.6 
Continued access to study intervention after end of study ................................................................ 40 
6.7 
Treatment of overdose ...................................................................................................................... 40 
6.8 
Concomitant therapy ......................................................................................................................... 40 
7 Discontinuation of study intervention and participant discontinuation/withdrawal .......................... 41 
7.1 
Discontinuation of study intervention ............................................................................................... 41 
7.1.1 
Temporary discontinuation of study intervention .............................................................. 42 
7.1.1.1 
Hepatic events requiring temporary discontinuation of study 
intervention .................................................................................................... 42 
7.2 
Participant discontinuation/withdrawal from the study .................................................................... 43 
7.2.1 
Replacement of participants .............................................................................................. 43 
7.3 
Lost to follow-up............................................................................................................................... 43 
8 Study assessments and procedures .......................................................................................................... 45 
8.1 
Efficacy assessments ......................................................................................................................... 46 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
4 of 109 
 
 
8.1.1 
Body measurements ........................................................................................................... 46 
8.1.2 
Magnetic resonance Imaging ............................................................................................. 47 
. 47 
8.1.4 
Clinical efficacy laboratory assessments ........................................................................... 47 
8.1.5 
Clinical outcome assessment ............................................................................................. 47 
8.2 
Safety assessments ............................................................................................................................ 47 
8.2.1 
Medical history/concomitant illness .................................................................................. 48 
8.2.2 
Mental health assessment instruments ............................................................................... 49 
8.2.3 
Physical examinations ....................................................................................................... 50 
8.2.4 
Vital signs .......................................................................................................................... 50 
8.2.5 
Electrocardiograms ............................................................................................................ 50 
8.2.6 
Clinical safety laboratory assessments .............................................................................. 50 
8.2.7 
Pregnancy testing and contraceptive counselling .............................................................. 51 
8.2.8 
Surgical procedures assessment ......................................................................................... 51 
8.3 
Adverse events and other safety reporting ........................................................................................ 51 
8.3.1 
Time period and frequency for collecting AE information ............................................... 52 
8.3.2 
Method of detecting AEs ................................................................................................... 52 
8.3.3 
Follow-up of AEs .............................................................................................................. 52 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 53 
8.3.5 
Pregnancy .......................................................................................................................... 53 
8.3.6 
Cardiovascular and death events ....................................................................................... 53 
8.3.7 
Technical complaints ......................................................................................................... 53 
8.4 
Pharmacokinetics and pharmacodynamics ....................................................................................... 53 
8.4.1 
Pharmacokinetics ............................................................................................................... 53 
8.4.2 
Pharmacodynamics ............................................................................................................ 54 
8.5 
Genetics ............................................................................................................................................ 54 
.. 54 
.. 54 
.. 55 
8.9 
Health economics .............................................................................................................................. 55 
9 Statistical considerations .......................................................................................................................... 56 
9.1 
Statistical hypotheses ........................................................................................................................ 56 
9.1.1 
Multiplicity adjustment...................................................................................................... 56 
9.2 
Analysis sets...................................................................................................................................... 57 
9.3 
Statistical analyses ............................................................................................................................ 58 
9.3.1 
General considerations ...................................................................................................... 58 
9.3.2 
Primary estimands analysis ............................................................................................... 59 
9.3.3 
Secondary estimands analysis ........................................................................................... 60 
9.3.3.1 
Confirmatory secondary estimands ................................................................ 60 
9.3.3.2 
Supportive secondary endpoints .................................................................... 61 
9.3.4 
Exploratory endpoint(s)/estimand(s) analysis ................................................................... 61 
9.3.5 
Other safety analyses ......................................................................................................... 61 
9.3.6 
Other analyses ................................................................................................................... 61 
9.3.6.1 
Pharmacokinetic and pharmacodynamic modelling ...................................... 61 
9.4 
Interim analysis ................................................................................................................................. 62 
9.5 
Sample size determination ................................................................................................................ 62 
9.6 
Reporting of the study ....................................................................................................................... 64 
10 Supporting documentation and operational considerations.................................................................. 66 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations .............................................. 66 
10.1.1 
Regulatory and ethical considerations ............................................................................... 66 
10.1.2 
Financial disclosure ........................................................................................................... 66 
10.1.3 
Informed consent process .................................................................................................. 67 
10.1.4 
Information to participants during the study ..................................................................... 67 
10.1.5 
Data protection .................................................................................................................. 67 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
5 of 109 
 
 
10.1.6 
Committees structure ......................................................................................................... 68 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 68 
10.1.7 
Dissemination of clinical study data .................................................................................. 68 
10.1.8 
Data quality assurance ....................................................................................................... 68 
10.1.8.1 
Case report forms ........................................................................................... 68 
10.1.8.2 
Monitoring ..................................................................................................... 69 
10.1.8.3 
Protocol compliance ....................................................................................... 70 
10.1.9 
Source documents .............................................................................................................. 70 
10.1.10 Retention of clinical study documentation ........................................................................ 70 
10.1.11 Study and site closure ........................................................................................................ 71 
10.1.12 Responsibilities .................................................................................................................. 71 
10.1.13 Indemnity statement .......................................................................................................... 72 
10.1.14 Publication policy .............................................................................................................. 72 
10.1.14.1 
Communication of results .............................................................................. 73 
10.1.14.2 
Authorship ...................................................................................................... 73 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 73 
10.1.14.4 
Investigator access to data and review of results ........................................... 74 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 75 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................................................... 78 
10.3.1 
Definition of AE ................................................................................................................ 78 
10.3.2 
Definition of an SAE ......................................................................................................... 78 
10.3.3 
Description of AEs requiring additional data collection ................................................... 79 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 81 
10.3.4.1 
AE and SAE recording ................................................................................... 81 
10.3.4.2 
Assessment of severity ................................................................................... 81 
10.3.4.3 
Assessment of causality ................................................................................. 81 
10.3.4.4 
Final outcome ................................................................................................. 82 
10.3.4.5 
Follow-up of AE and SAE ............................................................................. 83 
10.3.5 
Reporting of SAEs ............................................................................................................. 83 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 85 
10.4.1 
Definitions ......................................................................................................................... 85 
10.4.2 
Contraceptive guidance ..................................................................................................... 85 
10.4.3 
Collection of pregnancy information ................................................................................. 86 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 88 
10.5.1 
Definition of technical complaint ...................................................................................... 88 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 88 
10.6 Appendix 6: Hepatic Safety: Suggested actions and follow-up assessments .................................... 90 
.. 91 
10.8 Appendix 8: Mitigations to ensure participant safety and data integrity during an emergency 
situation ............................................................................................................................................. 93 
10.8.1 
Definition and scope of appendix ...................................................................................... 93 
10.8.2 
Visits .................................................................................................................................. 93 
10.9 Appendix 9: Monitoring of calcitonin .............................................................................................. 94 
10.10 Appendix 10: Country-specific requirements ................................................................................... 97 
10.11 Appendix 11: Abbreviations ............................................................................................................. 98 
10.12 Appendix 12: Protocol amendment history .................................................................................... 101 
11 References ................................................................................................................................................ 104 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
6 of 109 
 
 
1 
Protocol summary 
1.1 
Synopsis 
This is an interventional, multi-national, multi-centre, randomised, parallel group, double-blind, 
placebo-controlled, three-armed study.  
Rationale: 
Semaglutide s.c. 2.4 mg once-weekly (Wegovy®) has been approved for weight management in 
adults with obesity or overweight and the presence of at least one weight-related comorbidity. Some 
individuals may not reach their goals in terms of weight loss and cardiovascular benefits on 2.4 mg 
and may benefit from a higher dose of semaglutide. Modelling of data suggest that this can be 
achieved with an increased dose of semaglutide without jeopardising the safety of the individuals 
(Section 4.3).  
The present study is designed to evaluate the efficacy and safety of semaglutide s.c. 7.2 mg 
once-weekly versus placebo and semaglutide s.c. 2.4 mg once-weekly as an adjunct to 
reduced-calorie diet and increased physical activity in adults with obesity (BMI ≥ 30.0 kg/m2).  
Objectives, endpoints and estimand(s): 
Table 1-1 
Key objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
To demonstrate the superiority of semaglutide s.c. 
7.2 mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to relative change in body weight after 72 
weeks, in adults with obesity. 
Co-primary: 
Relative change in body 
weight 
From baseline 
(week 0) to end of 
treatment (week 72) 
% 
To demonstrate the superiority of semaglutide s.c. 
7.2 mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to achieving body weight reduction ≥ 5% 
after 72 weeks, in adults with obesity. 
≥5% body weight 
reduction (yes/no) 
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
Secondary 
Title 
Time frame 
Unit 
To demonstrate the superiority of semaglutide s.c. 7.2 
mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to achieving body weight reduction 
≥ 10% after 72 weeks, in adults with obesity. 
Confirmatory secondary: 
≥10% body weight 
reduction (yes/no)  
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide s.c. 7.2 
mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to achieving body weight reduction 
≥ 15% after 72 weeks, in adults with obesity. 
≥15% body weight 
reduction (yes/no)  
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide s.c. 7.2 
mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to achieving body weight reduction 
≥ 20% after 72 weeks, in adults with obesity. 
 ≥20% body weight 
reduction (yes/no) 
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
7 of 109 
 
 
Objectives 
Endpoints 
To demonstrate the superiority of semaglutide s.c. 7.2 
mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to achieving body weight reduction 
≥ 25% after 72 weeks, in adults with obesity. 
 ≥25% body weight 
reduction (yes/no) 
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide s.c. 7.2 
mg once-weekly versus placebo as an adjunct to a 
reduced-calorie diet and increased physical activity, 
with respect to change in waist circumference after 72 
weeks, in adults with obesity. 
Change in waist 
circumference 
From baseline 
(week 0) to end of 
treatment (week 72) 
Cm 
To demonstrate the superiority of semaglutide s.c. 
7.2 mg once-weekly versus semaglutide s.c. 2.4 mg as 
an adjunct to a reduced-calorie diet and increased 
physical activity, with respect to relative change in 
body weight after 72 weeks, in adults with obesity. 
Relative change in body 
weight 
From baseline 
(week 0) to end of 
treatment (week 72) 
% 
To demonstrate the superiority of semaglutide s.c. 
7.2 mg once-weekly versus semaglutide s.c. 2.4 mg as 
an adjunct to a reduced-calorie diet and increased 
physical activity, with respect to achieving body 
weight reduction ≥ 20% after 72 weeks, in adults with 
obesity. 
 ≥20% body weight 
reduction (yes/no) 
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide s.c. 
7.2 mg once-weekly versus semaglutide s.c. 2.4 mg as 
an adjunct to a reduced-calorie diet and increased 
physical activity, with respect to achieving body 
weight reduction ≥ 25% after 72 weeks, in adults with 
obesity. 
 ≥25% body weight 
reduction (yes/no) 
From baseline 
(week 0) to end of 
treatment (week 72) 
Count of 
participant 
Supportive secondary 
To compare the safety and tolerability of semaglutide 
s.c. 7.2 mg versus placebo, as an adjunct to 
reduced-calorie diet and increased physical activity in 
adults with obesity, after 81 weeks. 
Safety parameters  
Number of Adverse 
Events (AEs) 
From baseline 
(week 0) to end of 
study (week 81) 
Count of 
events 
Number of Serious 
Adverse Events (SAEs) 
From baseline 
(week 0) to end of 
study (week 81) 
Count of 
events 
To compare the safety of semaglutide s.c. 7.2 mg 
versus placebo, as an adjunct to reduced-calorie diet 
and increased physical activity, with respect to pulse 
after 72 weeks, in adults with obesity. 
Change in pulse 
From baseline 
(week 0) to end of 
treatment (week 72) 
Bpm 
To compare the safety and tolerability of semaglutide 
s.c. 7.2 mg versus semaglutide s.c. 2.4 mg, as an 
adjunct to reduced-calorie diet and increased physical 
activity in adults with obesity, after 81 weeks. 
Number of Adverse 
Events (AEs) 
From baseline 
(week 0) to end of 
study (week 81) 
Count of 
events 
Number of Serious 
Adverse Events (SAEs) 
From baseline 
(week 0) to end of 
study (week 81) 
Count of 
events 
Abbreviations: AEs = adverse events; SAEs = serious adverse events; s.c. = subcutaneous. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
8 of 109 
 
 
Co-primary estimands 
The co-primary estimands differ only by endpoint and population level summary. The co-primary 
estimands are described by the following attributes: 
 Population: Adults with obesity (defined as BMI ≥ 30 kg/m2), with or without weight-
related comorbidities. 
 Endpoint: 1) relative change from baseline to week 72 in body weight and 2) ≥ 5% body 
weight reduction (yes/no) at week 72. 
 Treatment condition: Semaglutide s.c. 7.2 mg once-weekly versus placebo regardless of 
discontinuation or dose reduction of randomised treatment, and regardless of initiating other 
anti-obesity therapies (weight management drugs or bariatric surgery). 
 Remaining intercurrent events: None, all intercurrent events (discontinuation or dose 
reduction of randomised treatment and initiation of other anti-obesity therapies) are captured 
by the treatment condition attribute and handled by the treatment policy strategy. 
 Population-level summary: 1) difference in mean changes and 2) odds ratio between 
treatment conditions.  
Secondary estimands 
The secondary estimands for both the confirmatory secondary and supportive secondary objectives 
are similar to the co-primary estimands except for the endpoint attribute and/or comparator.  
Additional estimands 
The additional estimands differ only by endpoint and population level summary. The additional 
estimands are described by the following attributes: 
 Population: Adults with obesity (defined as BMI ≥ 30 kg/m2), with or without weight-
related comorbidities. 
 Endpoint: 1) relative change from baseline to week 72 in body weight and 2) ≥ 5% body 
weight reduction at week 72. 
 Treatment condition: Semaglutide s.c. 7.2 mg once-weekly versus placebo both as an 
adjunct to a reduced-calorie diet and increased physical activity and regardless of dose 
reduction of randomised treatment.  
 Remaining intercurrent events: Treatment discontinuation and initiation of other anti-
obesity therapies are both handled by the hypothetical strategy. Dose reduction of 
randomised treatment, addressed in the treatment condition attribute, is handled by the 
treatment policy strategy. 
 Population-level summary: 1) difference in mean changes and 2) odds ratio between 
treatment conditions. 
A similar additional estimand also applies to all confirmatory and supportive secondary endpoints, 
as well as safety endpoints, in the population. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
9 of 109 
 
 
Overall design: 
The study consists of: 
 a 1-week screening period 
 a 20-week dose escalation period 
 a 52-week maintenance period 
 a 9-week follow-up period 
Study intervention groups and duration: 
Following a screening period of up to 1 week, the participants will be randomised 5:1:1 at the 
randomisation visit to semaglutide s.c. 7.2 mg once-weekly, semaglutide s.c. 2.4 mg once-weekly or 
placebo once-weekly as an adjunct to reduced-calorie diet and increased physical activity. 
The maximum duration of the study intervention for each participant is 72 weeks and the duration 
of the study for each participant is 81 weeks.  
The following trial products will be supplied by Novo Nordisk A/S: 
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose pen-injector  
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose pen-injector  
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose pen-injector 
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose 
pen-injector 
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose pen-injector 
 Semaglutide 
 mg/mL, solution for injection, DV3396 
 mL single-dose pen-injector*   
 Semaglutide placebo Ia, solution for injection, 
 mL single-dose pen-injector 
 Semaglutide placebo Ib, solution for injection, 
 mL single-dose pen-injector 
*The new drug-device combination product, which can administer 7.2 mg of the IMPs in a single s.c. injection will be 
introduced to all participants during the maintenance phase.  
Number of participants: 
Approximately 1610 participants will be screened to achieve 1400 participants randomly assigned 
to study intervention in a 5:1:1 ratio.  
Participant characteristics: 
The participants will be adult males and females who meet the following key inclusion criteria and 
none of the following key exclusion criteria: 
Key inclusion criteria 
 Male or female. 
 Age above or equal to 18 years at the time of signing informed consent. 
 BMI ≥ 30.0 kg/m2. 
 History of at least one self-reported unsuccessful dietary effort to lose body weight.  
Key exclusion criteria  
 HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
Status: 
Final 
Page: 
10 of 109 

History of type 1 or type 2 diabetes.

Treatment with glucose-lowering agent(s) within 90 days before screening.

A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening
irrespective of medical records.

Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or
medullary thyroid carcinoma.
Efficacy and safety data will be collected at regular intervals throughout the study. 
Data monitoring committee: No 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
Status: 
Final 
Page: 
15 of 109 
2 
Introduction 
2.1 
Study rationale 
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate.2-8 The medical and societal impacts are 
considerable and obesity is one of the most significant public health challenges worldwide.2-8 
Obesity is associated with increased risk of a variety of comorbidities including hyperglycaemia, 
type 2 diabetes (T2D), hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis, 
osteoarthritis, urinary incontinence, non-alcoholic steatohepatitis, cardiovascular disease, certain 
types of cancer, and risk of early death.9-23 Moreover, obesity adversely affects physical and mental 
health and reduces health related quality of life.24, 25 Obesity is also associated with decreased 
cardiorespiratory fitness, which also increases the risk of cardiovascular diseases and all-cause 
mortality.26 
The risk of obesity-related complications increases with increasing BMI, and a weight loss of 
5-10 % has significant health benefits in terms of slowing progression of T2D.27-30 Furthermore, a
weight loss of up to 15% improves many other obesity related complications as well as physical
symptoms and quality of life.31-39 Finally, studies suggest a beneficial impact of weight loss on
cardiovascular risk and mortality in both people with diabetes and obesity.40-42 Pharmacotherapy
providing high weight loss results will allow a higher proportion of people to achieve these benefits.
Lifestyle interventions 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 loss.43-52 Surgical treatments offer 
an effective alternative for some people with severe obesity, but surgery carries a risk in connection 
with the procedure and is not without complications. Furthermore, surgery requires close follow-up 
of the individual which can be cumbersome and costly.43-48, 53, 54 Pharmacotherapy may therefore 
serve as a valuable adjunct to lifestyle intervention for individuals with obesity in order to achieve 
and sustain a clinically relevant weight loss, to improve obesity related complications and to 
facilitate a healthier lifestyle. Few anti-obesity medications are currently available and there is a 
need for more safe and effective therapeutic options for treatment of obesity, especially treatments 
that also target weight maintenance, prevention, and treatment of complications.43-47, 55, 56  
The glucagon-like peptide-1 receptor agonist (GLP-1 RA) drug class is associated with multiple 
benefits; they have a well-documented safety profile, reduce body weight, improve blood pressure, 
lipid profile and other cardiovascular risk factors as well as glucose metabolism. Semaglutide is one 
of these GLP-1 RAs. 
Semaglutide s.c. 2.4 mg once-weekly (Wegovy®) has been approved for weight management in 
adults with obesity or overweight and the presence of at least one weight-related comorbidity (such 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
16 of 109 
 
 
as high blood pressure, T2D, or high cholesterol). Modelling of data based on exposure levels of 
what is to be expected suggest that a dose of 7.2 mg semaglutide could be an effective treatment 
option without jeopardising the safety of the individuals (Section 4.3).  
The present study is designed to evaluate the efficacy and safety of semaglutide s.c. 7.2 mg 
once-weekly versus placebo and semaglutide s.c. 2.4 mg once-weekly as an adjunct to 
reduced-calorie diet and increased physical activity in adults with obesity (BMI ≥ 30.0 kg/m2).  
2.2 
Background 
2.2.1 
Semaglutide 
Semaglutide is a long-acting glucagon-like petide-1 receptor agonist (GLP-1 RA), approved for 
weight management in doses of 2.4 mg/week (Wegovy®) and in lower doses for treatment of T2D 
in adults (Ozempic®). Semaglutide has a half-life of approximately 160 hours, making it suitable for 
once-weekly dosing.57  
GLP-1 is a physiological regulator of appetite and postprandial GLP-1 response is present in several 
areas of the brain involved in appetite regulation.58 In line with this, clinical and non-clinical data 
indicate that the body weight-reducing effect of semaglutide is mainly mediated by a reduced 
energy intake.59-65 
A comprehensive review of results from the non-clinical and clinical studies of semaglutide can be 
found in the current edition of the investigator’s brochure (IB)66 and any updates hereof. 
2.2.2 
Study population 
The study population will consist of participants with obesity (BMI ≥ 30.0 kg/m2). These 
participants represent a clinically relevant population for pharmacotherapeutic weight management 
as they are at significant risk of weight-related comorbidities 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 investigator as part of the medical history.  
 
First line treatment in weight management should be lifestyle modification through a 
reduced-calorie diet and increased physical activity. Thus, only participants who have tried but 
failed a dietary weight loss intervention will be included in accordance with regulatory guidelines.67, 
68 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
20 of 109 
 
 
Risk assessment has been conducted for DV3396 single-dose pen-injector for semaglutide and 
placebo in accordance with ISO 14971:2019. A general device risk assessment has been performed 
to ensure safe and accurate handling and dosing of semaglutide and placebo when using DV3396 in 
participants with obesity. 
In addition to the general device risk assessment, all new identified risks associated with using 
DV3396 for semaglutide and placebo according to the clinical procedures specified in this protocol 
have been reduced as far as possible and are acceptable, based on the current state of the art. The 
use of DV3396 for semaglutide and placebo in this study it therefore considered to be of non-
significant risk.  
2.3.2 
Benefit assessment 
Participants 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 study. The phase 3a programme has 
demonstrated clinically significant weight loss with semaglutide s.c. 2.4 mg once-weekly and a safe 
and well-tolerated profile, consistent with previous findings. Semaglutide s.c. 7.2 mg once-weekly 
is expected to provide substantial weight loss benefits without jeopardising the safety of the 
participants (Section 4.3). 
In addition, it is expected that all participants will benefit from participation through close contact 
with the study site and counselling by a dietician or a similar qualified healthcare professional, all 
of which will most likely result in intensified weight management. It is anticipated that all 
participants will benefit from participation, but the effect will be greater in participants randomised 
to semaglutide (7.2 mg or 2.4 mg) compared to placebo.  
2.3.3 
Overall benefit-risk conclusion 
Necessary precautions have been implemented in the design and planned conduct of the study to 
minimise the risks and inconveniences of participation in the study.  
The potential risks identified in association with participation in the present study are justified by 
the anticipated benefits that may be afforded to participants with obesity. 
More detailed information about the known and expected benefits and risks and expected AEs of 
semaglutide s.c. may be found in the IB66 and any updates hereof. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
21 of 109 
 
 
3 
Objectives, endpoints and estimands 
Table 3-1 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
To demonstrate the superiority of 
semaglutide s.c. 7.2 mg once-weekly versus 
placebo as an adjunct to a reduced-calorie diet 
and increased physical activity, with respect 
to relative change in body weight after 72 
weeks, in adults with obesity. 
Co-primary: 
Relative change in body 
weight 
From baseline (week 0) to 
end of treatment (week 72) 
% 
To demonstrate the superiority of 
semaglutide s.c. 7.2 mg once-weekly versus 
placebo as an adjunct to a reduced-calorie diet 
and increased physical activity, with respect 
to achieving body weight reduction ≥ 5% 
after 72 weeks, in adults with obesity. 
≥5% body weight 
reduction (yes/no) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
Secondary 
Title 
Time frame 
Unit 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus placebo as an 
adjunct to a reduced-calorie diet and 
increased physical activity, with respect to 
achieving body weight reduction ≥ 10% after 
72 weeks, in adults with obesity. 
Confirmatory secondary: 
≥10% body weight 
reduction (yes/no)  
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus placebo as an 
adjunct to a reduced-calorie diet and 
increased physical activity, with respect to 
achieving body weight reduction ≥ 15% after 
72 weeks, in adults with obesity. 
≥15% body weight 
reduction (yes/no)  
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus placebo as an 
adjunct to a reduced-calorie diet and 
increased physical activity, with respect to 
achieving body weight reduction ≥ 20% after 
72 weeks, in adults with obesity. 
 ≥20% body weight 
reduction (yes/no) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus placebo as an 
adjunct to a reduced-calorie diet and 
increased physical activity, with respect to 
achieving body weight reduction ≥ 25% after 
72 weeks, in adults with obesity. 
 ≥25% body weight 
reduction (yes/no) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus placebo as an 
adjunct to a reduced calorie diet and increased 
physical activity, with respect to change in 
waist circumference after 72 weeks, in adults 
with obesity. 
Change in waist 
circumference 
From baseline (week 0) to 
end of treatment (week 72) 
cm 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
22 of 109 
 
 
Objectives 
Endpoints 
To demonstrate the superiority of 
semaglutide s.c. 7.2 mg once-weekly versus 
semaglutide s.c. 2.4 mg as an adjunct to a 
reduced-calorie diet and increased physical 
activity, with respect to relative change in 
body weight after 72 weeks, in adults with 
obesity. 
Relative change in body 
weight 
From baseline (week 0) to 
end of treatment (week 72) 
% 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus semaglutide 
s.c. 2.4 mg as an adjunct to a reduced-calorie 
diet and increased physical activity, with 
respect to achieving body weight reduction ≥ 
20% after 72 weeks, in adults with obesity. 
 ≥20% body weight 
reduction (yes/no) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To demonstrate the superiority of semaglutide 
s.c. 7.2 mg once-weekly versus semaglutide 
s.c. 2.4 mg as an adjunct to a reduced-calorie 
diet and increased physical activity, with 
respect to achieving body weight reduction ≥ 
25% after 72 weeks, in adults with obesity. 
 ≥25% body weight 
reduction (yes/no) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
Supportive secondary: 
To compare the efficacy of semaglutide s.c. 
7.2 mg once-weekly versus placebo, as an 
adjunct to a reduced-calorie diet and 
increased physical activity in adults with 
obesity, on other factors related to body 
weight after 72 weeks. 
Body weight parameters 
Change in body weight 
From baseline (week 0) to 
end of treatment (week 72) 
kg 
Change in BMI 
From baseline (week 0) to 
end of treatment (week 72) 
kg/m2 
To compare the efficacy of semaglutide s.c. 
7.2 mg once-weekly versus placebo, as an 
adjunct to a reduced-calorie diet and 
increased physical activity in adults with 
obesity, on body composition after 72 weeks 
(for the MRI subgroup). 
Change in total fat mass From baseline (week 0) to 
end of treatment (week 72) 
%, L 
Change in lean body 
mass 
From baseline (week 0) to 
end of treatment (week 72) 
%, L 
Change in visceral fat 
mass 
From baseline (week 0) to 
end of treatment (week 72) 
%, L 
To compare the efficacy of semaglutide s.c. 
7.2 mg once-weekly versus placebo, as an 
adjunct to a reduced-calorie diet and 
increased physical activity in adults with 
obesity, on cardiovascular risk factors after 72 
weeks. 
Cardiovascular parameters 
Change in systolic blood 
pressure 
From baseline (week 0) to 
end of treatment (week 72) 
mmHg 
Change in diastolic 
blood pressure 
From baseline (week 0) to 
end of treatment (week 72) 
mmHg 
Change in total 
cholesterol 
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in high-density 
lipoprotein (HDL) 
cholesterol  
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in low-density 
lipoprotein (LDL) 
cholesterol  
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in very low-
density lipoprotein 
(VLDL) cholesterol  
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in triglycerides 
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
23 of 109 
 
 
Objectives 
Endpoints 
Change in free fatty 
acids 
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in high-
sensitivity c-reactive 
protein (hsCRP) 
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in lipid-lowering 
treatment (decrease, no 
change, increase) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
Change in 
antihypertensive 
treatment (decrease, no 
change, increase) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To compare the efficacy of semaglutide s.c. 
7.2 mg once-weekly versus placebo, as an 
adjunct to a reduced-calorie diet and 
increased physical activity in adults with 
obesity, on glucose metabolism after 72 
weeks. 
Glucose metabolism parameters 
Change in HbA1c 
From baseline (week 0) to 
end of treatment (week 72) 
% 
Change in fasting 
plasma glucose 
From baseline (week 0) to 
end of treatment (week 72) 
mg/dL 
Change in fasting serum 
insulin 
From baseline (week 0) to 
end of treatment (week 72) 
Ratio to 
baseline 
Change in glycaemic 
category 
(Normo-glycaemia, 
pre-diabetes, T2D) 
From baseline (week 0) to 
end of treatment (week 72) 
Count of 
participant 
To compare the safety and tolerability of 
semaglutide s.c. 7.2 mg versus placebo, as an 
adjunct to reduced-calorie diet and increased 
physical activity in adults with obesity, after 
81 weeks. 
Safety parameters 
Number of Adverse 
Events (AEs) 
From baseline (week 0) to 
end of study (week 81) 
Count of 
events 
Number of Serious 
Adverse Events (SAEs) 
From baseline (week 0) to 
end of study (week 81) 
Count of 
events 
To compare the safety of semaglutide s.c. 
7.2 mg versus placebo, as an adjunct to 
reduced-calorie diet and increased physical 
activity, with respect to pulse after 72 weeks, 
in adults with obesity. 
Change in pulse 
From baseline (week 0) to 
end of treatment (week 72) 
bpm 
To compare the safety and tolerability of 
semaglutide s.c. 7.2 mg versus semaglutide 
s.c. 2.4 mg, as an adjunct to reduced-calorie 
diet and increased physical activity in adults 
with obesity, after 81 weeks. 
Number of Adverse 
Events (AEs) 
From baseline (week 0) to 
end of study (week 81) 
Count of 
events 
Number of Serious 
Adverse Events (SAEs) 
From baseline (week 0) to 
end of study (week 81) 
Count of 
events 
Exploratory 
Title 
Time frame 
Unit 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
24 of 109 
 
 
Objectives 
Endpoints 
Abbreviations: AEs = adverse events; BMI = body mass index; 
; HbA1c = 
glycated haemoglobin; HDL = high-density lipoprotein; hsCRP = high-sensitivity c-reactive protein; LDL = low-
density lipoprotein; MRI = magnetic resonance imaging; SAEs = serious adverse events; s.c. = subcutaneous; T2D = 
type 2 diabetes; 
; VLDL = very low-
density lipoprotein. 
Co-primary estimands 
The primary clinical question of interest is: What is the treatment effect of semaglutide s.c. 7.2 mg 
once-weekly versus placebo, as an adjunct to reduced-calorie diet and increased physical activity in 
adults with obesity, measured by relative change from baseline (week 0) to week 72 in body weight 
and ≥ 5% body weight reduction at week 72, regardless of discontinuation or dose reduction of 
randomised trial product, and regardless of initiating other anti-obesity therapies (weight 
management drugs or bariatric surgery). 
The co-primary estimands differ only by endpoint and population level summary. The co-primary 
estimands are described by the following attributes: 
 Population: Adults with obesity (defined as BMI ≥ 30.0 kg/m2), with or without 
weight-related comorbidities. 
 Endpoint: 1) relative change from baseline to week 72 in body weight and 2) ≥ 5% body 
weight reduction (yes/no) at week 72. 
 Treatment condition: Semaglutide s.c. 7.2 mg once-weekly versus placebo regardless of 
discontinuation or dose reduction of randomised treatment, and regardless of initiating other 
anti-obesity therapies (weight management drugs or bariatric surgery). 
 Remaining intercurrent events: None, all intercurrent events (discontinuation or dose 
reduction of randomised treatment and initiation of other anti-obesity therapies) are captured 
by the treatment condition attribute and handled by the treatment policy strategy. 
 Population-level summary: 1) difference in mean changes and 2) odds ratio between 
treatment conditions.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
25 of 109 
 
 
Rationale for estimand: The co-primary estimands take into account both safety and efficacy and 
reflect clinical practice to the extent possible in a clinical study. The co-primary estimands are thus 
relevant to support regulatory decision making.  
Secondary estimands 
The secondary estimands for both the confirmatory secondary and supportive secondary objectives 
related to efficacy are similar to the co-primary estimands except for the endpoint attribute and/or 
comparator. The secondary estimands with continuous endpoints for secondary objectives are 
similar to the co-primary estimand relative weight change, with the exception of endpoints with 
units of ratio to baseline, for which the population-level summary is the ratio between treatment 
conditions. The secondary estimands with binary endpoints for secondary objectives are similar to 
the co-primary estimand for ≥ 5% body weight reduction. 
Additional estimands  
An additional clinical question of interest for the primary objective is: What is the treatment effect 
of semaglutide s.c. 7.2 mg once-weekly versus placebo, as an adjunct to reduced-calorie diet and 
increased physical activity in adults with obesity, measured by relative change from baseline 
(week 0) to week 72 in body weight and ≥ 5% body weight reduction at week 72, had they 
remained on their randomised trial product for the entire planned duration of the study and not 
initiated any other anti-obesity therapies (weight management drugs or bariatric surgery).  
The additional estimands differ only by endpoint and population level summary. The additional 
estimands are described by the following attributes: 
 Population: Adults with obesity (defined as BMI ≥ 30 kg/m2), with or without weight-
related comorbidities. 
 Endpoint: 1) relative change from baseline to week 72 in body weight and 2) ≥ 5% body 
weight reduction at week 72. 
 Treatment condition: Semaglutide s.c. 7.2 mg once-weekly versus placebo both as an 
adjunct to a reduced-calorie diet and increased physical activity and regardless of dose 
reduction of randomised treatment.  
 Remaining intercurrent events: Treatment discontinuation and initiation of other anti-
obesity therapies are both handled by the hypothetical strategy. Dose reduction of 
randomised treatment, addressed in the treatment condition attribute, is handled by the 
treatment policy strategy. 
 Population-level summary: 1) difference in mean changes and 2) odds ratio between 
treatment conditions. 
Rationale for estimand: The additional estimand aims at reflecting the treatment effect (including 
all doses of semaglutide) without the confounding effects of other anti-obesity therapies or trial 
product discontinuation. 
A similar additional estimand also applies to all confirmatory and supportive secondary objectives 
in the population. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
26 of 109 
 
 
4 
Study design 
4.1 
Overall design 
This is an interventional, multi-national, multi-centre, randomised, parallel group, double-blind, 
placebo-controlled, three-armed study.  
Approximately 1400 participants will be randomised 5:1:1 to receive either semaglutide s.c. 7.2 mg, 
semaglutide s.c. 2.4 mg or placebo once-weekly, as an adjunct to reduced-calorie diet and increased 
physical activity. The study population consists of adults with obesity.   
A sub-population of approximately 50 randomised participants will have their body composition 
assessed by MRI at the beginning and at the end of the treatment to investigate the degree to which 
weight loss is caused by reduction in fat mass, in accordance with the EMA and FDA guidelines.67, 
68  
The study consists of: 
 a 1-week screening period 
 a 20-week dose escalation period 
 a 52-week maintenance period 
 a 9-week follow-up period 
The duration of the study intervention (trial product and lifestyle intervention) is 72 weeks followed 
by a 9-week follow-up period without study interventions (Figure 4-1).  
Efficacy and safety data will be collected at regular intervals throughout the study.  
Figure 4-1 
Study design 
 
Note: ‘end of study intervention’ (week 72) corresponds to both end of IMP treatment and end of lifestyle intervention. 
4.2 
Scientific rationale for study design 
A 72-week treatment duration (20 week of dose escalation and 52 weeks on maintenance dose) is 
considered sufficient to assess weight loss, safety and tolerability of semaglutide s.c. 7.2 mg versus 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
27 of 109 
 
 
semaglutide s.c. 2.4 mg once-weekly and placebo in accordance with regulatory guidelines.67, 68 The 
9 weeks follow-up period is included to account for the exposure and long half-life of semaglutide.  
A randomised, double-blind, placebo-controlled, multi-national, multi-centre, three-armed, parallel 
trial design is chosen to minimise bias in the assessment of the efficacy and safety of semaglutide 
s.c. 7.2 mg once-weekly versus semaglutide s.c. 2.4 mg once-weekly and placebo, as an adjunct to 
reduced-calorie diet and increased physical activity. 
The study population is chosen in accordance with regulatory guidelines67, 68 to consist of adults 
with BMI ≥ 30.0 kg/m2 with or without weight-related comorbidities. 
4.3 
Justification for dose 
In the phase 2 dose-finding trial (NN9536-4153), 5 once-daily doses of semaglutide were explored. 
Study results showed a monotone dose-response relation within the investigated dose interval from 
0.05 to 0.4 mg once-daily with a steadily increasing effect with increasing dose. Hence, from the 
dose-finding study the effect of semaglutide did not seem to plateau within the investigated dose 
interval from 0.05 to 0.4 mg once-daily, indicating the effect on weight change of semaglutide 
might not yet have reached a saturation point at the highest investigated dose level. 
Exposure-response relationships have characterised the relative weight loss from baseline to week 
52, following administration of once-daily s.c. semaglutide doses. This analysis supported the 
selection of 2.4 mg once-weekly semaglutide for phase 3 development in weight management. 
The phase 3a weight management programme (STEP 1-4) demonstrated a clinically significant 
weight loss with semaglutide s.c. 2.4 mg once-weekly and statistically significant improvements in 
waist circumference, systolic blood pressure and physical functioning. This resulted in a favourable 
balance between benefits and risks. Additionally, the once-weekly dosing was anticipated to ease 
the burden of drug administration in clinical practice.  
To fully utilize data from the semaglutide weight management development programme 
(NN9536-4153 and STEP), a post-hoc longitudinal exposure-response analysis was undertaken, 
developing a model that is suited for simulation of the time-course weight loss across different dose 
regimens and time points. The simulations show that substantial weight loss benefits may be 
realised with the 7.2 mg once-weekly.  
The predicted exposure range following s.c. 7.2 mg semaglutide is within the exposure range 
observed for the once-daily oral dose of 
 mg in the clinical pharmacology study 
. 
The safety and tolerability profile of the participants in study 
 with exposure levels 
within the predicted exposure range of 7.2 mg was in line with the expected safety profile of 
semaglutide and did not indicate any unexpected safety findings. Thus, an increase of dose to 
7.2 mg is expected to be possible without jeopardising the safety of the participants.   
Safety of semaglutide s.c. 7.2 mg once-weekly versus semaglutide s.c. 2.4 mg will be evaluated in 
this study to support bridging of the safety profile to previous studies.   
A low starting dose and fixed-dose escalation regimen is expected to mitigate the risk of developing 
gastrointestinal (GI) AEs. A fixed-dose escalation regimen, with dose escalation every 4 weeks 
until the target dose is reached, will be followed. Participants start with a once-weekly dose of 0.25 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
28 of 109 
 
 
mg and increases the dose every 4 weeks (to 0.5, 1.0, 1.7, 2.4 mg/week). After 20 weeks 
participants will start on their respective maintenance doses of 7.2 mg/week, 2.4 mg/week or 
placebo. To increase GI tolerability, dose level reductions and extensions of dose-escalation periods 
will be allowed based on clinical evaluation made by the investigator.  
Please refer to Section 6.1 for more details on trial product doses and Section 6.5 for dose 
modification and mitigation of GI symptoms. 
4.4 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last visit (‘end of study’ according to the flowchart, Section 1.2).  
The primary endpoint is evaluated at visit 22 (week 72). The primary completion date (PCD) is 
defined as the date of visit 22 (week 72) on which the last participant in the clinical study has an 
assessment for the primary endpoint. If the last participant is withdrawn early, the PCD is 
considered the date when the last participant would have completed visit 22.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
29 of 109 
 
 
5 
Study population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
 
Pre-screening is defined as review of the patient medical records, including handing out participant 
information, as well as database review. Any pre-screening activities must be documented on site 
by the investigator. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Informed consent obtained before any study-related activities. Study-related activities are any 
procedures that are carried out as part of the study, including activities to determine suitability 
for the study. 
2. Male or female. 
3. Age above or equal to 18 years at the time of signing informed consent. 
4. Body mass index (BMI)a ≥ 30.0 kg/m2.  
5. History of at least one self-reported unsuccessful dietary effort to lose body weight. 
aBMI as calculated in the eCRF at screening (Section 8.1.1) 
MRI sub-population 
To be qualified for the MRI sub-population, the following criteria must be answered "yes". 
Participants who do not fulfil the below criteria can be randomised in the study outside the MRI 
sub-group.    
1. Body weight < 149.0 kg at screening.  
2. No metal implants e.g., pacemaker, intracranial clips, cochlear implant, infusion pump or 
neurostimulators 
3. Suitable for MRI as per Investigator’s discretion e.g., no claustrophobia. 
All inclusion criteria will be assessed at the investigator’s discretion unless otherwise stated.  
For country specific requirements, see Section 10.10. 
5.2 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Known or suspected hypersensitivity to study intervention(s) or related products. 
2. Previous participation in this study. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using highly effective contraceptive method, as defined in Appendix 4 
(Section 10.4). 
4. Participation (i.e., signed informed consent) in any interventional, clinical study within 90 
days before screening. 
5. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening. 
6. History of type 1 or type 2 diabetes.a 
7. Treatment with glucose-lowering agent(s) within 90 days before screening. 
8. Treatment with GLP-1 receptor agonist within 180 days prior to screening. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
30 of 109 
 
 
9. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
10. Treatment with any medication for the indication of obesity within 90 days before screening.  
11. Previous or planned (during the trial period) obesity treatment with surgery or a weight loss 
device. However, the following are allowed: 1) liposuction and/or abdominoplasty, if 
performed > 1 year before screening, 2) lap banding, if the band has been removed > 1 year 
before screening, 3) intragastric balloon, if the balloon has been removed > 1 year before 
screening, or 4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year 
before screening.  
12. Uncontrolled thyroid disease per investigator’s discretion.  
13. Active or unstable depression or other active or unstable psychiatric conditionsa which in the 
investigator’s opinion can jeopardize participant’s safety or compliance with the protocol. 
14. A Patient Health Questionaire-9 (PHQ-9) score of ≥ 15 at screening. 
15. A lifetime history of suicidal attempt.a 
16. Suicidal behaviour within 30 days before screening.a 
17. Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) within 30 days before screening. 
18. Presence of acute pancreatitis within 180 days before screening.a  
19. History or presence of chronic pancreatitis.a 
20. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma.a  
21. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
< 15 mL/min/1.73 m2 as defined by KDIGO 201270 by the central laboratory at screening. 
22. Presence or historya of malignant neoplasm (other than basal or squamous cell skin cancer, in-
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of 
screenings. 
23. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina or 
transient ischaemic attack within 60 days before screening.  
24. Participants presently classified as being in New York Heart Association (NYHA) class IV. 
25. Surgery scheduled for the duration of the trial, expect for minor surgical procedures, in the 
opinion of the investigator.  
26. Known or suspected abuse of alcohol or recreational drugs.  
27. Other participant(s) from the same household participating in any semaglutide trial.  
28. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, 
which in the investigator’s opinion, might jeopardise the participant’s safety or compliance 
with the protocol.  
aAs declared by the participant or reported in the medical records.  
The criteria will be assessed at the investigator’s discretion unless otherwise stated.  
For country specific requirements, see Section 10.10. 
5.3 
Lifestyle considerations 
To ensure alignment of performance of assessments across participants and study sites, the below 
restrictions apply.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
31 of 109 
 
 
5.3.1 
Meals and dietary restrictions 
 Participants must attend the visits fasting, if indicated, according to the flowchart. 
 Fasting is defined as no food or liquids, except for water, at least 8 hours overnight before the 
visit. Participants should be encouraged to stop drinking water 2 hours before the time they 
are scheduled to arrive for the visit. 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 participant is not fasting as required, the participant should be called in for a new visit 
within the visit window to have the fasting procedures done. Procedures requiring participant 
to fast include blood sampling of fasting plasma glucose (FPG), fasting serum insulin, lipids, 
. 
5.4 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently eligible for participation according to the inclusion/exclusion criteria. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure participants 
to meet requirements from regulatory authorities. Minimal information includes informed consent 
date, demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
A screen failure must be made in the system (randomisation and trial suppliers management system 
[RTSM]/interactive web response system [IWRS]). 
Individuals who do not meet the criteria for participation in this study may not be rescreened. If the 
participant has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g., 
haemolysed or lost), re-sampling is allowed for the affected parameter(s). 
5.5 
Run-in criteria and randomisation criteria and dosing day criteria 
Not applicable for this study.  
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
32 of 109 
 
 
6 
Study intervention(s) and concomitant therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study protocol. 
Diet and physical activity counselling is also regarded as study intervention.  
Trial product comprise investigational medicinal products (IMPs), including placebo and 
comparators, non-investigational medicinal products (NIMPs) and/or investigational devices. 
6.1 
Study intervention(s) administered 
Table 6-1 and Table 6-2 provides an overview of the study interventions. Participants will be 
transitioned to the single injection administration using the new drug-device combination product, 
during their next planned site visit from when the new drug-device combination product is available 
on site. 
Table 6-1 
Study interventions 
Intervention/Arm 
name 
Semaglutide 7.2 mg 
Semaglutide 2.4 mg 
Placebo 
Any other 
interventions 
Intervention name 
 
Semaglutide 
 
mg/mL DV3396 or 
Semaglutide 
 
mg/mL DV3396 
Semaglutide 
 
mg/mL DV3396 
Placebo 
 
Diet and physical 
activity 
counselling 
Intervention type 
IMP 
IMP 
IMP, reference 
therapy 
Background 
intervention 
Pharmaceutical 
form 
Solution for injection 
Solution for injection 
Solution for injection 
 
Route of 
administration  
Subcutaneous 
Subcutaneous 
Subcutaneous 
 
Trial product 
strength 
See Table 6-2 
 for details 
See Table 6-2 
 for details 
See Table 6-2 
 for details 
 
Dose and dose 
frequency 
Dose: see Table 6-2 
Dose frequency: 
once-weekly 
Dose: see Table 6-2 
Dose frequency: 
once-weekly 
Dose: see Table 6-2 
Dose frequency: 
once-weekly 
 
Dosing 
instructions and 
administration  
Once-weekly injection, 
at the same day of the 
week (to the extent 
possible) throughout 
the study.  
Injection(s) may be 
administered in the 
thigh, abdomen, or 
upper arm, at any time 
of day irrespective of 
meals.  
Once-weekly 
injection, at the same 
day of the week (to 
the extent possible) 
throughout the study.  
Injections may be 
administered in the 
thigh, abdomen, or 
upper arm, at any 
time of day 
irrespective of meals.  
Once-weekly 
injection, at the same 
day of the week (to 
the extent possible) 
throughout the study.  
Injections may be 
administered in the 
thigh, abdomen, or 
upper arm, at any 
time of day 
irrespective of meals.  
 
Sourcing 
Manufactured and 
supplied by Novo 
Nordisk A/S. 
Manufactured and 
supplied by Novo 
Nordisk A/S. 
Manufactured and 
supplied by Novo 
Nordisk A/S. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
33 of 109 
 
 
Intervention/Arm 
name 
Semaglutide 7.2 mg 
Semaglutide 2.4 mg 
Placebo 
Any other 
interventions 
Packaging and 
labelling 
 
 
Labelled and 
packaged by Novo 
Nordisk A/S. 
 
Labelled in 
accordance with 
Annex 13,71 local 
regulations and 
study 
requirements. 
 
IMP is provided in 
a DV3396 single-
dose pen-injector) 
(see Table 6-2). 
 
Labelled and 
packaged by 
Novo Nordisk 
A/S. 
 
Labelled in 
accordance with 
Annex 13,71 
local regulations 
and study 
requirements. 
 
IMP is provided 
in a DV3396 
single-dose pen-
injector (device 
constituent of 
approved drug-
device 
combination 
product) (see 
Table 6-2). 
 
Labelled and 
packaged by 
Novo Nordisk 
A/S. 
 
Labelled in 
accordance with 
Annex 13,71 
local regulations 
and study 
requirements. 
 
IMP is provided 
in a DV3396 
single-dose pen-
injector (see 
Table 6-2). 
 
Abbreviations: IMP = investigational medicinal product.  
 
The investigator must document that directions for use was given to the participant verbally and in 
writing as a directions for use (DFU) document at the first dispensing visit (as specified in the 
flowchart).  
Investigational medicinal products (IMP) 
All trial products listed in Table 6-2 are considered IMPs. 
See Section 6.5 for details on dose escalation, dose adjustment and missed doses.   
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
35 of 109 
 
 
Other study intervention(s) 
All participants will receive counselling with regards to diet (approximately 500 kcal deficit per day 
relative to the estimated total daily energy expenditure [TEE] calculated once at randomisation) and 
physical activity (increasing from baseline to at least 150 min of physical activity per week is 
encouraged, e.g., walking or using the stairs). Counselling should be done by a dietician or similarly 
qualified health care professional every 4th week via visits/phone contacts.  
Calculation of estimated total energy expenditure 
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (See Table 6-3) 
with a Physical Activity Level value of 1.3.72 
TEE = BMR x 1.3 
Table 6-3 
Equation for estimated Basal Metabolic Rate (BMR) 
Sex 
Age 
BMR (kcal/day) 
Men 
18-30 years 
15.057 × weight at randomisation in kg + 692.2 
 
31-60 years 
11.472 × weight at randomisation in kg + 873.1 
 
> 60 years 
11.711 × weight at randomisation in kg + 587.7 
Women 
18-30 years 
14.818 × weight at randomisation in kg + 486.6 
 
31-60 years 
8.126 × weight at randomisation in kg + 845.6 
 
> 60 years 
9.082 × weight at randomisation in kg + 658.5 
 
Auxiliary supplies including non-investigational medical device(s) 
Auxiliary supplies will be provided in accordance with the trial materials manual (TMM) and 
Table 6-4. 
Table 6-4 
Auxiliary supplies provided by Novo Nordisk A/S 
Auxilliary supply 
Details 
Direction for use (DFU) 
DFU for DV3396 single-dose pen-injector. 
Not included in the dispensing unit and to be handed out separately. 
 
The DV3396 pen-injector, is a single use, fixed dose disposable pen-injector for self-injection with 
a build-in needle. Information about the DV3396 single-dose pen-injector may be found in the IB66 
and any updates hereof. Information about the use of the DV3396 single-dose pen-injector can be 
found in the DFU. 
6.2 
Preparation, handling, storage and accountability 
Only participants enrolled in the study may use study intervention and only delegated site staff may 
supply study intervention. 
Each site will be supplied with sufficient study intervention for the study on an ongoing basis 
according to recruitment and randomisation. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
36 of 109 
 
 
For selected countries and if permitted by local regulations, the investigator may offer to send study 
intervention from the study site or pharmacy to the participant’s home by courier service. The 
process for sending study intervention from the study site or pharmacy to a participant’s home is 
described in the “Study site/pharmacy instruction for shipment of trial product to participants’ 
homes” document.  This document contains detailed instructions for preparing packaging and 
setting up the pick-up of study intervention, handover of study intervention from the study site or 
pharmacy staff to the courier, required temperature monitoring of study intervention, delivery to 
and receipt of study intervention by the participant. The process for returning study intervention to 
the study site or pharmacy by courier is also described in this document. Investigators, study 
site/pharmacy staff and participants who will be involved in shipment of study intervention to the 
participant’s home will be adequately trained in this process. 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that 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 
delegated site staff. 
The investigator must inform Novo Nordisk immediately if any trial product has been stored outside 
specified conditions. The trial product must not be dispensed to any participant before it has been 
evaluated and approved for further use by Novo Nordisk. Additional details regarding handling of 
temperature deviations can be found in the Trial Materials Manual (TMM). 
The investigator or designee is responsible for trial product accountability and record maintenance 
(i.e., receipt, accountability and final disposition records). Drug accountability is performed on item 
level by using the RTSM/IWRS. 
The investigator or designee must instruct the participant in what to return at next visit. The 
participant must return all used and unused trial product including empty packaging materials 
during the study as instructed by the investigator.  
The investigator or designee must instruct the participant on how to manage the in-use time of the 
dispensed products. 
 
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, if not 
otherwise agreed at the site selection.  
All returned, expired or damaged trial products (for technical complaint samples, see Appendix 5 
[Section 10.5]) 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 site. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
37 of 109 
 
 
6.3 
Measures to minimise bias: Randomisation and blinding 
All participants will be screened and centrally randomised using the system (RTSM or IWRS) and 
assigned to the next available trial product according to the randomisation schedule. Trial product 
will be allocated by the system and dispensed by the investigator at the study visits summarised in 
the flowchart. 
This is a double-blind study in which participants, care providers, investigators and outcome 
assessors are blinded to trial product allocation. 
The system (RTSM/IWRS) is used for blind-breaking. In case of an emergency, the investigator has 
the sole responsibility for determining if unblinding of a participant’s trial product is warranted. 
Participant safety must always be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, the investigator should make every effort to 
contact Novo Nordisk prior to unblinding a participant’s study intervention unless this could delay 
emergency treatment of the participant. 
If a participant’s trial product is unblinded, Novo Nordisk (Global Safety department) must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation. The person breaking the blind must print the blind 
break confirmation notification generated by the RTSM/IWRS, sign and date the document. If the 
system (RTSM/IWRS) is not accessible at the time of blind break, the RTSM/IWRS helpdesk 
should be contacted. Contact details are listed in Attachment I. 
Participant will continue on trial product if there are no safety concerns at the discretion of the 
investigator. 
6.4 
Study intervention compliance 
Drug treatment compliance 
Throughout the study, the investigator will remind the participants to follow the study procedures 
and requirements to encourage participant compliance. Treatment compliance will be assessed by 
monitoring of drug accountability and by discussing treatment compliance and dosing conditions 
with the participant. If a participant is found to be non-compliant the investigator will remind the 
participant of the importance of following the instructions given, including taking the trial products 
as prescribed. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
38 of 109 
 
 
When participants self-administer trial product at home, compliance with trial product 
administration will be assessed, and the assessment documented in source documents at each visit 
where information is available. The participant will be asked about date of first dose at visit 3. 
Information about treatment compliance will be collected at every visit/phone contact from 
randomisation. Information on treatment dose start and stop dates will be recorded in the CRF. If 
any suspicion of non-compliance arises, the site must enter into a dialogue with the participant, re-
emphasizing the importance of compliance and uncover barriers to compliance. This dialogue must 
be documented.  
6.5 
Dose modification 
Dose escalation 
 Participants will be initiated at a once-weekly dose of 0.25 mg and follow a fixed-dose 
escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7, and 2.4 
mg/week). After 20 weeks participants will start on their respective target dose of 
7.2 mg/week, 2.4 mg/week or placebo. All participants should aim at reaching the 
recommended target dose.  
 During escalation one injection should be administered per week. During the maintenance 
period 3 consecutive injections (3 x 2.4 mg, 2.4 mg + 2 x placebo, or 3 x placebo) should be 
administered per week to obtain the target dose of 7.2 mg semaglutide and maintain blinding. 
The 2nd and 3rd injection should be administered immediately after the 1st injection using a 
different site of injection, either within the same or a new body region, but at least 5 cm from 
the first injection site. A new drug-device combination product which can administer 7.2 mg 
semaglutide s.c. in a single injection, will be using the DV3396 single-dose pen-injector and 
will be introduced during this study . When the new drug-device combination product is 
introduced the maintenance dose will be administered as a single injection for all treatment 
arms.  
 If a participant does not tolerate the current dose, consider delaying the dose escalation or 
reducing the dose. This should only be allowed if the participant would otherwise 
discontinue trial product completely and if considered safe to continue trial product, as per 
the investigator’s discretion. It is recommended that the participant makes at least one 
attempt to re-escalate. If re-escalation is not tolerated participants should stay at a lower dose 
level.   
 De-escalation should follow the regimen outlined in Figure 6-1. If the maintenance dose (all 
treatment arms) is not tolerated, the participant shall be de-escalated to 1.7 mg, to maintain 
blinding. If 1.7 mg is tolerated for 4 weeks, the participant can be re-escalated to 2.4 mg. If 
this dose is tolerated for 4 weeks, the participant can be re-escalated to maintenance dose. 
Re-escalation after < 4 weeks is allowed if feasible as per the investigator’s discretion. It is 
recommended that the participant makes at least one attempt to re-escalate to maintenance 
dose.  
 Participants will be contacted by phone within day 3-7 after escalation (phone visit 9) to the 
target dose, to ensure the dose is tolerated (see Section 1.2).  
 It is recommended that the investigator consults with Novo Nordisk in case of persistent 
deviations from the planned escalation regimen.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
39 of 109 
 
 
 A dose reminder card will be handed out to the participants at dose escalation site visits and 
regularly during the maintenance period.   
Figure 6-1 
De-escalation guide 
 
Note: Maintenance dose is referring to 7.2 mg/2.4 mg/placebo dose. 
Mitigation of GI symptoms 
The investigator should support participants in escalating and maintaining their respective IMP 
dose. To mitigate and manage GI symptoms the investigator should:  
 Advise participants to eat slowly, eat smaller meals, and stop eating when feeling full.  
 In cases of persistent GI AEs, at any time during the study, symptomatic medication (e.g., 
antiemetic or antidiarrheal) should be prescribed, at the investigator’s discretion.  
Dose adjustment 
 If the participant with a BMI within the lower normal range continues to lose weight, and 
there is a health concern, the investigator must consider reducing the dose of the IMP. The 
investigator can contact Novo Nordisk for guidance. If the participant reaches a 
BMI < 18.5 kg/m2, the dose of IMP must be reduced and Novo Nordisk should be contacted 
for guidance.  
Missed dose(s) 
 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 participant 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 participant should be encouraged to 
recommence the trial product if considered safe as per investigator’s discretion and if the 
participant does not meet any of the discontinuation criteria (Section 7.1). 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.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
40 of 109 
 
 
6.6 
Continued access to study intervention after end of study 
There is no treatment following the end of the study. When discontinuing study intervention, the 
participant should be transferred to a suitable marketed product at the discretion of the investigator. 
6.7 
Treatment of overdose 
Overdose with semaglutide may be associated with gastrointestinal disorders which could lead to 
dehydration.   
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to participant’s clinical signs and symptoms. 
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the participant for overdose-
related AEs/SAEs and laboratory abnormalities, and appropriate supportive treatment should be 
initiated according to the participants’ clinical signs and symptoms. 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 participant. 
For more information on overdose, also consult the current version of the investigator’s brochure 
(IB).66 
6.8 
Concomitant therapy 
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of the first visit or receives until end of study must be recorded 
along with: 
 Trade name or generic name 
 Dose and dosing frequency for antihypertensive, lipid-lowering and antipsychotic 
medication, and anti-obesity preparations. 
 Primary indication 
 Dates of administration including start and stop dates 
During the study, participants should not initiate any anti-obesity medication or treatment which is 
not part of the study procedures. If such treatment is initiated, the participants should be instructed 
to stop the treatment.  
Changes in concomitant therapy must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 8.3. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
41 of 109 
 
 
7 
Discontinuation of study intervention and participant 
discontinuation/withdrawal 
Discontinuation of specific sites or of the study as a whole is detailed in Appendix 1 
(Section 10.1.11). 
7.1 
Discontinuation of study intervention 
Study intervention may be discontinued at any time during the study at the discretion of the 
participant or at the discretion of the investigator for safety, behavioural, compliance or 
administrative reasons. 
The end-of-study visit (visit 23) is scheduled approximately 9 weeks after end of study intervention 
to account for the exposure and long half-life of semaglutide and to ensure the safety of the 
participant. If the participant has discontinued trial product > 9 weeks prior to the ‘end of treatment’ 
visit, and the requirements for the follow-up period prior to the end-of-study visit are fulfilled, then 
the end-of-study visit can be omitted. 
Efforts must be made to have participants attend and complete all scheduled visit procedures. Only 
participants who withdraw consent will be considered as withdrawn from the study. Participants 
must be informed about the continued scientific importance of their data, even if they discontinue 
study intervention. 
If the participant 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 participant 
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 study’ visit. 
The study intervention must be discontinued, if any of the following applies for the participant: 
1. Safety concerns as judged by the investigator 
2. Suspicion of acute pancreatitis 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical study 
6. Suspicion of drug induced liver injury 
7. Calcitonin ≥ 100 ng/L (see Appendix 9, Section 10.9) 
If acute pancreatitis is suspected appropriate actions should be initiated, including local 
measurement of amylase and lipase (see Appendix 3, Section 10.3 for reporting). 
Participants meeting discontinuation of trial product criteria no. 1, 2, 3, 4 and 6 are allowed to 
resume trial product, if the criteria are no longer met (see section 7.1.1).  
The primary reason for discontinuation of study intervention must be specified in the CRF, and final 
trial product accountability must be performed. Treatment discontinuation must be made in the 
RTSM/IWRS. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
42 of 109 
 
 
Pregnancy testing is advised 9 weeks after premature discontinuation of study intervention (see 
Appendix 4, Section 10.4). 
7.1.1 
Temporary discontinuation of study intervention 
If a participant has discontinued trial product due to temporary safety concern not related to trial 
product and is allowed to resume, the participant should follow the guide for missed doses. 
Similarly, a participant who discontinues trial product on their own initiative should be encouraged 
to resume trial product (Section 6.5). 
In such cases a treatment discontinuation should not be made in the RTSM/IWRS. 
If a treatment discontinuation previously has been made in RTSM/IWRS to indicate discontinuation 
of trial product, a 'resume treatment' must be made to resume trial product. Information on treatment 
dose start and stop dates will be recorded in the CRF. 
In case of suspicion of acute pancreatitis, the randomised treatment should promptly be interrupted 
(discontinuation of randomised treatment should not be made in RTSM/IWRS before diagnosis of 
acute pancreatitis is confirmed). Appropriate actions should be initiated, including local 
measurements of amylase and lipase (see Appendix 3 [Section 10.3] for reporting).  
Participants with suspected acute pancreatitis are allowed to resume trial product at the 
investigator’s discretion if the Atlanta criteria73 are not fulfilled and thus, the suspicion of acute 
pancreatitis is not confirmed. Trial product may be resumed for participants with a gallstone-
induced pancreatitis in case of cholecystectomy.   
If acute pancreatitis is confirmed, randomised treatment should not be restarted, and discontinuation 
of randomised treatment must be made in RTSM/IWRS.  
7.1.1.1 
Hepatic events requiring temporary discontinuation of study intervention 
Temporary discontinuation of study intervention is required for hepatic events, defined as 
 ALT (or AST) ≥ 3 x upper limit of normal (ULN) and total bilirubin ≥ 2 x ULN or ALT (or 
AST) ≥ 3 x ULN and international normalised ratio (INR) > 1.5 (if INR measured), which 
may indicate severe liver injury (potential Hy’s law)a  
 ALT (or AST) ≥ 3 x ULN with the appearance of fatigue, nausea, vomiting, anorexia, 
abdominal pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
aPlease note that such an event must be reported as a SAE using the important medical event criterion if no other 
seriousness criteria are applicable (as described in Appendix 3, Section 10.3). 
Temporary discontinuation of study intervention is also required in case of abnormal liver 
laboratory values not meeting protocol-specified discontinuation criteria, if the investigator deems 
that it is in the best interest of the participant. 
Study intervention can be restarted only if an alternative aetiology is definitively identified, and 
liver blood parameters have returned to pre-event levels. If an alternative aetiology is not 
definitively defined and/or liver blood parameters have not returned to pre-event levels, drug-
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
43 of 109 
 
 
induced liver injury (DILI) cannot be excluded, and study intervention must be permanently 
discontinued.  
Please see Appendix 6 (Section 10.6) for follow-up information on hepatic safety.  
Please also see the criteria for an AE and Hepatic Event form in Appendix 3 (Section 10.3.3).   
7.2 
Participant discontinuation/withdrawal from the study 
A participant may withdraw consent at any time at his/her own request. 
If a participant withdraws consent or is withdrawn by the investigator prior to randomisation, he/she 
will not be asked to have any follow-up assessments performed. The following data must be 
collected: Demography, eligibility criteria, date of informed consent, date of screening and the date 
when participant’s participation ended. The end of study form must be completed. 
If a participant withdraws consent or is withdrawn by the investigator after randomisation, the 
investigator must ask the participant if he/she is willing, as soon as possible, to have assessments 
performed according to visit 22 (end of treatment) and have a blood sample taken for 
immunogenicity assessment > 9 weeks after last treatment dose. See the flowchart (Section 1.2) for 
data to be collected. 
Final trial product accountability must be performed even if the participant is not able to come to 
the site. Treatment discontinuation must be made in the RTSM/IWRS. 
If the participant withdraws consent, Novo Nordisk may retain and continue to use any data 
collected before such a withdrawal of consent for the purpose of the study or scientific research. 
If a participant withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the medical record. 
Although a participant 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 participant’s 
rights. Where the reasons are obtained, the primary reason for withdrawal must be specified in the 
CRF. 
7.2.1 
Replacement of participants 
If a participant discontinues study intervention, withdraws consent or is withdrawn by the 
investigator, he/she will not be replaced. 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. The final classification of the participant as lost to 
follow-up will not be until the initial date for the end of treatment visit.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
44 of 109 
 
 
The following actions must be taken if a participant fails to return to the site for a required visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, at least three telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the participant’s 
source document. 
 Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
45 of 109 
 
 
8 
Study assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart. 
Informed consent must be obtained before any study-related activity, see Appendix 1 
(Section 10.1.3). 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all inclusion criteria and none of the exclusion criteria. Additional, participants should be 
evaluated for participation in the MRI subgroup (Section 5.1). 
The investigator will maintain a screening log to record details of all participants screened to 
confirm eligibility or record reason for screen failure, as applicable. 
At screening, participants will be provided with a card stating that they are participating in a study 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
Adherence to the study design requirements, including those specified in the flowchart, is essential 
and required for study conduct. 
Review of diaries, clinical outcome assessment, mental health assessment, ECG, and laboratory 
reports must be documented in the source documents or the participant’s medical record. If 
clarification of entries or discrepancies is needed, the participant must be questioned, and a 
conclusion made in the participant’s source documents. Care must be taken not to bias the 
participant. 
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further details on laboratory 
samples. 
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 (ECG, see Section 8.2.5), vital signs (see Section 8.2.4) and body 
measurements (see Section 8.1.1) 
2. Blood samples (see Appendix 2 [Section 10.2]) 
3. Clinical outcome assessment (see Section 8.1.5) and Mental health assessment instruments (see 
Section 8.2.2) 
4. Other assessments  
Results of pregnancy testing must be documented in the participant’s medical records. 
For participants receiving antihypertensive or lipid-lowering treatment, the investigator should 
evaluate changes in the participants’ treatment intensity within each therapeutic area. The 
evaluation should be based on whether an overall change in treatment intensity from randomisation 
until the time of the evaluation has occurred (i.e., either increase, decrease or no change) after 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
46 of 109 
 
 
reviewing all available relevant information e.g., changes in drug dose, drug class, number of drugs 
or a combination of these. 
Participants must receive training in how to collect dosing information prior to PK sampling in a 
designated paper diary (PK diary) to be handed out as outlined in the flowchart. See Section 8.4 for 
a description of the data to be entered in the PK diary.  
The barriers and motivation interview identifies barriers to and motivation for lifestyle change and 
compliance with the protocol. The interview will be conducted at screening to assist in identifying 
participants who are unable or unwilling to comply with protocol procedures as per the exclusion 
criteria. In addition, the interview will ensure that any minor barriers are addressed during lifestyle 
counselling. The results of the interview will not be entered into the CRF. It will be at the 
investigator’s discretion to evaluate the motivation of the participant and related eligibility. 
The investigator will evaluate the participant’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 participant’s 
glycaemic status will be categorised as normo-glycaemia, prediabetes or diagnosed with type 2 
diabetes according to the American Diabetes Association’s definitions. 
For participants in the MRI sub-population, MRI must be performed according to the manual from 
the supplier (see Section 8.1.2). 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart. 
8.1.1 
Body measurements 
Body weight must be measured at all site visits without shoes, with an empty bladder and only 
wearing light clothing. Body weight must be measured on a digital scale and recorded in kilograms 
or pounds (one decimal i.e., X.2 or X.7) using the same scale throughout the study. The scale must 
be calibrated according to manufacturer’s recommendation or local requirements. 
Height is measured without shoes in centimetres or inches (one decimal i.e., X.2 or X.7). BMI will 
be calculated in the eCRF at each clinic visit based on height at screening and body weight at the 
clinic visit. BMI calculated in the eCRF at screening must be in agreement with inclusion criterion 
no. 4 and thus verified after entry of screening results in the eCRF. 
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 (rounding is required). The tape should touch the skin 
but not compress soft tissue and twists in the tape should be avoided. The participant should be 
asked to breathe normally. The same measuring tape should be used throughout the study. The 
measuring tape will be provided by Novo Nordisk to ensure standardisation. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
47 of 109 
 
 
8.1.2 
Magnetic resonance Imaging 
The 2 MRI scans will only be performed on a subgroup of approximately 50 randomised 
participants. The subgroup will consist of participants who fulfil the MRI inclusion criteria 
(Section 5.1). The first MRI scan should be performed between screening (V1) and randomisation 
(V2). The second MRI scan should be performed up to 7 days before end-of-treatment visit (V22) 
or at the time of end of treatment visit (V22). 
The results of the MRI scan and the MRI scan image will be transferred from the central imaging 
laboratory to the Novo Nordisk database.  
MRI scan must be performed according to the supplier’s manual.   
8.1.4 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.1.5 
Clinical outcome assessment  
The questionnaires will be filled in electronically at site. Participants should be given the 
opportunity to complete the questionnaires by themselves without interruption. The questionnaires 
take approximately 15 minutes to complete.  
The following patient reported outcome questionnaire will be used:  
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
48 of 109 
 
 
8.2.1 
Medical history/concomitant illness  
Medical history is a medical event that the participant experienced prior to the time point from 
which AEs are collected. Only relevant and significant medical history as judged by the investigator 
should be recorded. 
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other study procedures performed before 
exposure to study intervention under clinical investigation. 
In case of an abnormal and clinically significant finding fulfilling the definition of medical history 
or concomitant illness, the investigator must record the finding on the medical history/concomitant 
illness form. 
Medical history/concomitant illness includes but is not limited to the below list of pre-specified 
disease classes in the eCRF.  
 Allergies, symptoms and predisposing conditions 
 Breast neoplasm 
 Cardiovascular disorder and procedure 
 Dyslipidaemia 
 Eating disorder 
 Gallbladder disease and procedure 
 Gastrointestinal disorder and neoplasm 
 Genitourinary tract disorder 
 Glucose metabolism disorder 
 Heart failure 
 Kidney disease 
 Liver disease 
 Musculoskeletal system disorder 
 Neuropathy 
 Pancreatic disease 
 Psychiatric disorder 
 Respiratory disorder 
 Skin cancer and skin disorder 
 Thyroid disorder 
 Weight disorder 
Information on weight related co-morbidities will be collected as part of medical 
history/concomitant illness at screening (visit 1) and an evaluation will be done at the end of 
treatment (visit 22).  
Weight history (including previous weight, debut time of overweight, maximum weight, age at 
maximum weight, previous weight loss attempts, previous use of anti-obesity prescription 
medication, other methods to lose weight, and considerations regarding bariatric surgery) must be 
documented at screening. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
49 of 109 
 
 
To be used in the overall safety evaluation of the IMP, the following must be documented at 
screening: Risk factors for breast cancer (for female participants only), skin cancer and colon 
neoplasm, including both 1) family history of breast cancer, colon neoplasm and/or skin cancer in 
first-degree relatives, age at time of diagnosis for relevant family members and 2) predisposing 
factors for breast and skin cancer, such as menarche/menopause, alcohol intake above guidelines, 
hormone replacement therapy (HRT), sun exposure, light skin colour. Follow-up questions related 
to breast neoplasm (for female participants only) and colon neoplasm, will be asked at end of 
treatment and end of study. 
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix 3, Section 10.3) during the study and any clinically 
significant worsening from baseline must be reported as an AE (see Section 8.3).  
8.2.2 
Mental health assessment instruments 
Two patient reported outcome questionnaires will be used. The questionnaires will be filled in 
electronically at site. Participants should complete the questionnaires at site at screening (visit 1), 
visit 8, visit 10, visit 14, visit 18, and end-of-treatment (visit 22).    
PHQ-975 is a 9-item depression module of the patient health questionnaire, which is a self-
administered diagnostic tool used for assessment of mental disorders. The questionnaire will be 
available in a linguistically validated translated version. The questionnaire shall be filled in 
electronically after instructions from site staff. Participants should be given the opportunity to 
complete the questionnaires by themselves without interruption. 
If a participant has a PHQ-9 score of 10-14 (both inclusive) the participant should be referred to a 
mental health professional (MHP) if judged relevant by the investigator. If referral is not deemed 
relevant this along with the reason why must be documented in the participant’s medical records.  
C-SSRS76 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.  
Prior to administering the C-SSRS questionnaire, the investigator or qualified delegate must 
complete sufficient training. 
A participant must be referred to a MHP if:  
 the participant has a PHQ-9 score ≥15 or 
 the participant has any suicidal behaviour or 
 the participant has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment or 
 in the opinion of the investigator, it is necessary for the safety of the participant  
If one or more of the referral criteria are met, the investigator should explain to the participant why 
the referral and psychiatric evaluation by a MHP is needed. If the participant refuses to be referred 
to a MHP, the participant’s decision should be documented in participant’s medical record and the 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
50 of 109 
 
 
investigator must assess if it is safe for the participant to continue in the trial or if the participant 
should be discontinued from trial product. 
If a participant’s psychiatric disorder can be adequately treated with psychotherapy and/or 
pharmacotherapeutic treatment, then the participant, at the discretion of the investigator (and in 
agreement with the MHP), may continue in the trial. Otherwise, the participant must be 
discontinued from trial product due to safety concern as judged by the investigator. 
8.2.3 
Physical examinations 
A physical examination will include assessments of the cardiovascular, respiratory, gastrointestinal, 
neurological system, breast (females) and skin. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.4 
Vital signs 
Pulse rate, as well as systolic and diastolic blood pressure will be assessed. 
The method for measuring pulse rate, systolic and diastolic blood pressure needs to follow the 
standard clinical practice at site. 
However, as a minimum:  
 Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., no use of television, cell 
phones). 
 Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not 
available. 
Blood pressure and pulse rate are collected at all physical visits (including screening, 
randomisation, end of treatment and end of study). 
8.2.5 
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, QT and QTc intervals. 
QTc will also be estimated at a central ECG supplier, but local review for clinical significant 
abnormal findings must be performed by the investigator.  
ECG must be performed according to the manual from supplier if the devices is provided by a 
vendor.   
8.2.6 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the protocol flowchart. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
51 of 109 
 
 
8.2.7 
Pregnancy testing and contraceptive counselling 
Urine pregnancy tests provided by central laboratory must be performed for women of childbearing 
potential (WOCBP) at screening and as specified in the flowchart.  
WOCBP should only be included after a negative, highly sensitive urine pregnancy test (refer to 
Appendix 2, Section 10.2). 
Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy is 
otherwise suspected. 
Pregnancy testing is advised 9 weeks after premature discontinuation of randomised study 
intervention, see Appendix 4 (Section 10.4). 
Additional pregnancy testing should be performed during the treatment period, if required locally, 
refer to Appendix 10 (Section 10.10). 
WOCBP must receive contraceptive counselling, at each site visit, to ensure effective contraception. 
The content of the contraceptive counselling session is the responsibility of the investigator and per 
the investigator’s discretion. The contraceptive counselling and the result of the pregnancy test must 
be documented in the eCRF.   
8.2.8 
Surgical procedures assessment 
While enrolled in this study, participants are not encouraged to commence other anti-obesity 
medication or bariatric surgery. However, if due to clinical reasons a participant does undergo 
bariatric surgery, hip surgery or knee surgery while enrolled in this study, the investigator should 
record this in the Procedures Form described below.  
During site and/or phone visits marked in the Flowchart, the investigator should ask the participant 
if they have undergone the surgical procedures listed below, since their previous assessment. If the 
participant has undergone the procedure(s), the investigator should fill out the Procedures Form. A 
separate form should be filled out for separate procedures. 
Bariatric surgery – including bariatric gastric balloon insertion/removal, duodenal-jejunal bypass 
sleeve therapy, endoscopic sleeve gastroplasty, gastric banding (includes laparoscopic adjustable 
gastric band), gastric band repositioning, gastric banding reversal, gastric bypass (roux-en-y), 
gastric bypass reversal or duodenal switch. 
Knee surgery – including partial knee replacement or total knee replacement. 
Hip surgery – including partial hip replacement or total hip replacement 
8.3 
Adverse events and other safety reporting 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.  
 
The definition of AEs and SAEs can be found in Appendix 3 (Section 10.3), along with a 
description of AEs requiring additional data collection.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
52 of 109 
 
 
Some AEs require additional data collection on a specific event form. The relevant event(s) are 
listed below in Table 8-1.  
Table 8-1 
AEs requiring additional data collection 
Event type  
AE requiring additional data collection 
Medication errora 
X 
Misuse and abuse of trial producta 
X 
Acute pancreatitis 
X 
Acute gallbladder disease 
X 
Hepatic eventb 
X 
Malignant neoplasm 
X 
Acute kidney injury 
X 
aAdditional data for Misuse and abuse of trial product is reported on the medication error event form. 
bSee further guidance in Section 10.3.3.  
 
Definitions and reporting timelines for the events mentioned in the above table can be found in 
Appendix 3 (Section 10.3).  
8.3.1 
Time period and frequency for collecting AE information 
All AEs and SAEs must be collected from the first study-related activity after obtaining informed 
consent and until the end of study visit in accordance with the flowchart (Section 1.2) or whenever, 
within the above time period, the site becomes aware of an AE or SAE.  
Conditions present prior to the timepoint from which AEs are collected and anticipated day-to-day 
fluctuations of these conditions, including those identified during screening or during other study-
related procedures performed before exposure to study intervention under clinical investigation, will 
be recorded as medical history/concomitant illness. 
AE and SAE reporting timelines can be found in Appendix 3 (Section 10.3). All SAEs must be 
recorded and reported to Novo Nordisk within 24 hours, and 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 study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant has 
been discontinued from/completed the study, and the investigator considers the event to be related 
to the IMP or related to study participation, the investigator must promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs  
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 3 (Section 10.3). 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or until the 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
53 of 109 
 
 
participant is lost to follow-up as described in Section 7.3. Further information on follow-up and 
final outcome of events is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention 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 study intervention under clinical investigation. Novo 
Nordisk will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected 
serious adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing an 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. 
8.3.5 
Pregnancy  
Details of pregnancies in female participants will be collected after obtaining informed consent and 
until the end-of-study. For details regarding collection and reporting of pregnancy information, 
please refer to Appendix 4 (Section 10.4). 
If a female participant becomes pregnant, the participant must discontinue randomised trial product 
as described in Section 7.1. 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3 and 
Appendix 3 (Section 10.3). 
8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form. 
8.4 
Pharmacokinetics and pharmacodynamics 
8.4.1 
Pharmacokinetics 
Single blood samples for measuring plasma concentration of semaglutide will be drawn for both 
semaglutide and placebo participants on visits specified in the flowchart (Section 1.2). 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
54 of 109 
 
 
The purpose of measuring plasma semaglutide levels is to perform population pharmacokinetic 
(Pop-PK) analyses. Having Pop-PK in this study will further support bridging of Pop-PK from 
studies conducted in other populations. 
Samples will be used to evaluate the pharmacokinetics of semaglutide. Each plasma sample will be 
divided into 2 aliquots (e.g., one for PK and a backup) and may also be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study. Residual PK samples may 
be used for exploratory metabolite analysis. Potential metabolite analysis will be reported separately 
from the CSR. Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained.  
Participants must receive training in how to collect dosing information prior to PK sampling in the 
designated PK diary. Only participants must make entries and corrections in the diaries, unless the 
section is specified for site staff.   
The PK dosing information from the PK diary (i.e., the actual dose of trial product (mg), the date 
and time of administration) should be transcribed into the CRF for the last 2 doses of trial product 
prior to the PK assessment as outlined in the flowchart.  
The exact timing of obtaining the PK sample must be recorded on the laboratory form. 
8.4.2 
Pharmacodynamics 
Not applicable for this study.  
8.5 
Genetics 
Refer to Section 8.8 and Appendix 7 (Section 10.7) for further details.  
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
55 of 109 
 
 
8.9 
Health economics 
Not applicable for this study. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
56 of 109 
 
 
9 
Statistical considerations 
The statistical analysis plan (SAP) will be finalised prior to database lock (DBL) and it will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important estimands, including 
the co-primary and confirmatory secondary estimands. 
9.1 
Statistical hypotheses 
For the co-primary estimands with co-primary endpoints, 1) change in body weight (%) from 
baseline to end of treatment (week 72) and 2) body weight reduction ≥ 5% (yes/no) at end of 
treatment (week 72) the following 1-sided hypotheses are planned to be tested for semaglutide s.c. 
7.2 mg versus placebo. Let the mean treatment difference in 1) be defined as:  
μ = ([semaglutide 7.2 mg] minus [placebo]) 
and let the odds ratio of 2) be defined as:  
OR = (odds[semaglutide 7.2 mg] divided by odds[placebo]). 
Superiority 
1) H01: μ ≥ 0.0 percentage points against Ha1: μ < 0.0 percentage points 
and 
2) H02: OR ≤ 1 against Ha2: OR > 1 
Operationally the hypotheses will be evaluated by 2-sided tests with significance level of α = 0.05.  
For each of the confirmatory secondary estimands with the endpoints body weight reduction 
≥ 10 %, ≥ 15 %, ≥ 20 %, and ≥ 25 % (yes/no) at end of treatment (week 72) a hypothesis similar to 
2) will be tested. 
For the confirmatory secondary estimand with the endpoint change in waist circumference (cm) and 
relative change in body weight (%) (semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg) from 
baseline (week 0) to end of treatment (week 72) a hypothesis similar to 1) will be tested. 
9.1.1 
Multiplicity adjustment 
The type I error will be controlled in the strong sense using a hierarchical (fixed sequence) testing 
procedure. This is based on priority ordering of the null hypotheses and testing them in this order 
using the 2-sided 95% confidence interval approach until an insignificant result appears. 
Consequently, the second null hypothesis will only be tested if the first null hypothesis has been 
rejected in favour of semaglutide s.c. 7.2 mg. 
The steps in the hierarchical testing procedure are as follows: 
 Step 1: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to both co-primary 
estimands. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
57 of 109 
 
 
 Step 2: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to secondary 
estimand with endpoint body weight reduction ≥ 10 % (yes/no) at end of treatment (week 
72). 
 Step 3: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to secondary 
estimand with endpoint body weight reduction ≥ 15 % (yes/no) at end of treatment (week 
72). 
 Step 4: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to secondary 
estimand with endpoint body weight reduction ≥ 20 % (yes/no) at end of treatment (week 
72). 
 Step 5: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to secondary 
estimand with endpoint body weight reduction ≥ 25 % (yes/no) at end of treatment (week 
72). 
 Step 6: Superiority of semaglutide s.c. 7.2 mg versus placebo with respect to secondary 
estimand with the endpoint change in waist circumference from baseline (week 0) to end of 
treatment (week 72). 
 Step 7: Superiority of semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg with respect to 
secondary estimand with the endpoint relative change in body weight (%) from baseline 
(week 0) to end of treatment (week 72). 
 Step 8: Superiority of semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg with respect to 
secondary estimand with endpoint body weight reduction ≥ 20 % (yes/no) at end of treatment 
(week 72). 
 Step 9: Superiority of semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg with respect to 
secondary estimand with endpoint body weight reduction ≥ 25 % (yes/no) at end of treatment 
(week 72). 
9.2 
Analysis sets 
The following participant analysis sets are defined:  
Table 9-1 
Participant analysis sets 
Participant Analysis Set 
Description 
Full analysis set 
All randomised participants. 
Safety analysis set 
All participants who are exposed to at least one dose of randomised IMP. 
 
For the full analysis set (FAS) participants will be included in the analyses according to the planned 
intervention. For the safety analysis set (SAS) participants will be included in the analyses 
according to the intervention they actually received.  
The following data points sets are defined: 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
58 of 109 
 
 
9.3 
Statistical analyses 
9.3.1 
General considerations 
This section is a summary of the planned statistical estimation of the most important estimands 
including primary and confirmatory secondary estimands.  
The last available observation at or before randomisation is used as the baseline value. If no 
assessments are available, the mean value at randomisation across all participants is used as the 
baseline value.  
All randomised participants in all treatment arms contribute to the analysis. All tests are tests of 
superiority of semaglutide s.c. 7.2 mg once-weekly versus placebo unless stated otherwise. All 
estimand treatment contrasts between semaglutide s.c. 7.2 mg versus placebo (or semaglutide s.c. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
59 of 109 
 
 
2.4 mg) will be reported together with the associated two-sided 95% confidence interval (CI) and 
corresponding p-value.  
9.3.2 
Primary estimands analysis 
The co-primary endpoints are:  
 Relative change in body weight (%) from baseline (week 0) to end of treatment (week 72) 
 Body weight reduction ≥ 5 % (yes/no) at end of treatment (week 72) 
The two primary analyses are aligned with the two co-primary estimands in Section 3.  
The analysis model for relative change in body weight (%) will be a linear regression (ANCOVA) 
with randomised treatment as factor and baseline body weight (kg) as covariate. The model will 
allow the variances to differ across treatment groups.  
The analysis model for the body weight reduction ≥ 5% is a logistic regression using randomised 
treatment as factor and baseline body weight (kg) as covariate.  
All available data at week 72 are used and missing values at week 72 will be imputed and the 
endpoints will be derived from the imputed continuous values. It is assumed that values are missing 
at random (MAR) conditional on factors and covariates in the imputation model. The imputation 
approach for the primary analysis is a multiple imputation similar to the one described by McEvoy 
et al.77 For participants in the semaglutide s.c. 7.2 mg once-weekly, the semaglutide s.c. 2.4 mg 
once-weekly and the placebo groups, missing measurements at week 72 for non-retrieved 
participants are imputed using assessments from retrieved participants in each treatment group, 
missing measurements at week 72 for participants on randomised treatment are imputed by 
sampling from available measurements at week 72 from participants on randomised treatment in 
each intervention group. The imputation model will be a linear regression of gender (male/female) 
as factor and baseline body weight (kg), timing of last available observation during the on-treatment 
period (LAO-OT) and LAO-OT as covariates. Details of the multiple imputation approach will be 
provided in the SAP. 
 Sensitivity analyses 
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
72 for both active treatment groups and placebo group are imputed by sampling among all available 
assessments at week 72 in the placebo group. This approach makes the assumption that participants 
instantly after discontinuation lose any effect of randomised treatment beyond what can be expected 
from placebo treatment as adjunct to reduced-calorie diet and increased physical activity. The J2R-
MI analysis targets the robustness of the MAR assumption in the main analysis. Details of the 
multiple imputation approach are provided in the SAP. 
Tipping-point multiple imputation analysis (TP-MI): This analysis will be performed only if 
superiority of semaglutide 7.2 mg is concluded with respect to the co-primary estimands. First, 
missing data are imputed according to the primary multiple imputation approach. Then, a penalty is 
added to the imputed values at week 68. The approach is to explore a range of penalties for both 
treatment groups, and the impact these would have on the study conclusions. The 2-dimensional 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
60 of 109 
 
 
space of penalties covering the range from -30% to 30% will be explored for both treatment groups. 
The TP-MI analysis addresses the MAR assumption in the main analysis. 
Non-retrieved participants as non-responders: For the analysis of body weight reduction ≥ 5% an 
analysis using non-retrieved participants as non-responders in the logistic regressions will be done. 
This analysis also targets the MAR assumption. 
Supplementary analyses 
The following statistical analyses are designed to address the additional estimand for the primary 
objective. 
The estimation of the additional estimand with the endpoint relative change in body weight (%) will 
be a mixed model for repeated measurements (MMRM). The MMRM will be fitted using 
randomised treatment as factor and baseline body weight (kg) as covariate all nested within visit as 
a factor. An unstructured covariance matrix for measurements within the same participant will be 
employed. Measurements for different participants are assumed to be independent. 
The estimation of the additional estimand with the endpoint body weight reduction ≥ 5% is a 
logistic regression where any missing values at week 72 will be predicted from the MMRM. The 
predicted values will be used to classify each participant as 5% responder or not. The logistic 
regression model will include randomised treatment as factor and baseline body weight (kg) as 
covariate. 
All subjects contribute to the analysis, however, data points collected after treatment 
discontinuation and initiation of anti-obesity medication, as detailed in Section 9.2, will not be 
included in the analyses addressing the additional estimand. 
9.3.3 
Secondary estimands analysis 
9.3.3.1 
Confirmatory secondary estimands 
All tests are tests of superiority of semaglutide s.c. 7.2 mg to placebo unless stated otherwise. The 
confirmatory secondary endpoints related to the secondary objective are: 
 Body weight reduction ≥ 10% (yes/no) at end of treatment (week 72) 
 Body weight reduction ≥ 15% (yes/no) at end of treatment (week 72) 
 Body weight reduction ≥ 20% (yes/no) at end of treatment (week 72) 
 Body weight reduction ≥ 25% (yes/no) at end of treatment (week 72) 
 Change in waist circumference (cm) from baseline (week 0) to end of treatment (week 72) 
 Relative change in body weight (%) (semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg) 
from baseline (week 0) to end of treatment (week 72) 
 Body weight reduction ≥ 20% (yes/no) (semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 
mg) at end of treatment (week 72) 
 Body weight reduction ≥ 25% (yes/no) (semaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 
mg) at end of treatment (week 72) 
All confirmatory secondary estimands will be analysed using the same analysis model and 
imputation approach as used to address the co-primary estimand for the co-primary objectives. For 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
61 of 109 
 
 
the estimands with binary endpoints, in any cases where response rates close to 0% or 100% in any 
treatment group lead to non-convergence, Firth’s maximum-likelihood estimation will be used 
when performing the logistic regression. 
Sensitivity analysis 
For the change in waist circumference and relative change in body weight (%) (semaglutide s.c. 7.2 
mg versus semaglutide s.c. 2.4 mg) a sensitivity analysis using jump to reference as imputation 
approach will be carried out. For binary confirmatory secondary endpoints, a sensitivity analysis 
using non-retrieved participants as non-responders will be carried out. 
Supplementary analysis 
The estimation of the additional estimands for the secondary objectives will be similar to those 
described for the additional estimands for the primary objective.  
9.3.3.2 
Supportive secondary endpoints 
Supportive secondary endpoints are described in Section 3, and the statistical analyses are detailed 
in the SAP. 
Safety related supportive secondary endpoints 
The estimation of the estimand with the safety endpoint change in pulse will be an MMRM as 
described in Section 9.3.2.  
Adverse events will be summarised by descriptive statistics, such as frequencies and rates. No 
formal statistical inference will be carried out based on the number of AEs. 
9.3.4 
Exploratory endpoint(s)/estimand(s) analysis 
Exploratory endpoints are listed in Section 3 and the statistical analyses are detailed in the SAP.  
9.3.5 
Other safety analyses 
Please refer to the SAP for details. 
9.3.6 
Other analyses 
9.3.6.1 
Pharmacokinetic and pharmacodynamic modelling 
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety and further to support the 7.2 mg s.c. dose of semaglutide in 
participants with obesity. First, plasma semaglutide concentrations will be analysed using a 
population pharmacokinetic model, quantifying covariates (such as baseline body weight, age, 
gender, race, ethnicity and device) effects on semaglutide exposure. Second, model-based estimates 
of steady-state average concentrations will be derived for each participant, in order to facilitate 
subsequent exposure-response analyses. Relevant efficacy and safety endpoints will be related to 
steady-state average concentrations and subjected to model-based analysis. Data from historical 
weight management trials may be included to support the model-based analyses.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
62 of 109 
 
 
A modelling analysis plan will be prepared prior to first database lock and the results will be 
reported separately from the clinical study report.  
9.4 
Interim analysis 
There is no interim analysis planned for this study. 
9.5 
Sample size determination 
The sample size for this study was determined primarily to ensure adequate exposure to semaglutide 
s.c. 7.2 mg. It is considered sufficient if 1000 participants are randomised to the 7.2 mg dose. With 
a 5:1:1 randomisation, this results in a total sample size of 1400 randomised participants. In 
STEP phase 3a program, among participants with BMI ≥30 kg/m2, approximately 70% in the 
semaglutide s.c. 2.4 mg treatment group were exposed to the 2.4 mg dose for at least 1 year. Based 
on this, it is assumed in this study that at least 65% of participants (n = 650) randomised to the 
semaglutide s.c. 7.2 mg treatment group will be exposed to the 7.2 mg dose for at least 1 year.  
Given the study sample size, the effective power of statistical tests for the primary and confirmatory 
secondary estimands is >84%. The effective power was calculated under the assumption of 
independence of endpoints by multiplying the respective marginal powers successively which is a 
conservative approach. The power calculations for continuous endpoints are based on a t-test on the 
mean difference assuming unequal variances, whereas those for the categorical endpoints are based 
on the Pearson chi-square test for two independent proportions. 
Assumptions for the power calculations are presented in Table 9-3 and are based on findings from 
, which had similar eligibility criteria to this study. Exposure-response 
modeling was performed in order to simulate the change (%) in body weight expected among 
participants completing treatment with semaglutide s.c. 7.2 mg. This predicted mean change was 
assumed to be normally distributed, and thereby used to derive expected proportions of participants 
achieving body weight reduction ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, and ≥ 25%. The amount by which 
this predicted mean change exceeds the change (%) in body weight observed among treatment 
completers in STEP 1, combined with the change in waist circumference observed in STEP 1, was 
also used to derive the predicted change in waist circumference among participants completing 
treatment with semaglutide s.c. 7.2 mg.   
Based on STEP 1, where 18.9% permanently discontinued trial product it is assumed that 20% of 
participants will discontinue trial product permanently before week 72. It is assumed that 
approximately 60% of these will be retrieved at week 72. It is further assumed that, beyond the dose 
reductions observed in STEP 1 (in which 10.4% of treatment completers were on a reduced dose at 
end of treatment), an additional 5% of participants in the semaglutide 7.2 mg group will complete 
treatment at a lower dose. All participants in the placebo arm are assumed to have same effect as 
participants who complete the study on placebo. Retrieved participants in the semaglutide s.c. 7.2 
mg group are assumed to have the same effect to half the treatment difference (compared to 
placebo) of participants who complete the study on semaglutide s.c. 7.2 mg. Non-retrieved 
participants in the semaglutide s.c. 7.2 mg once-weekly arm are assumed to have an effect 
corresponding to placebo. The expected mean effect on relative change in body weight in 
semaglutide 2.4 mg group is assumed to be equal to the one estimated in STEP 1 for the treatment 
policy estimand (similar to primary estimand defined in this study). The expected proportions of 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
63 of 109 
 
 
participants achieving body weight reduction ≥ 20%, and ≥ 25% in the semaglutide 2.4 mg group 
are assumed to be equal to observed proportions from the in-trial period in STEP 1. 
Based on data from the NN9536 global phase 3a studies, it is expected that < 1% of participants 
will initiate other anti-obesity therapies, so the impact of this intercurrent event is expected to be 
negligible. The impact of dose reduction is included in the assumed mean and proportions in 
Table 9-3. Under these assumptions and a 5:1:1 randomisation ratio, a sample size of 1400 
participants randomised to either receive semaglutide s.c. 7.2 mg once-weekly (1000 participants), 
semaglutide s.c. 2.4 mg once-weekly (200 participants) or placebo (200 participants) yields an 
effective power of >84% for all confirmatory endpoints. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
64 of 109 
 
 
Table 9-3 
Assumptions, marginal power, and effective power for each endpoint in the 
hierarchical testing procedure 
Step Endpoint 
Assumed mean (SD) 
or proportion for 
completers 
Expected mean (SD) or 
proportion 
Expected 
difference or 
proportion 
ratio 
Marginal 
power (%) 
Effective 
power 
(%) 
Sema 7.2 
mg 
Placebo 
(or Sema 
2.4 mg) 
Sema 7.2 mg Sema 2.4 mg 
Population of 1400 participants randomised (5:1:1) to either semaglutide 7.2 mg, semaglutide 2.4 mg or placebo 
1 
Relative 
change in 
body weight 
(%) 
21.3 (10) 
3.1 (6.5) 
18.4 (10) 
- 
 15.3 %-
points 
> 99 
> 99 
1 
Body weight 
reduction 
≥5%  
94.8% 
31.5% 
83.8% 
- 
2.7 
> 99 
> 99 
2 
Body weight 
reduction 
≥10% 
87.0% 
12.0% 
74.2% 
- 
6.2 
> 99 
> 99 
3 
Body weight 
reduction 
≥15%  
73.5% 
4.9% 
62.5% 
- 
12.7 
> 99 
> 99 
4 
Body weight 
reduction 
≥20% 
55.1% 
1.7% 
45.9% 
- 
27.0 
> 99 
> 99 
5 
Body weight 
reduction 
≥25%  
35.5% 
0.4% 
29.1% 
- 
72.7 
> 99 
> 99 
6 
Change in 
waist 
circumference 
(cm)  
18.9 (10) 
5.0 (7.5) 
16.4 (10) 
- 
11.4 cm 
> 99 
> 99 
7 
Relative 
change in 
body weight 
(%)a 
21.3 (10) 
16.9 (10) 
18.4 (10) 
14.9 (10) 
3.5 %-point 
> 99 
> 99 
8 
Body weight 
reduction 
≥20%a 
55.1% 
34.8% 
45.9% 
32.0% 
1.4 
>95 
>95 
9 
Body weight 
reduction 
≥25% a 
35.5% 
20.0% 
29.1% 
18.6% 
1.5 
>88 
>84 
asemaglutide s.c. 7.2 mg versus semaglutide s.c. 2.4 mg 
Abbreviations: SD = standard deviation. 
9.6 
Reporting of the study 
A database lock is planned shortly after last participant last visit (week 81) of the study. The results 
will thereafter be reported in a CSR. A partial DBL may be performed at the end of the treatment 
period for all participants, i.e., after the date of the last patient last treatment (LPLT) visit (week 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
65 of 109 
 
 
72). The database will be updated after the partial DBL to include remaining data. A detailed plan 
for data handling, blinding, data analysis, and operational aspects of the DBLs and the database 
update will be finalised before the partial DBL   
Novo Nordisk may decide to opt out of the partial DBL. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
66 of 109 
 
 
10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki78 and applicable ICH Good Clinical Practice (GCP) Guideline79 
 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 study is initiated. 
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the CSR according to national requirements. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate safety hazard to 
study participants. 
Before a site is allowed to start screening participants, written notification from Novo Nordisk must 
be received. 
The investigator will be responsible for: 
 providing written summaries of the status of the study annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
 notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
 providing oversight of the conduct of the study at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations 
 ensuring submission of the CSR synopsis to the IRB/IEC 
 reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
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 study and one 
year after completion of the study. 
For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
67 of 109 
 
 
10.1.3 
Informed consent process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. This includes the use of 
an impartial witness where required according to local requirements. 
The investigator must ensure the participant ample time to come to a decision whether or not to 
participate in the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign and date a statement of informed consent that meets the requirements of local regulations, ICH 
GCP79 guidelines, Declaration of Helsinki,78 privacy and data protection requirements, where 
applicable, and the IRB/IEC or site. 
The medical record must include a statement that written informed consent was obtained before any 
study-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 
study-related activity. 
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
Participants must be re-consented to the most current version of the informed consent form(s) 
during their participation in the study. 
A copy of the informed consent form(s) must be provided to the participant. 
10.1.4 
Information to participants during the study 
The site will be offered a communication package for the participant during the conduct of the 
study. The package content is issued by Novo Nordisk. The communication package will contain 
written information intended for distribution to the participants. The written information will be 
translated and adjusted to local requirements and distributed to the participant at the discretion of 
the investigator. The participant may receive a “thank you for your participation letter” after 
completion of the study. Further, the participant may receive other written information during the 
study. 
All written information to participants must be sent to IRB/IEC for approval/favourable opinion and 
to regulatory authorities for approval or notification according to local regulations. 
10.1.5 
Data protection 
Participants will be assigned a 6-digit unique identifier, a subject ID. Any participant records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct identifiers 
from the participant are transferred to Novo Nordisk. 
The participant and any biological material obtained from the participant will be identified by 
subject ID, visit number and study ID. Appropriate measures such as encryption or leaving out 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
68 of 109 
 
 
certain identifiers will be enforced to protect the identity of participants as required by local, 
regional and national requirements. 
The participant must be informed about his/her privacy rights, including that his/her personal study-
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 participant. 
The participant 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. 
Personal data may be collected from participants due to process requirements from Novo Nordisk’s 
suppliers. This data is needed to ensure that the relevant data analysis for the study can be 
performed, but will not be part of the data transferred to Novo Nordisk, the assessment of the study 
endpoints or the clinical study report. A list of any such data values must be kept as part of the 
study documentation along with an explanation of why it was required. 
10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal study-independent ad hoc 
group may be established in order to maintain the blinding of the study personnel. 
10.1.7 
Dissemination of clinical study data 
Study information will be disclosed at clinicaltrials.gov and novonordisk-trials.com and, if 
applicable, also on other national or regional study registries. It will be disclosed according to 
applicable requirements, relevant recommendations or regulations, such as the Declaration of 
Helsinki,78 the International Committee of Medical Journal Editors (ICMJE),80 the Food and Drug 
Administration Amendment Act (FDAAA),81 European Commission Requirements1, 82, 83 and in 
accordance with Novo Nordisk commitment to clinical transparency. If a participant requests to be 
included in the study via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the participant. As a result of increasing requirements 
for transparency, some countries require public disclosure of investigator names and their 
affiliations. 
10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
Novo Nordisk or designee is responsible for the data management of this study including quality 
checking of the data. 
To demonstrate his/her oversight of the collected data, the investigator should sign the CRF on a 
regular basis during the conduct of the study as well as at the end of the study, as described in the 
CRF completion guideline. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
69 of 109 
 
 
All participant data relating to the study will be recorded on 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. 
The following will be provided as paper CRFs:  
 Pregnancy forms 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable:  
 AE forms  
 Safety information forms 
 Technical complaint forms (also to be used to report complaints on study intervention not yet 
allocated to a participant) 
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. 
10.1.8.2 
Monitoring 
The investigator must permit study-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 study. If the electronic source data 
does not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition, the relevant site staff should be available for discussions at monitoring visits 
and between monitoring visits (e.g., by telephone). 
Study monitors will perform ongoing source data verification of critical data points to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete and verifiable from 
source documents. Study monitors will perform ongoing source data review to ensure that the study 
is being conducted in accordance with the current approved protocol and any other study 
agreements, ICH GCP79, and all applicable regulatory requirements, evaluating the adequacy of 
critical processes at site for the execution of the protocol, collection of study data, to ensure that the 
safety and rights of participants are being protected. 
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 sites. 
Quality tolerance limits (QTLs) will be predefined in the relevant monitoring plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. These 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
70 of 109 
 
 
predefined parameters will be monitored during the study, and important deviations from the QTLs 
and remedial actions taken will be summarised in the clinical study report. 
10.1.8.3 
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 study database. 
10.1.9 
Source documents 
All data entered in the CRF must be verifiable in source documentation other than the CRF. For 
clinical outcome and mental health assessment questionnaires the service providers’ database is 
considered source data.  
If source data is entered directly in a paper CRF, each data entry or clear series of data entries must 
be signed and dated separately by the study staff making the entry. BMI is calculated in the eCRF 
based on entries of height and weight. Thus, the eCRF will be the source for BMI. 
The original of the completed diaries must not be removed from the site, unless they form part of 
the CRF and a copy is kept at the site. 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the site. Any source data generated by 
investigator’s subcontractors must be archived and accessible by the site. 
Data that is transcribed into the CRF 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 participant’s medical history in source documents, such as participant’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 
site. There will only be one source document defined at any time for any data element. 
10.1.10 Retention of clinical study documentation 
Records and documents, including signed informed consent forms, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after end of study 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. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
71 of 109 
 
 
The investigator must be able to access his/her study documents without involving Novo Nordisk in 
any way. If applicable, electronic CRF (eCRF) and other participant data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems supplied by 
Novo Nordisk. Site-specific CRFs and other participant data (in an electronic readable format or as 
paper copies or prints) must be retained by the site. A copy of all data will be stored by Novo 
Nordisk. 
Participant’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 Study and site closure 
Novo Nordisk reserves the right to close the site or terminate the study at any time for any reason at 
the sole discretion of Novo Nordisk. If the study is suspended or terminated, the investigator must 
inform the participants 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. 
Sites will be closed upon study completion. A site is considered closed when all required documents 
and study supplies have been collected and a site closure visit has been performed. 
The investigator may initiate 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 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 participants by the investigator 
 discontinuation of further study intervention development. 
10.1.12 Responsibilities 
The investigator is accountable for the conduct of the study at his/her site and must ensure adequate 
supervision of the conduct of the study at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified study-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the study. It is the investigator’s responsibility to supervise the 
conduct of the study and to protect the rights, safety, and well-being of the participants. 
A qualified physician, who is an investigator or a sub investigator for the study, must be responsible 
for all study-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 study and the quality of the data 
produced) in the investigator trial master file. The documents, including the participant 
identification code list must be kept in a secure locked facility so that no unauthorised persons can 
get access to the data. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
72 of 109 
 
 
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. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). 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 
participants to a specific qualified physician who will be readily available to participants 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). 
10.1.13 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 studies 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 study or by persons for whom the said site or investigator are 
responsible. 
 
Novo Nordisk accepts liability in accordance with country-specific laws, acts and guidelines.  
10.1.14 Publication policy 
The information obtained during the conduct of this study 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 study intervention. All information supplied by Novo Nordisk in connection 
with this study 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 study. 
The information obtained during this study may be made available to other investigators who are 
conducting other clinical studies with the study intervention, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this study to researchers who require access for research projects studying the same 
or related diseases and/or study intervention studied in this study. 
Novo Nordisk may publish on its clinical studies website a redacted CSR for this study. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
73 of 109 
 
 
One investigator will be appointed by Novo Nordisk to review and sign the CSR (signatory 
investigator) on behalf of all participating investigators. 
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of studies 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 study 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 CSR 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 study. 
At the end of the study, 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 study 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. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the study concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.84 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication. 
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical study, analyses based on single-site data usually have significant 
statistical limitations and frequently do not provide meaningful information for healthcare 
professionals or participants, and therefore may not be supported by Novo Nordisk. Thus, Novo 
Nordisk may deny a request or ask for deferment of the publication of individual site results until 
the primary manuscript is accepted for publication. In line with Good Publication Practice, such 
individual reports should not precede the primary manuscript and should always reference the 
primary manuscript of the study. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
74 of 109 
 
 
10.1.14.4 
Investigator access to data and review of results 
As owner of the study database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research participants’ data and will be provided with 
the randomisation code after results are available. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
75 of 109 
 
 
10.2 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 10-1 and Table 10-2 will be performed by the local laboratory, the 
central laboratory or by the special laboratory. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, 
e.g., to follow up on AEs, this must be done at a local laboratory. 
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 
laboratory SOPs. These data will not be transferred to the study 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. 
The investigator must keep an overview, e.g., a log, of laboratory samples not handled according to 
the laboratory manual. In addition, the investigator must keep an overview, e.g., a log, of laboratory 
samples stored at site. 
For haematology samples (differential count) where the test result is not normal, then a part of the 
sample may be kept for up to two years or according to local regulations. 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
 
Fasting plasma glucose 
 
HbA1c 
 
Fasting serum insulin 
Lipids 
 
Cholesterol 
 
High density lipoprotein (HDL) cholesterol 
 
Low density lipoprotein (LDL) cholesterol 
 
Triglycerides 
 
Very low-density lipoprotein (VLDL) 
 
Free fatty acids 
 
Abbreviations: HbA1c = glycated haemoglobin; 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
76 of 109 
 
 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
 
Basophils 
 
Eosinophils 
 
Erythrocytes 
 
Haematocrit 
 
Haemoglobin 
 
Leucocytes 
 
Lymphocytes 
 
Thrombocytes 
 
Monocytes 
 
Neutrophils 
 
Platelets 
Biochemistrya 
 Alanine Aminotransferase (ALT)b 
 Albumin 
 Albumin corrected calcium 
 Alkaline phosphatase 
 Amylasef 
 Aspartate Aminotransferase (AST)b 
 Calcitoning 
 Creatine kinase 
 Creatinine 
 Gamma Glutamyl Transferase 
 Lipasef 
 Potassium 
 Sodium 
 Thyroid stimulating hormone (TSH)c 
 Total bilirubin 
 Direct bilirubin 
 Urea 
 Cystatin c 
 Calcium 
Pregnancy Testing 
 
Highly sensitive urine human chorionic 
gonadotropin (hCG) pregnancy testd  
Other tests 
 
eGFR calculated by the central laboratory based 
on the creatinine value using the CKD-EPI 
equation 
 
Semaglutide plasma concentration 
 
 
aDetails of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 3 (Section 10.3) (Hy’s Law). bDetails on hepatic safety, suggested actions and follow-
up assessment are given in Section 7.1.1.1, Table 10-3, and Appendix 6 (Section 10.6). cIf TSH level is out of normal 
range, additional testing will be performed by central laboratory: total and free T3 and T4 except at screening visit. 
dLocal urine testing will be standard unless serum testing is required by local regulation or IRB/IEC, see Appendix 4 
(Section 10.4). 
 
. In case of suspicion of drug induced severe acute systemic 
hypersensitivity, samples will be collected for the measurement of tryptase and drug specific IgE. fNot collected at 
V1 or V2. gNot collected at V1, V2 or V10. 
Abbreviations: CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular 
filtration rate. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
77 of 109 
 
 
Laboratory/analyte results that could unblind the study will not be reported to the sites until the 
study has been unblinded.  
Hepatic laboratory outlier: If the following hepatic laboratory parameters are above the cut-off 
values in Table 10-3, it is considered hepatic laboratory outliers and should be reported by 
completing a hepatic event form in the eCRF. It is at the investigator’s discretion to determine 
whether it should be reported as an AE (see Appendix 3, Section 10.3). 
Table 10-3 Criteria for hepatic laboratory outliers 
 
Cut-off 
Alkaline phosphatase 
> 10 × UNL 
ALT 
> 5 × UNL 
AST 
> 5 × UNL 
Total bilirubin 
> 3 × UNL 
Please note that in case of a hepatic event defined as ALT or AST > 3 × upper limit of normal (ULN) 
and total bilirubin > 2 × ULN, 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.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
78 of 109 
 
 
10.3 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures 
for recording, evaluating, follow-up, and reporting 
10.3.1 
Definition of AE 
An AE is any untoward medical occurrence in a clinical study participant that is temporally 
associated with the use of IMP, whether or not considered related to the IMP. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or 
disease (new or exacerbated) temporally associated with the use of an IMP. 
Events to be reported as AEs: 
 Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
 Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected 
 Exacerbation/worsening of a chronic or intermittent 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 IMP 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 to be reported as AEs: 
 Conditions present prior to the time point from which AEs are collected and anticipated day-
to-day fluctuations of these conditions. This includes those conditions identified during 
screening or identified during other study procedures performed before exposure to IMP.  
Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
 Medical or surgical procedures (e.g., endoscopy, appendectomy). The condition that leads to 
the procedure is the AE. 
 Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
10.3.2 
Definition of an SAE 
An SAE is any untoward medical occurrence that fulfils at least one of the following criteria: 
 Results in death 
 Is life-threatening 
 The term ‘life-threatening’ refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused 
death, if it were more severe. 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the participant has been admitted at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in the 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
79 of 109 
 
 
physician’s office or outpatient setting. Complications that occur during hospitalisation are 
AEs. If a complication prolongs hospitalisation or fulfils any other seriousness criteria, the 
event is serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
 Hospitalisation for elective treatment (e.g., elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note: Hospitalisations for administrative, study-related, social and convenience reasons do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions 
for medical or surgical procedures, planned before study inclusion, are not considered AEs or 
SAEs 
 Results in persistent or significant disability/incapacity 
 The term ‘disability’ means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experience of relatively minor 
medical significance, such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle), that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Important medical event: 
 Medical or scientific judgment should be exercised by the investigator 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 participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion. 
 The following must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable: 
o 
Suspicion of transmission of infectious agents via IMP 
o 
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3x ULN and total bilirubin >2x ULN where no alternative 
aetiology exists (Hy’s law) 
10.3.3 
Description of AEs requiring additional data collection   
Adverse events requiring additional data collection 
An AE requiring additional data collection is an AE where Novo Nordisk has evaluated that 
additional data is needed in the evaluation of safety. The selection of these events is based on the 
non-clinical and clinical data with semaglutide, knowledge from the GLP-1 RA drug class as well 
as regulatory requirements. 
Acute pancreatitis: 
The diagnosis of acute pancreatitis requires two of the following three features: 
 Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back) 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
80 of 109 
 
 
 Serum lipase activity (and/or amylase activity) at least three times greater than the upper 
limit of normal  
 Characteristic findings of acute pancreatitis on imaging 
Acute kidney injury  
Events of an abrupt or rapid decline in renal filtration function. This condition is usually marked by 
a rise in serum creatinine concentration or by azotemia (a rise in blood urea nitrogen [BUN] 
concentration). 
Acute gallbladder disease:  
Events of symptomatic acute gallbladder disease (including gallstones and cholecystitis) 
Hepatic event: 
Hepatic event defined as: 
 Disorders of the liver including cholestatic conditions and liver related signs and symptoms 
 ALT or AST > 3x ULN and total bilirubin > 2x ULN or INR > 1.5a 
 ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
aPlease note that in case of a hepatic event defined as ALT or AST > 3x ULN and total bilirubin > 2x ULN, 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. 
Malignant neoplasm:  
Malignant neoplasm by histopathology or other substantial clinical evidence. 
Medication error: 
 A medication error is an unintended failure in the IMP treatment process that leads to, or has 
the potential to lead to, harm to the participant, such as: 
 administration of wrong drug  
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error 
unless it results in administration of wrong drug. 
 wrong route of administration, such as intramuscular instead of subcutaneous 
 accidental administration of a higher dose than intended. The administered dose must deviate 
from the intended dose to an extent where clinical consequences for the study participant 
were likely to happen as judged by the investigator, although they did not necessarily occur. 
 Missed doses should not be reported as a medication error  
Misuse and abuse: 
 Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g., overdose to maximise effect) 
 Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g., overdose with the intention to cause harm) 
Note: Medication error, misuse and abuse must always be reported on an AE form and a specific 
event form must be completed. The AE diagnosis on the AE form must reflect what occurred (e.g., 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
81 of 109 
 
 
accidental overdose, intentional overdose or other). If the medication error and/or misuse and abuse 
resulted in a clinical consequence, this must be reported on an additional AE form. 
10.3.4 
Recording and follow-up of AE and/or SAE 
10.3.4.1 
AE and SAE recording 
The investigator will record all relevant AE/SAE information in the CRF. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory and diagnostics reports) related to the event. 
There may be instances when copies of source documents (e.g., medical records) for certain cases 
are requested by Novo Nordisk. In such cases, all participant identifiers, with the exception of the 
subject ID, must be redacted on the copies of the source documents before submission to Novo 
Nordisk. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the study at the latest. For sign-off of SAE-related forms, refer to “AE and 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 study, it 
is important that the suspected relationship is reported to Novo Nordisk, e.g., in the alternative 
aetiology section on the safety information form. Novo Nordisk may need to report this AE to 
relevant regulatory authorities 
10.3.4.2 
Assessment of severity 
The investigator will assess severity for each event reported during the study and assign it to one of 
the following categories: 
 Mild: An event that is easily tolerated by the participant, 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: An AE that is assessed as severe should not be confused with an SAE. Both AEs and 
SAEs can be assessed as severe. 
10.3.4.3 
Assessment of causality 
The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. The investigator will use clinical judgment to determine the relationship.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
82 of 109 
 
 
Relationship between an AE/SAE and the relevant IMP 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 IMP. 
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, 
as well as the temporal relationship of the event to IMP administration, should be considered and 
investigated. 
The investigator should use the investigator’s brochure66 and any updates hereof 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 
update the causality assessment in the CRF. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements 
10.3.4.4 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The participant has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed when first documented 
 Recovering/resolving: The condition is improving, and the participant is expected to recover 
from the event.  This term may also be applicable for AEs ongoing at the time of death 
(where death was due to another AE). 
Note: For SAEs, this term is only applicable if the participant has completed the follow-up 
period and is expected to recover. 
 Recovered/resolved with sequelae: The participant has recovered from the condition but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
 Not recovered/not resolved: The condition of the participant has not improved, and the 
symptoms are unchanged, or the outcome is not known. This term may be applicable in cases 
of chronic conditions, cancer or AEs ongoing at time of death (where death is due to another 
AE). 
 Fatal: This term is only applicable if the participant died from a condition related to the 
reported AE. Outcomes of other reported AEs in a participant 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 participant is lost to follow-up 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
83 of 109 
 
 
10.3.4.5 
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, Hy’s 
law). This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognised follow-up period, the 
investigator should, upon request, provide Novo Nordisk with a copy of the autopsy report 
including histopathology. 
New or updated information should be recorded in the CRF. 
10.3.5 
Reporting of SAEs 
AE and SAE reporting via CRF 
Relevant forms must be completed in the CRF. 
For SAEs, initial notification via telephone is acceptable, although it does not replace the need for 
the investigator to complete the AE and safety information forms within the designated reporting 
timelines (see Table 10-1): 
 AE form within 24 hours 
 Safety information form within 5 calendar days 
 Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
 Specific event form within 14 calendar days. 
If the eCRF is unavailable for more than 24 hours, then the sites will use the paper AE form, and if 
the eCRF is unavailable for more than 5 calendar days, then the site will use the paper safety 
information form. The site should enter the SAE data in the eCRF as soon as it becomes available. 
The relevant CRF forms (AE and safety information forms) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
After the study is completed, the study database will be locked, and 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 participant or receives updated information on a previously reported 
SAE after CRF decommission, the site can report this information on a paper AE and safety 
information form (see below) or to Novo Nordisk by telephone. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
84 of 109 
 
 
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
 
 
Contact details for SAE reporting can be found in the investigator trial master file. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
85 of 109 
 
 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
10.4.1 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 
Documented total hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
For females with permanent infertility due to an alternate medical cause other than the above 
(e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in 
determining study enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for at least 12 months without an 
alternative medical cause in a female > 45 years of age.  Alternative medical causes for 
amenorrhoea include, but are not limited to, hormonal contraception or hormonal 
replacement therapy.  
 Females ≥ 60 years of age can be considered postmenopausal. 
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use one of the highly effective contraception methods.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of participant’s 
medical records, medical examination or medical history interview. 
10.4.2 
Contraceptive guidance 
Male participants 
No contraception measures are needed for male participants because the risk of 
teratogenicity/fetotoxicity caused by transfer of semaglutide in seminal fluid is considered unlikely. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use methods 
of contraception consistently and correctly. Table 10-4 lists the highly effective methods of 
contraception allowed. Local regulations may apply, see Appendix 10 (Section 10.10). 
Highly effective contraception should be utilised for a least 9 weeks (63 days) after last dose of IMP 
(corresponding to time during treatment and until the end of relevant systemic exposure). 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
86 of 109 
 
 
Table 10-4 
Highly effective contraceptive methods allowed85 
Highly effective methodsa (Failure rate of <1% per year when used consistently and correctly): 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb 
 
oral 
 
intravaginal 
 
transdermal 
 
Progestogen-only hormone contraception associated with inhibition of ovulation 
 
oral 
 
injectable 
 
implantable 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential, and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days. 
 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant. 
NOTES 
a. Contraceptive use by men or women should comply with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, contraceptive methods 
are limited to those which inhibit ovulation as the primary mode of action. 
 
The following methods are not acceptable methods of contraception: Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM). 
In addition, a combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are not considered highly effective methods of contraception. 
10.4.3 
Collection of pregnancy information 
Female participants who become pregnant 
Investigator will collect pregnancy information on any female participant who becomes pregnant 
while participating in this study. 
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a participant’s pregnancy (see Table 10-2). 
The participant will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on participant and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month beyond 
the delivery date. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
87 of 109 
 
 
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 AE in connection with pregnancy 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. If 
relevant, consider adding ‘gestational’, ‘pregnancy-related’ or a similar term when reporting the 
AE/SAE. 
Pregnancy outcome should be documented in the participant’s medical record. Abnormal pregnancy 
outcome (e.g., spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. In case of abnormal pregnancy outcome, paternal information 
should be recorded in the appropriate form after obtaining the necessary signed paternal informed 
consent. 
If the investigator learns of an SAE occurring as a result of a post-study pregnancy which is 
considered related to the IMP by the investigator, the SAE should be reported to Novo Nordisk as 
described in Appendix 3 (Section 10.3) 
Figure 10-2 Decision tree for determining the forms to complete for collection of pregnancy 
information and timelines for reporting – For female participants 
 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention.  
 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
88 of 109 
 
 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
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 study interventions (e.g., 
discoloration, particles or contamination) 
 Problems with packaging material including labelling 
 Problems related to devices  
Time period for detecting technical complaints 
All technical complaints which occur from the time of receipt of the product at site until the time of 
the last usage of the product must be collected for products predefined on the technical complaint 
form. 
10.5.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
For contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints on products allocated to a participant must be reported on a separate technical 
complaint form: 
1. For products with DUN: One technical complaint form must be completed for each affected 
DUN. 
Timelines for reporting technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
 24 hours if related to an SAE 
 5 calendar days for all other technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a product that is not yet 
allocated to a participant, the information must be provided on a paper form 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. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
89 of 109 
 
 
Collection, storage and shipment of technical complaint samples  
The investigator must collect the technical complaint sample and all associated parts and notify the 
monitor within 5 calendar days of obtaining the sample at site. The sample and all associated parts 
must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a 
copy of the completed technical complaint form. The technical complaint sample should contain the 
batch, code or lot number and, if available, the DUN. If the technical complaint sample is 
unobtainable, the reason must be stated on the technical complaint form. If several samples are 
shipped in one shipment, the sample and the corresponding technical complaint form should be kept 
together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the study intervention. 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
90 of 109 
 
 
10.6 
Appendix 6: Hepatic Safety: Suggested actions and follow-up assessments 
For all hepatic events, defined as: 
 ALT (or AST) ≥ 3 x upper limit of normal (ULN) and total bilirubin ≥2 x ULN or ALT (or 
AST) ≥ 3 x ULN and international normalised ratio (INR) > 1.5 (if INR measured), which 
may indicate severe liver injury (potential Hy’s law) 
 ALT (or AST) ≥ 3 x ULN with the appearance of fatigue, nausea, vomiting, anorexia, 
abdominal pain or tenderness, fever, rash, and/or eosinophilia (>5%),  
where no alternative or competing aetiology exists, repeat testing within 48 to 72 hours, follow-up 
assessments and work-up for alternative aetiologies must be performed, including: 
 Complete liver profile including ALT, AST, ALP, total bilirubin, liver function tests 
(INR/coagulation factors, albumin, PT), performed at the central laboratory. Repeat testing 
and frequency of retesting should be determined at the discretion of the investigator.  
 Detailed clinical information, such as related symptoms, risk factors, medical history, family 
history, including contributing conditions (e.g., viral hepatitis, autoimmune hepatitis, 
alcoholic hepatitis, hypoxic/ischemic hepatopathy, hepatobiliary or pancreatic disorders, 
exposure to environmental chemical agents) should be gathered to seek a possible alternative 
aetiology of the observed laboratory test abnormalities.  
 Evaluation of the need for imaging and other examinations and procedures such as liver 
biopsy, ultrasonography, computerised tomography (CT) scan, magnetic resonance imaging 
(MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde 
cholangiopancreatography (ERCP), echocardiography.  
 History of concomitant drug use (including non-prescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, special diets, recent 
events of food poisoning or excessive physical activity should also be evaluated. 
 Referral to hepatologist/gastroenterologist should be considered. 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
91 of 109 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
92 of 109 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
93 of 109 
 
 
10.8 
Appendix 8: Mitigations to ensure participant safety and data integrity during an 
emergency situation 
10.8.1 
Definition and scope of appendix 
A major emergency is defined as a situation that causes substantial restrictions to study site access 
for participants and/or sponsor representatives. 
In case local restrictions due to a major emergency lead to lock-down of a site, the site must contact 
Novo Nordisk to allow for implementation of mitigations mentioned in this appendix based on 
mutual agreement. 
According to local regulation, health authorities and independent ethics committees should be 
notified in case elements of the emergency appendix are activated. 
Section 10.8.2 indicates the minimum requirements for assessments that should be performed 
during a lock-down, but sites should always try to follow the assessments outlined in the original 
flowchart (Section 1.2) to the extent possible. Implementation of specific mitigations should be 
based on assessment of feasibility at the individual site. 
Sites should comply with local regulations, requirements and/or guidelines if they are issued. 
10.8.2 
Visits 
Screening (Visit 1) and randomisation (Visit 2) should always be performed as on-site visits. If a 
site is unable to perform these visits on-site, screening and randomisation of new participants at that 
site should be on hold until on-site visits are possible. 
Visits 10, 22 and 23 should be performed as on-site visits, if in any way possible. If not, 
assessments can be conducted remotely (video, phone or similar) or as home or off-site visits. 
On-site visits (Visits 3, 4, 5, 6, 7, 8, 12, 14, 16, 18, and 20) can be converted to remote visits (video, 
phone or similar) or home or off-site visits.  
At each visit, the investigator must indicate in the CRF how the visit was performed and specify the 
reason for the preferred assessment method. 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
94 of 109 
 
 
10.9 
Appendix 9: Monitoring of calcitonin  
Background 
Two-year (104 weeks) carcinogenicity studies with semaglutide were completed with no adverse 
effects on tolerability and survival. The thyroid gland was the principal target organ in both species, 
with hyperplastic and neoplastic changes observed in the thyroid C-cells at all doses and in both 
sexes. No other treatment-related tumours were observed in the studies. 
Proliferative C-cell changes in rodents are a known effect following GLP-1 receptor activation by 
GLP-1 RAs.86 The findings in rodents are caused by a non-genotoxic, specific GLP-1 receptor-
mediated mechanism to which rodents are particularly sensitive, and the effect is not related to the 
RET proto-oncogene activation as often seen in human medullary thyroid cancer.87 The GLP-1 
receptor is not expressed in the normal human thyroid,69 and accordingly, the risk of GLP-1 
receptor-mediated C-cell changes in humans is considered to be low. 
No signs of C-cell activation (i.e., no increase in serum calcitonin) or C-cell proliferation were seen 
in cynomolgus monkey studies of up to 52 weeks’ duration, applying doses up to 10-fold the human 
AUC exposure at 2.4 mg/week. 
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia88, the interpretation of values 
between the upper limit of normal and 100 ng/L can become problematic. 
There are several known factors affecting calcitonin levels, namely renal dysfunction, smoking, 
several drug classes (proton pump inhibitors, beta-blockers, insulin secretagogues). Physiology of 
C-cell activation in various clinical conditions and in different patient populations (i.e., with various 
co-morbidities) 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 
Participants with a personal or family (family is defined as a first degree relative) history of MTC or 
multiple endocrine neoplasia syndrome type 2 (MEN2) must be excluded from the study (See 
Section 5.2).  
In case a participant has a calcitonin value ≥10 ng/L, the algorithm outlined in Figure 10-3 and 
described below should be followed. The algorithm applies for all calcitonin values in the study. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
96 of 109 
 
 
Calcitonin ≥ 50 and < 100 ng/L 
Action: The participant should be referred to a endocrinologist or thyroid specialist for further 
evaluation. The participant should remain in the study and can continue trial product. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease88. Two of these participants 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 participants 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 participant can continue in the study, on study product. Continue sampling of 
calcitonin according to the protocol. 
If  the value is from the last sample taken in the study, the participant should be referred to a  
endocrinologist or thyroid specialist for further evaluation. 
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of participants of the 
population of 5817 patients with thyroid nodular disease88. 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.88 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 conclusions.89, 90 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
97 of 109 
 
 
10.10 Appendix 10: Country-specific requirements 
Czech Republic 
 Section 1.2 Participant’s full date of birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
 Section 5.2 and Appendix 4 (Section 10.4): Monthly pregnancy test (urine) for female 
participant of childbearing potential is needed. The additional pregnancy testing will not be 
reported in the CRF. In case of pregnancy, trial product will be discontinued. 
Germany  
 Section 1.2 Participant’s full date of birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
 Section 8.3.1 Time period and frequency for collecting AE information: All SAEs must be 
recorded and reported to Novo Nordisk immediately, without undue delay, and the 
investigator must submit any updated SAE data to Novo Nordisk immediately, without 
undue delay. 
Hungary 
 Section 1.2 Participant’s full date of birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
South Africa 
Slovakia 
The investigator will be responsible for: 
 notifying the IRB/IEC of SAEs – only death, as required by IRB/IEC procedures and local 
regulations 
 providing oversight of the conduct of the study at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations 
 reporting any potential serious breaches to the sponsor immediately after discovery 
 
The sponsor will be responsible for: 
 providing written summaries of the status of the study annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
 notifying the IRB/IEC of SAEs or other significant safety findings according to local 
regulations and procedures established by the IRB/IEC and/or regulatory authorities  
 ensuring submission of protocol, protocol amendments, ICF, investigator brochure, CSR 
synopsis and other relevant documents to the IRB/IEC and/or regulatory authorities.
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
98 of 109 
 
 
10.11 Appendix 11: Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
BMR 
basal metabolic rate  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CFR 
Code of Federal Regulations  
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
case report form 
CRP 
c-reactive protein 
CSR 
clinical study report 
CT 
(serum) calcitonin 
CTFG 
clinical trial facilitation group 
DBL 
database lock 
DFU 
directions for use 
DPS 
data points set 
DUN 
dispensing unit number 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EMA 
European medicines agency 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 RA 
Glucagon-like peptide-1 receptor agonist 
HbA1c 
glycated haemoglobin 
HDL 
High-density lipoprotein 
HRT 
hormone replacement therapy 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
99 of 109 
 
 
hsCRP 
High sensitive C-reactive Protein 
IB 
investigator’s brochure 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors  
ID 
identification 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INR 
international normalised ratio  
IRB 
institutional review board 
ISO 
International Organization for Harmonization 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
J2R-MI 
Jump to reference multiple imputation approach 
KDIGO 
Kidney Disease: Improving Global Outcomes 
LAM 
lactational amenorrhoea method  
LAO-OT 
last available observation during the on-treatment period 
LDL 
low-density lipoprotein 
LPLT 
last patient last treatment  
MAR 
missing at random 
MEN2 
multiple endocrine neoplasia type 2  
MHP 
mental health professional 
MMRM 
mixed model for repeated measurements  
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid carcinoma 
NIMP 
non-investigational medicinal product 
NYHA 
New York Heart Association  
OR 
odds ratio 
PCD 
primary completion date  
PD 
pharmacodynamics 
PHQ-9 
Patient Health Questionaire-9 
PK 
pharmacokinetics  
Pop-PK 
population pharmacokinetic  
PYE 
patient years of exposure  
PYO 
patient years of observation 
QTLs 
quality tolerance limits 
RET 
rearranged during transfection 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
100 of 109 
 
 
RTSM/IWRS 
Systems used for randomisation and trial supplies management (also Interactive Web Response 
System) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis set 
s.c. 
subcutaneous(ly) 
SD 
standard deviation 
SOP 
standard operational procedures 
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
Type 2 diabetes 
TEE 
total daily energy expenditure  
TMM 
Trial Materials Manual 
TP-MI 
Tipping-point multiple imputation analysis 
TSH 
Thyroid stimulating hormone  
ULN 
upper limit of normal 
US 
United States of America 
VLDL 
very low-density lipoprotein 
WOCBP 
woman of childbearing potential 
 
 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
101 of 109 
 
 
10.12 Appendix 12: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 2.0: 30 June 2022, global 
The amendment from version 1.0 of the protocol to version 2.0 was an administrative amendment 
as version 1.0 of the protocol was an internal version.  
Protocol version 3.0: 28 September 2022, global 
The amendment from version 2.0 of the protocol to version 3.0 is substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
Overall rationale for the amendment 
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
Editorial changes e.g. spelling errors, 
punctuation or updates to more exact 
wording.   
To improve readability. 
Section 1.1 Synopsis 
Updated with the relevant changes 
described below. 
For completeness of the document.  
Section 1.2 Flowchart 
Discontinuation criteria line added. 
 
It shall be confirmed at all visits from visit 3 to 
visit 21 that the participant is still eligible to 
continue trial product.  
 
Crosses corrected for contraceptive 
counselling, attend visit fasting, anti 
semaglutide antibodies and 
administration of trial product.   
To align with treatment procedures and avoid 
unnecessary blood sampling.  
Section 3 Objectives, 
endpoints and estimands  
Two confirmatory secondary 
endpoints added.  
To evaluate the difference in treatment effect 
between semaglutide 7.2 mg and 2.4 mg.  
Section 4.1 Overall design  
Number of participants increased to 
1400 and randomisation changed to 
5:1:1. 
Figure 4-1 updated accordingly.  
To increase the safety database for semaglutide 
7.2 mg.  
 
Number of participants in the MRI 
subpopulation increased to 210. 
To reflect the changes in number of participants 
and randomisation.  
Section 5.2 Exclusion 
criteria 
New criteria 8 added.  
To avoid interference on endpoints from 
previous use of GLP-1 receptor agonists. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
102 of 109 
 
 
Section # and name 
Description of change 
Brief rationale 
Section 7.1.1.1 Hepatic 
events requiring temporary 
discontinuation of study 
intervention 
New section added. 
Collection of hepatic events has been updated.  
Section 8.3 Adverse events 
and other safety reporting 
New footnote added to Table 8-1 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
Hepatic event text deleted. 
Section 10.6 Appendix 6: 
Hepatic Safety: Suggested 
actions and follow-up 
assessments.  
New appendix added.  
Section 9.1.1 Multiplicity 
adjustment 
Text added. 
To align with the new endpoints added in 
Section 3.  
Section 9.3.3.1 
Confirmatory secondary 
estimands 
Section 9.5 Sample size 
determination 
Numbers updated 
Updated to reflect the increased sample size.  
 
Protocol version 4.0: 20 January 2023, global 
The amendment from version 3.0 of the protocol to version 4.0 is substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. The primary reason for this protocol amendment was to include additional 
safety and clinical outcome assessments.  
Overall rationale for the amendment 
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
Editorial changes e.g. spelling errors, 
punctuation or updates to more exact 
wording.   
To improve readability. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
103 of 109 
 
 
Section 1.2 Flowchart 
Biochemistry and haematology 
assessments added at V16. 
To add an additional assessments 
approximately half-way through the 
maintenance period. 
Section 1.2 Flowchart 
PHQ-9 and C-SSRS added to V8, 
V10, V14 and V18. Removed from 
V12. 
To improve the evaluation of mental 
health for the participants on the 7.2 
mg dose. 
Section 1.2 Flowchart 
Handout of PK diaries at V22 
removed from flowchart.  
Participants will not administer 
treatment after V22. 
6.5 Dose modification 
Added that delaying dose escalation 
is allowed. 
This was previously only mentioned 
in the justification for dose section. 
Added in this section as well for 
clarity. 
Section 7. 1 Discontinuation of study 
intervention 
Calcitonin ≥ 100 ng/L added as a 
discontinuation criterion. 
To evaluate safety for semaglutide 
7.2 mg. 
Section 8.2.2. Mental health 
assessment instruments 
PHQ-9 and C-SSRS at V8, V10, 
V14 and V18 added to text. 
Removed from V12 from text. 
To improve the evaluation of mental 
health for the participants on the 7.2 
mg dose. 
Section 8.3 Table 8-1 
Added ‘Acute kidney injury’. 
Added based on feedback from 
FDA. 
Section 10.2 Appendix 2 Table 10-2 
Added direct bilirubin, amylase, 
calcitonin and lipase. 
To evaluate safety for semaglutide 
7.2 mg. 
Section 10.2 Appendix 2 Table 10-3 
Criteria for hepatic laboratory 
outliers added. 
Added based on feedback from 
FDA. 
Section 10.3.3 
Added ‘Acute kidney injury’. 
Added based on feedback from 
FDA. 
Section 10.9 Appendix 9: 
Monitoring of calcitonin.  
Appendix added. 
To evaluate safety for semaglutide 
7.2 mg. 
Section 10.10 Appendix 10 Country-
specific requirements 
Slovakia requirements added.  
Added based on feedback from 
IRB/IEC.  
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
104 of 109 
 
 
11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and 
projections to 2030. Int J Obes (Lond). 2008;32(9):1431-7. 
3. 
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in 
the United States, 2011-2012. JAMA. 2014;311(8):806-14. 
4. 
Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM, et al. National, regional, 
and global trends in adult overweight and obesity prevalences. Popul Health Metr. 
2012;10(1):22. 
5. 
NCD Risk Factor Collaboration. Trends in adult body-mass index in 200 countries from 
1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 
million participants. Lancet. 2016;387(10026):1377-96. 
6. 
Finkelstein EA, DiBonaventura M, Burgess SM, Hale BC. The costs of obesity in the 
workplace. J Occup Environ Med. 2010;52(10):971-6. 
7. 
Van Nuys K, Globe D, Ng-Mak D, Cheung H, Sullivan J, Goldman D. The association 
between employee obesity and employer costs: evidence from a panel of U.S. employers. 
Am J Health Promot. 2014;28(5):277-85. 
8. 
Wang YC, Pamplin J, Long MW, Ward ZJ, Gortmaker SL, Andreyeva T. Severe Obesity In 
Adults Cost State Medicaid Programs Nearly $8 Billion In 2013. Health Aff (Millwood). 
2015;34(11):1923-31. 
9. 
Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: 
pathophysiology and clinical implications. Gastroenterology. 2012;142(4):711-25.e6. 
10. 
Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-
morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC 
Public Health. 2009;9:88. 
11. 
Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, et al. General 
and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105-20. 
12. 
Berghofer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN. Obesity 
prevalence from a European perspective: a systematic review. BMC Public Health. 
2008;8:200. 
13. 
Masters RK, Reither EN, Powers DA, Yang YC, Burger AE, Link BG. The impact of 
obesity on US mortality levels: the importance of age and cohort factors in population 
estimates. Am J Public Health. 2013;103(10):1895-901. 
14. 
Arnold M, Pandeya N, Byrnes G, Renehan AG, Stevens GA, Ezzati M, et al. Global burden 
of cancer attributable to high body-mass index in 2012: a population-based study. Lancet 
Oncol. 2015;16(1):36-46. 
15. 
World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Report 
of a WHO Consultation. World Health Organisation Geneva, Switzerland. 2000. 
16. 
Thomsen M, Nordestgaard BG. Myocardial Infarction and Ischemic Heart Disease in 
Overweight and Obesity With and Without Metabolic Syndrome. JAMA internal medicine. 
2013;174(1):15-22. 
17. 
Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity 
and type 2 diabetes: what can be unified and what needs to be individualized? J Clin 
Endocrinol Metab. 2011;96(6):1654-63. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
105 of 109 
 
 
18. 
Khaodhiar L, Cummings S, Apovian CM. Treating diabetes and prediabetes by focusing on 
obesity management. Curr Diab Rep. 2009;9(5):348-54. 
19. 
Wheaton AG, Perry GS, Chapman DP, Croft JB. Sleep disordered breathing and depression 
among U.S. adults: National Health and Nutrition Examination Survey, 2005-2008. Sleep. 
2012;35(4):461-7. 
20. 
Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, 
Emberson J, et al. Body-mass index and cause-specific mortality in 900 000 adults: 
collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083-96. 
21. 
Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden 
associated with overweight and obesity. JAMA. 1999;282(16):1523-9. 
22. 
Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Biltoff E, et al. Association of 
cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty 
liver disease. Gastroenterology. 2006;130(7):2023-30. 
23. 
Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the 
knee in older adults: a systematic review and meta-analysis. Osteoarthr Cartil. 
2010;18(1):24-33. 
24. 
Garner RE, Feeny DH, Thompson A, Bernier J, McFarland BH, Huguet N, et al. 
Bodyweight, gender, and quality of life: a population-based longitudinal study. Qual Life 
Res. 2012;21(5):813-25. 
25. 
Kearns B, Ara R, Young T, Relton C. Association between body mass index and health-
related quality of life, and the impact of self-reported long-term conditions - cross-sectional 
study from the south Yorkshire cohort dataset. BMC Public Health. 2013;13:1009. 
26. 
Wei M, Kampert JB, Barlow CE, Nichaman MZ, Gibbons LW, Paffenbarger RS, et al. 
Relationship between low cardiorespiratory fitness and mortality in normal-weight, 
overweight, and obese men. JAMA. 1999;282(16):1547-53. 
27. 
Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. 
Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired 
glucose tolerance. N Engl J Med. 2001;344(18):1343-50. 
28. 
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. 
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N 
Engl J Med. 2002;346(6):393-403. 
29. 
Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, et al. The long-term effect of lifestyle 
interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year 
follow-up study. Lancet. 2008;371(9626):1783-9. 
30. 
Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, 
Christophi CA, Hoffman HJ, et al. 10-year follow-up of diabetes incidence and weight loss 
in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677-86. 
31. 
Foster GD, Borradaile KE, Sanders MH, Millman R, Zammit G, Newman AB, et al. A 
Randomized Study on the Effect of Weight Loss on Obstructive Sleep Apnea Among Obese 
Patients With Type 2 Diabetes The Sleep AHEAD Study. Archives of Internal Medicine. 
2009;169(17):1619-26. 
32. 
Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces the risk 
for symptomatic knee osteoarthritis in women. The Framingham Study. Ann Intern Med. 
1992;116(7):535-9. 
33. 
Dengo AL, Dennis EA, Orr JS, Marinik EL, Ehrlich E, Davy BM, et al. Arterial destiffening 
with weight loss in overweight and obese middle-aged and older adults. Hypertension. 
2010;55(4):855-61. 
34. 
Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: 
a meta-analysis. Am J Clin Nutr. 1992;56(2):320-8. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
106 of 109 
 
 
35. 
Anderson JW, Konz EC. Obesity and disease management: effects of weight loss on 
comorbid conditions. Obes Res. 2001;9 Suppl 4:326S-34S. 
36. 
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. 
American Association of Clinical Endocrinologists' Comprehensive Diabetes Management 
Algorithm 2013 Consensus Statement - Executive Summary. Endocrine Practice. 
2013;19(3):536-47. 
37. 
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest 
weight reduction. Obes Res. 2000;8(3):270-8. 
38. 
Deitel M, Stone E, Kassam HA, Wilk EJ, Sutherland DJ. Gynecologic-obstetric changes 
after loss of massive excess weight following bariatric surgery. J Am Coll Nutr. 
1988;7(2):147-53. 
39. 
Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. 
American association of clinical endocrinologists and american college of endocrinology 
comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr 
Pract. 2016;22 Suppl 3:1-203. 
40. 
Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a 
prospective controlled intervention study of bariatric surgery. J Intern Med. 
2013;273(3):219-34. 
41. 
Gregg EW, Jakicic JM, Blackburn G, Bloomquist P, Bray GA, Clark JM, et al. Association 
of the magnitude of weight loss and changes in physical fitness with long-term 
cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-
hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 
2016;4(11):913-21. 
42. 
Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, et al. Health Effects of 
Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017;377(1):13-27. 
43. 
The American Society for Metabolic and Bariatric Surgery, The Obesity Society, The 
American Society of Bariatric Physicians and the American Association of Clinical 
Endocrinologists. Obesity is a Disease: Leading Obesity Groups Agree (Joint Press 
Release). 19 June 2013. 
44. 
Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. American Association of Clinical 
Endocrinologists' position statement on obesity and obesity medicine. Endocr Pract. 
2012;18(5):642-8. 
45. 
Toplak H, Woodward E, Yumuk V, Oppert JM, Halford JC, Frühbeck G. 2014 EASO 
position statement on the use of anti-obesity drugs. Obes Facts. 2015;8(3):166-74. 
46. 
Fruhbeck G, Toplak H, Woodward E, Yumuk V, Maislos M, Oppert JM, et al. Obesity: the 
gateway to ill health - an EASO position statement on a rising public health, clinical and 
scientific challenge in Europe. Obes Facts. 2013;6(2):117-20. 
47. 
Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. 
Pharmacological management of obesity: an endocrine Society clinical practice guideline. J 
Clin Endocrinol Metab. 2015;100(2):342-62. 
48. 
Ferguson C, David S, Divine L, Kahan S, Gallagher C, Gooding M, et al. Obesity Drug 
Outcome Measures. A Consensus Report of Considerations Regarding Pharmacologic 
Intervention [Internet]. 2012 [cited 2018 8 Aug]. 
49. 
Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Long-
term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-
604. 
50. 
Schwartz A, Doucet E. Relative changes in resting energy expenditure during weight loss: a 
systematic review. Obes Rev. 2010;11(7):531-47. 
51. 
Pasman WJ, Saris WH, Westerterp-Plantenga MS. Predictors of weight maintenance. Obes 
Res. 1999;7(1):43-50. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
107 of 109 
 
 
52. 
Dombrowski SU, Knittle K, Avenell A, Araujo-Soares V, Sniehotta FF. Long term 
maintenance of weight loss with non-surgical interventions in obese adults: systematic 
review and meta-analyses of randomised controlled trials. BMJ. 2014;348:g2646. 
53. 
Brethauer SA, Chand B, Schauer PR. Risks and benefits of bariatric surgery: current 
evidence. Cleve Clin J Med. 2006;73(11):993-1007. 
54. 
Schauer PR, Ikramuddin S, Gourash W, Ramanathan R, Luketich J. Outcomes after 
laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg. 2000;232(4):515-29. 
55. 
Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European Guidelines 
for Obesity Management in Adults. Obes Facts. 2015;8(6):402-24. 
56. 
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22. 
57. 
Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the once-
weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 
2015;58(18):7370-80. 
58. 
Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, et al. Glucagon-like 
peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. 
Am J Physiol. 1999;276(5 Pt 2):R1541-4. 
59. 
Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy and 
safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 
diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, 
multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-60. 
60. 
Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and safety of 
once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or 
without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a 
randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet 
Diabetes Endocrinol. 2017;5(5):355-66. 
61. 
Ahrén B, Masmiquel L, Kumar H, Sargin M, Karsbøl JD, Jacobsen SH, et al. Efficacy and 
safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, 
thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, 
double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5(5):341-54. 
62. 
Ahmann A, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and 
safety of once-weekly semaglutide vs exenatide ER after 56 Weeks in subjects with type 2 
diabetes (SUSTAIN 3).  European Association for the Study of Diabetes, 52nd meeting 
2016, Oral Presentation #1472016. 
63. 
Rodbard H, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, et al. Efficacy and safety 
of semaglutide once-weekly vs placebo as add-on to basal insulin alone or in combination 
with metformin in subjects with type 2 diabetes (SUSTAIN 5) [abstract]. Diabetologia. 
2016;59(Suppl 1):364-5. 
64. 
Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, et al. Effects of once-
weekly semaglutide on appetite, energy intake, control of eating, food preference and body 
weight in subjects with obesity. Diabetes Obes Metab. 2017;19(9):1242-51. 
65. 
Lu TT, Secher A JJ, Alanentalo T, Juel Paulsen S, Hecksher-Sørensen J, Larsen JN, 
Baquero A, Knudsen LB. Semaglutide interacts with hypothalamic neurons and lowers body 
weight in mice.  Poster discussion 1072-P. American Diabetes Association, 77th Scientific 
Sessions, San Diego, CA, USA.9–13 June 2017. 
66. 
Novo Nordisk A/S. Investigator's brochure, semaglutide s.c. 2.4 mg for weight management, 
projects NN9536 and EX9536 (edition 7). 04 Jun 2021. 
67. 
European Medicines Agency. Guideline on clinical evaluation of medicinal products used in 
weight management (EMA/CHMP/311805/2014). 23 Jun 2016. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
108 of 109 
 
 
68. 
Food and Drug Administration. Center for Drug Evaluation and Research (CDER). 
Guidance for Industry Developing Products for Weight Management. Revision 1 (FDA-
2007-D-0435). Feb 2007. 
69. 
Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 
receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 
2015;28(3):391-402. 
70. 
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl. 2013;3(1):1-150. 
71. 
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products  (ENTR/F/2/AM/an D(2010) 
3374). 03 Feb 2010. 
72. 
FAO/WHO/UNU. Human energy requirements. Report of a joint FAO/WHO/UNU expert 
consultation. FAO: food and nutrition technical report series 1. 2004. 
73. 
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11. 
74. 
75. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9 - Validity of a brief depression severity 
measure. J Gen Intern Med. 2001;16(9):606-13. 
76. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-43. 
77. 
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6. 
78. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
79. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Current 
step 4 version. 09 Nov 2016. 
80. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
81. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
82. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
83. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
CONFIDENTIAL

Protocol 
 
Date: 
22 June 2023 Novo Nordisk 
Study ID: NN9536-4999 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
109 of 109 
 
 
84. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
85. 
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agency. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
86. 
Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. 
Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin 
release and C-cell proliferation. Endocrinology. 2010;151(4):1473-86. 
87. 
Madsen LW, Knauf JA, Gotfredsen C, Pilling A, Sjogren I, Andersen S, et al. GLP-1 
receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor 
and not associated with RET activation. Endocrinology. 2012;153(3):1538-47. 
88. 
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive 
value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma 
in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 
2007;92(2):450-5. 
89. 
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer. 
2009;16(1):243-53. 
90. 
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403. 
 
CONFIDENTIAL