Clinical trial NCT04998136
Conditions: Obesity
Sponsor: Novo Nordisk A/S
Start date: 2022-08-15; Completion date: 2023-11-20
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study looks at how well semaglutide helps people lose weight. This study will look at the change in the participants' body weight from the start to the end of the study. The study compares the weight loss in people who get semaglutide to the weight loss in people who get placebo. Placebo is a "dummy" medicine that looks like the study medicine, but has no effect on the body.

Participants will either get semaglutide or "dummy" medicine - which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm.

Participants will also have talks with study staff about healthy food choices, how to be more physically active and what participants can do to lose weight.

The study will last for about a year (50 weeks). Participants will have 10 clinic visits and 8 phone calls. At 6 of the clinic visits participants will have blood samples taken.

Participants cannot take part if participants have or have had diabetes. Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Semaglutide 2.4 mg intervention 2: Placebo (semaglutide 2.4 mg)
Intervention descriptions: intervention 1: Administered subcutaneously (s.c., under the skin) as well as reduced-calorie diet and increased physical activity for 44 weeks. Doses gradually increased to 2.4 mg intervention 2: Administered s.c. as well as reduced-calorie diet and increased physical activity for 44 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04998136 
Sponsor trial ID: 
NN9536-4707 
Official title of study: 
Efficacy and safety of semaglutide 2.4 mg once-weekly in 
Asians with obesity diagnosed as BMI ≥ 25 kg/m2 according 
to local guidelines. 
Document date*: 
16 December 2022 
*Document date refers to the date on which the document was most recently updated.


Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
6.0 
     
Status: 
Final 
     
Page: 
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Protocol 
 
Protocol Title:  
Efficacy and safety of semaglutide 2.4 mg once-weekly in Asians with obesity diagnosed as BMI 
≥ 25 kg/m2 according to local guidelines. 
Substance name: Semaglutide 
Universal Trial Number: U1111-1265-5285  
Study phase: 3b 
 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
6.0 
     
Status: 
Final 
     
Page: 
2 of 91 
 
 
Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or site(s)  
Protocol Version 6.0 
16 December 2022 
Global 
Protocol Version 5.0 
20 June 2022 
Global 
Protocol version 4.0 
09 February 2022 
Global 
Protocol version 3.0 
15 September 2021 
Global 
Protocol version 2.0 
25 June 2021 
Global 
Original protocol version 1.0 
04 June 2021 
 
 
Protocol version 6.0 (16 December 2022) 
This amendment is non-substantial based on a criterion set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, because it neither 
significantly impacts the safety or physical/mental integrity of participants nor the scientific value 
of the study. 
Overall rationale for preparing protocol, version 6.0: 
It is identified that statements instructing drug accountability in protocol section 6.2 differs than that 
of the trial materials manual (TMM). To mitigate this discrepancy in the protocol, the statements 
instructing investigator or designee responsible for drug accountability have been removed and the 
reference to the TMM has been added for more details.  
Section # and name 
Description of change 
Brief rationale 
6.2 Preparation, handling, storage and 
accountability 
 
Text revised to define the drug 
accountability level.  
To align with project-based decisions.  
6.2 Preparation, handling, storage and 
accountability 
Removed the text “product should be 
disposed of in a safe manner and will 
not be retained for drug accountability 
purposes. Empty packaging will be 
used to perform accountability of used 
trial product.”  Added the text 
“Additional details regarding 
handling of drug accountability can 
be found in the TMM.” 
To align with TMM  
CONFIDENTIAL


Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
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Status: 
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Page: 
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Table of Contents 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 Protocol summary ....................................................................................................................................... 6 
1.1 
Synopsis .............................................................................................................................................. 6 
1.2 
Flowchart .......................................................................................................................................... 10 
2 Introduction ............................................................................................................................................... 12 
2.1 
Study rationale .................................................................................................................................. 12 
2.2 
Background ....................................................................................................................................... 13 
2.2.1 
Semaglutide ....................................................................................................................... 13 
2.3 
Benefit-risk assessment ..................................................................................................................... 14 
2.3.1 
Risk assessment ................................................................................................................. 14 
2.3.2 
Benefit assessment ............................................................................................................. 16 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 16 
3 Objectives, endpoints and estimands ....................................................................................................... 18 
4 Study design ............................................................................................................................................... 21 
4.1 
Overall design ................................................................................................................................... 21 
4.2 
Scientific rationale for study design .................................................................................................. 21 
4.3 
Justification for dose ......................................................................................................................... 22 
4.4 
End of study definition ...................................................................................................................... 22 
5 Study population ....................................................................................................................................... 24 
5.1 
Inclusion criteria ............................................................................................................................... 24 
5.2 
Exclusion criteria .............................................................................................................................. 24 
5.3 
Lifestyle considerations .................................................................................................................... 25 
5.3.1 
Meals and dietary restrictions ............................................................................................ 25 
5.3.2 
Caffeine, alcohol, and tobacco .......................................................................................... 25 
5.4 
Screen failures ................................................................................................................................... 25 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria ......................................................... 26 
6 Study intervention(s) and concomitant therapy ..................................................................................... 27 
6.1 
Study intervention(s) administered ................................................................................................... 27 
6.2 
Preparation, handling, storage and accountability ............................................................................ 30 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 31 
6.4 
Study intervention compliance.......................................................................................................... 32 
6.5 
Dose modification ............................................................................................................................. 32 
6.6 
Continued access to study intervention after end of study ................................................................ 32 
6.7 
Treatment of overdose ...................................................................................................................... 33 
6.8 
Concomitant therapy ......................................................................................................................... 33 
7 Discontinuation of study intervention and participant discontinuation/withdrawal .......................... 34 
7.1 
Discontinuation of study intervention ............................................................................................... 34 
7.1.1 
Temporary discontinuation of study intervention .............................................................. 35 
7.2 
Participant discontinuation/withdrawal from the study .................................................................... 35 
7.2.1 
Replacement of participants .............................................................................................. 36 
7.3 
Lost to follow-up............................................................................................................................... 36 
8 Study assessments and procedures .......................................................................................................... 37 
8.1 
Efficacy assessments ......................................................................................................................... 38 
8.1.1 
Body measurements ........................................................................................................... 38 
8.1.2 
Clinical efficacy laboratory assessments ........................................................................... 38 
8.2 
Safety assessments ............................................................................................................................ 38 
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Protocol 
CONFIDENTIAL 
Date: 
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Study ID: NN9536-4707 
Version: 
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8.2.1 
Physical examinations ....................................................................................................... 39 
8.2.2 
Vital signs .......................................................................................................................... 40 
8.2.3 
Clinical safety laboratory assessments .............................................................................. 40 
8.2.4 
Pregnancy testing ............................................................................................................... 40 
8.2.5 
Surgical procedures assessment ......................................................................................... 40 
8.3 
Adverse events and other safety reporting ........................................................................................ 41 
8.3.1 
Time period and frequency for collecting AE information ............................................... 41 
8.3.2 
Method of detecting AEs ................................................................................................... 42 
8.3.3 
Follow-up of AEs .............................................................................................................. 42 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 42 
8.3.5 
Pregnancy .......................................................................................................................... 42 
8.3.6 
Cardiovascular and death events ....................................................................................... 42 
8.3.7 
Technical complaints ......................................................................................................... 42 
8.4 
Pharmacokinetics and pharmacodynamics ....................................................................................... 43 
8.4.1 
Pharmacokinetics ............................................................................................................... 43 
8.4.2 
Pharmacodynamics ............................................................................................................ 43 
8.5 
Genetics ............................................................................................................................................ 43 
8.6 
Biomarkers ........................................................................................................................................ 43 
8.7 
Immunogenicity assessments ............................................................................................................ 43 
8.8 
Health economics .............................................................................................................................. 43 
9 Statistical considerations .......................................................................................................................... 44 
9.1 
Statistical hypotheses ........................................................................................................................ 44 
9.1.1 
Multiplicity adjustment...................................................................................................... 44 
9.2 
Analysis sets...................................................................................................................................... 45 
9.3 
Statistical analyses ............................................................................................................................ 47 
9.3.1 
General considerations ...................................................................................................... 47 
9.3.2 
Primary estimands analysis ............................................................................................... 47 
9.3.3 
Secondary estimands analysis ........................................................................................... 48 
9.3.3.1 
Confirmatory secondary estimands ................................................................ 48 
9.3.3.2 
Supportive secondary estimands .................................................................... 49 
9.3.4 
Exploratory endpoints analysis .......................................................................................... 49 
9.3.5 
Safety analyses .................................................................................................................. 49 
9.3.6 
Other analyses ................................................................................................................... 49 
9.4 
Interim analysis ................................................................................................................................. 50 
9.5 
Sample size determination ................................................................................................................ 50 
10 Supporting documentation and operational considerations.................................................................. 53 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations .............................................. 53 
10.1.1 
Regulatory and ethical considerations ............................................................................... 53 
10.1.2 
Financial disclosure ........................................................................................................... 53 
10.1.3 
Informed consent process .................................................................................................. 53 
10.1.4 
Information to participants during the study ..................................................................... 54 
10.1.5 
Data protection .................................................................................................................. 54 
10.1.6 
Committees structure ......................................................................................................... 55 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 55 
10.1.7 
Dissemination of clinical study data .................................................................................. 55 
10.1.8 
Data quality assurance ....................................................................................................... 55 
10.1.8.1 
Case report forms ........................................................................................... 55 
10.1.8.2 
Monitoring ..................................................................................................... 56 
10.1.8.3 
Protocol compliance ....................................................................................... 57 
10.1.9 
Source documents .............................................................................................................. 57 
10.1.10 Retention of clinical study documentation ........................................................................ 57 
10.1.11 Study and site closure ........................................................................................................ 58 
10.1.12 Responsibilities .................................................................................................................. 58 
10.1.13 Indemnity statement .......................................................................................................... 59 
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Protocol 
CONFIDENTIAL 
Date: 
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Study ID: NN9536-4707 
Version: 
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Status: 
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10.1.14 Publication policy .............................................................................................................. 59 
10.1.14.1 
Communication of results .............................................................................. 60 
10.1.14.2 
Authorship ...................................................................................................... 60 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 60 
10.1.14.4 
Investigator access to data and review of results ........................................... 61 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 62 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................................................... 64 
10.3.1 
Definition of AE ................................................................................................................ 64 
10.3.2 
Definition of an SAE ......................................................................................................... 64 
10.3.3 
Description of AEs requiring additional data collection ................................................... 65 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 67 
10.3.4.1 
AE and SAE recording ................................................................................... 67 
10.3.4.2 
Assessment of severity ................................................................................... 67 
10.3.4.3 
Assessment of causality ................................................................................. 67 
10.3.4.4 
Final outcome ................................................................................................. 68 
10.3.4.5 
Follow-up of AE and SAE ............................................................................. 68 
10.3.5 
Reporting of SAEs ............................................................................................................. 69 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 71 
10.4.1 
Definitions ......................................................................................................................... 71 
10.4.2 
Contraceptive guidance ..................................................................................................... 71 
10.4.3 
Collection of pregnancy information ................................................................................. 72 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 74 
10.5.1 
Definition of technical complaint ...................................................................................... 74 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 74 
10.5.3 
Reporting of technical complaints from products not included in the technical 
complaint form .................................................................................................................. 75 
10.6 Appendix 6: Mitigations to ensure participant safety and data integrity during an emergency 
situation ............................................................................................................................................. 76 
10.6.1 
Definition and scope of appendix ...................................................................................... 76 
10.6.2 
Visits .................................................................................................................................. 76 
10.6.3 
Assessments ....................................................................................................................... 76 
10.6.4 
Study intervention ............................................................................................................. 77 
10.7 Appendix 7: Country-specific requirements ..................................................................................... 80 
10.8 Appendix 8: Abbreviations ............................................................................................................... 81 
10.9 Appendix 9: Protocol amendment history ........................................................................................ 83 
11 References .................................................................................................................................................. 86 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments. 
 
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Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
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Status: 
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1 
Protocol summary 
1.1 
Synopsis 
This is an interventional, multi-national, multi-centre, randomised, double-blind, placebo-
controlled, two-armed, parallel group clinical study. 
Rationale: 
The prevalence of obesity has reached epidemic proportions in most countries around the world  
and continues to increase.1-7 The risk of obesity-related complications and comorbidities increases 
with increasing BMI, and a weight loss of 5−10% has significant health benefits by improving 
obesity-related comorbidities including slowing progression to T2D, and improving physical 
symptoms and quality of life.8-14 Lifestyle intervention in the form of diet and exercise is first-line 
treatment for obesity, but most people with obesity struggle to achieve and maintain their weight 
loss.15-25 Currently, only few pharmacological options are approved for weight management. The 
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.  
Most studies that examine the risk of adverse health associated with obesity have been based on 
data from Europe or the United States. However, the increased health risks associated with obesity 
occur in people with lower BMIs in the Asia Pacific region. This has supported calls by obesity 
researchers for lower BMI cut-offs for overweight and obesity in Asian populations than those in 
the international WHO classification.26, 27 
The present 44-week study is designed to show the reduction in body weight and compare the 
efficacy and safety of semaglutide subcutaneous (s.c.) once weekly versus placebo as an adjunct to 
a reduced-calorie diet and increased physical activity in people from Republic of Korea and 
Thailand with obesity, defined as BMI ≥ 25.0 kg/m2, reflecting local diagnostic practices. Thus, the 
study will provide more information about the efficacy and safety of semaglutide s.c. 2.4 mg once 
weekly in people of Asian descent with obesity as defined by regional guidelines. 
Objectives, endpoints and estimand(s): 
Primary objective: To demonstrate the superiority of semaglutide s.c. 2.4 mg once weekly versus 
placebo as an adjunct to a reduced-calorie diet and increased physical activity in participants with 
obesity, classified as BMI ≥ 25 kg/m2 according to local guidelines in Republic of Korea and 
Thailand on:  
 Body weight 
 ≥5% weight reduction 
Secondary objectives:  
 To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus placebo, as an adjunct 
to a reduced-calorie diet and increased physical activity in participants with obesity, classified 
as BMI ≥ 25 kg/m2 according to local guidelines in Republic of Korea and Thailand, on 
cardiovascular risk factors 
CONFIDENTIAL


Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
6.0 
     
Status: 
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Page: 
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 To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus placebo, as an adjunct 
to a reduced-calorie diet and increased physical activity in participants with obesity, classified 
as BMI ≥ 25 kg/m2 according to local guidelines in Republic of Korea and Thailand, on glucose 
metabolism 
 
Co-primary endpoints:  
 Change in body weight (%) from baseline (week 0) to end of treatment (week 44) 
 ≥5% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
Confirmatory secondary endpoints: 
 ≥10% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 ≥15% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 Change in waist circumference from baseline (week 0) to end of treatment (week 44) 
 
Estimands: 
 Co-primary estimands: The estimands will quantify the average treatment effect of 
semaglutide s.c. 2.4 mg once weekly as an adjunct to a reduced-calorie diet and increased 
physical activity in patients with obesity defined according to local guidelines in Republic of 
Korea and Thailand, measured by relative change from baseline (week 0) to week 44 in body 
weight, and ≥ 5% body weight reduction at week 44,  regardless of discontinuation or dose 
reduction of randomised trial product, and regardless of initiating other anti-obesity therapies 
(weight management drugs or bariatric surgery). 
 Secondary estimand: The secondary estimands for both the confirmatory secondary and 
supportive secondary endpoints are similar to the co-primary estimands except for the endpoint 
attribute. For continuous endpoints, the secondary estimands for primary and secondary 
objectives are similar to the co-primary estimand for % weight change. For binary endpoints, 
the secondary estimands for primary and secondary objectives are similar to the co-primary 
estimand for ≥5% body weight reduction.   
 Additional estimand: The estimand will quantify the average treatment effect of semaglutide 
s.c. 2.4 mg once weekly as an adjunct to a reduced-calorie diet and increased physical activity in 
patients with obesity defined according to local guidelines in Republic of Korea and Thailand, 
measured by relative change from baseline (week 0) to week 44 in body weight, and ≥ 5% body 
weight reduction at week 44, had they remained on their randomised treatment for the entire 
planned duration of the study and not initiated any other anti-obesity therapies (weight 
management drugs or bariatric surgery). 
Overall design: 
The study consists of: 
 a 1-week screening period 
 a 16-week dose escalation period 
 a 28-week maintenance period 
 a 5-week follow-up period 
CONFIDENTIAL


Protocol 
CONFIDENTIAL 
Date: 
16 December 2022 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
6.0 
     
Status: 
Final 
     
Page: 
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Study intervention groups and duration: 
Following a screening period of up to 1 week, the participants will be randomised 2:1 at the 
randomisation visit to semaglutide s.c. 2.4 mg once weekly or placebo once weekly as an adjunct to 
a reduced-calorie diet and increased physical activity.  
The maximum duration of the study intervention for each participant is 44 weeks and the duration 
of the study for each participant is 49 weeks.  
The following trial products will be provided by Novo Nordisk A/S: 
 Semaglutide B 0.68 mg/mL and semaglutide placebo, solution for injection, 1.5 mL PDS290 
pen-injector 
 Semaglutide B 1.34 mg/mL and semaglutide placebo, solution for injection, 1.5 mL PDS290 
pen-injector 
 Semaglutide B 1.34 mg/mL and semaglutide placebo, solution for injection, 3 mL PDS290 pen-
injector 
 Semaglutide B 2.27 mg/mL and semaglutide placebo, solution for injection, 3 mL PDS290 pen-
injector 
 Semaglutide B 3.2 mg/mL and semaglutide placebo, solution for injection, 3 mL PDS290 pen-
injector 
Number of participants: 
Approximately 176 participants will be screened to achieve 150 participants randomly assigned to 
study intervention.  
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:  
 Age above or equal to 18 years at the time of signing informed consent. 
 BMI ≥ 25.0 kg/m2 at screening. 
 Both parents of Asian descent. 
 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. 
 History of type 1 or type 2 diabetes mellitus. 
 A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
 Any participant where a substantial weight loss, in the investigator’s opinion, might jeopardise 
the participant’s safety. 
 Renal impairment with estimated Glomerular Filtration Rate (eGFR) < 15 mL/min/1.73 m2 at 
screening. 
Efficacy and safety data will be collected at regular intervals throughout the study.  
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Data monitoring committee: No 
 
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Protocol 
      
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1.2 
Flowchart 
 
Screening Randomisation 
Intervention period 
End of study 
interventiona 
End of 
study 
Visit 
V1 
V2 
P3 V4 P5 V6 P7 V8 P9 V10 V11 P12 V13 P14 V15 P16 
V17 
P18 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
40 
44 
49 
Visit Window (Days) 
-7 
0 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
Informed Consent and Demographyb (10.1.3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Concomitant Illness (8.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility Criteria (5.1 and 5.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation (6.3) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication (6.8) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Childbearing Potentialc (10.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Used (5.3.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (8.2.4) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
Evaluation of Antihypertensive Treatment (8) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Evaluation of Glycaemic Status (8) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Evaluation of Lipid-lowering Treatment (8) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Discontinuation Criteria (7) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Surgical Procedures Form (8.2.5) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (8.1.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight (8.1.1) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Waist Circumference (8.1.1) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Physical Examination (8.2.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Protocol 
      
Date: 
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Status: 
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Screening Randomisation 
Intervention period 
End of study 
interventiona 
End of 
study 
Visit 
V1 
V2 
P3 V4 P5 V6 P7 V8 P9 V10 V11 P12 V13 P14 V15 P16 
V17 
P18 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
40 
44 
49 
Visit Window (Days) 
-7 
0 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
Vital Signs (8.2.2) 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Laboratory Assessments (10.2) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Adverse Event (8.3 and 10.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling (8.4.1) 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Breast Neoplasms Follow-upc (8.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Colon Neoplasms Follow-up (8.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug Dispensing (6.2) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Drug Accountability (6.2) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Training in Trial Product, Pen-handling (6.1) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Hand Out Direction for Use (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand Out Dose Reminder Card 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Hand Out and Instruct in PK Diary (8) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Diet and Physical Activity Counselling (6.1) 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Barriers and Motivation Interview (8) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. End of study intervention includes both end of IMP treatment (‘end of treatment’) and end of lifestyle intervention b. Demography consists of date of birth, sex, ethnicity, and race 
(according to local regulation); c. For all female participants; d. Smoking is defined as smoking at least one cigarette or equivalent daily 


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2 
Introduction 
2.1 
Study rationale 
The prevalence of obesity has reached epidemic proportions in most countries around the world  
and continues to increase.1-7 Obesity is currently considered one of the most significant public 
health challenges worldwide due to its substantial medical, societal and economic impact.1, 6, 7, 28-30 
Obesity increases the risk of developing cardiovascular disease and certain types of cancers, which 
are some of the leading causes of early death in these patients.31, 32 In addition, obesity is a well-
established risk factor for other serious conditions including, but not limited to, T2D, hypertension, 
dyslipidaemia, obstructive sleep apnoea, osteoarthritis, urinary incontinence, asthma and non-
alcoholic steatohepatitis.33-48 Obesity also significantly impacts health-related quality of life.49, 50  
The risk of obesity-related complications and comorbidities increases with increasing BMI, and a 
weight loss of 5−10% has significant health benefits by improving obesity-related comorbidities 
including slowing progression to T2D, and improving physical symptoms and quality of life.8-14 
Studies suggest a beneficial impact of weight loss on cardiovascular risk and mortality in people 
with obesity, with or without T2D.48, 51, 52 
Lifestyle intervention in the form of diet and exercise is first-line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss.15-25 Bariatric surgery offers 
an effective alternative for some people with severe obesity, but carries a risk in connection with the 
procedure and for complications afterwards, and requires close follow-up which can be 
cumbersome and costly.15-20, 53, 54  
Pharmacotherapy may serve as a valuable alternative to bariatric surgery as a supplement to 
lifestyle intervention to achieve and sustain a clinically relevant weight loss. Currently, only few 
pharmacological options are approved for weight management. Furthermore, some are only 
indicated for short term use whereas others are associated with significant adverse effects.  
Collectively, there is a clear unmet medical need for a convenient, efficacious, and safe weight-
lowering drug with beneficial effects on obesity-related comorbidities. The 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. 
Most studies that examine the risk of adverse health associated with obesity have been based on 
data from Europe or the United States. However, the increased health risks associated with obesity 
occur in people with lower BMIs in the Asia Pacific region. The Nurses’ Health Study found that 
after 20 years, at a given BMI, the risk of developing T2D in Asian women was more than double 
that of Caucasian women.55 Similarly, compared with Caucasians, people of Asian descent with a 
BMI 25.0−29.9 kg/m2 have been shown to have a significantly elevated all-cause mortality risk.56 
This has supported calls by obesity researchers for lower BMI cut-offs for overweight and obesity 
in Asian populations than those in the international WHO classification.26, 27 The WHO has 
proposed a BMI classification for the Asia-Pacific region with lower cut-offs for overweight (≥ 23 
kg/m2) and obesity (≥ 25 kg/m2) compared to those in the original WHO criteria, as these were 
mainly based on data from Europe and the United States.57-59 Furthermore, according to the WHO 
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recommendations for the Asia-Pacific region, pharmacotherapy is to be considered at BMI ≥ 
25 kg/m2.58 
The present 44-week study is designed to show the reduction in body weight and compare the 
efficacy and safety of semaglutide subcutaneous (s.c.) once weekly versus placebo as an adjunct to 
a reduced-calorie diet and increased physical activity in people from Republic of Korea and 
Thailand with obesity, defined as BMI ≥ 25.0 kg/m2. Thus, the study will provide more information 
about the efficacy and safety of semaglutide s.c. 2.4 mg once weekly in people of Asian descent 
with obesity as defined by regional guidelines. 
2.2 
Background 
2.2.1 
Semaglutide 
Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), approved for 
the treatment of T2D in adults (Ozempic®), which is currently under development by Novo Nordisk 
for the treatment of weight management at higher doses. Semaglutide has a half-life of 
approximately 160 hours, making it suitable for once-weekly dosing.60 
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.61 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.62-68  
A global phase 3a clinical development programme with semaglutide s.c. 2.4 mg once weekly has 
been completed (STEP programme), having enrolled approximately 4,500 adults with overweight 
or obesity. The programme consists of four studies (NN9536-4373, NN9536-4374, NN9536-4375 
and NN9536-4376). The 68-week phase 3a weight management studies STEP 1 (NN9536-4373) 
and STEP 2 (NN9536-4374) have demonstrated clinically significant weight loss with semaglutide 
s.c. 2.4 mg once weekly. In STEP 1, 1,961 participants with overweight or obesity were included. 
At week 68, participants in the semaglutide s.c. 2.4 mg once-weekly group achieved an average 
weight loss of 14.85% compared to 2.41% in the placebo group. In STEP 2, 1,210 participants with 
overweight or obesity and T2D were included. At week 68, participants in the semaglutide s.c. 
2.4 mg once-weekly group achieved an average weight loss of 9.64% compared to 3.42% in the 
placebo group. In both studies, semaglutide s.c. 2.4 mg once weekly appeared to have a safe and 
well-tolerated profile, consistent with previous findings. 
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) and any updates hereof.69  
The study population will consist of participants from Republic of Korea and Thailand with obesity 
diagnosed according to local guidelines, with BMI ≥ 25 kg/m2. Studies have shown that people of 
Asian descent experience co-morbidities at a lower BMI than what is observed in people of other 
ethnic origins.55, 56, 70-73 These participants represent a clinically relevant population for 
pharmacotherapeutic weight management as they are at significant risk for weight-related 
morbidities and mortality and are likely to benefit from weight reduction.  
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First line treatment in weight management should always be lifestyle modification through a 
reduced calorie diet and increased physical activity. Thus, only participants who have tried but 
failed a dietary weight loss intervention will be included in accordance with regulatory and clinical 
guidelines. 
2.3 
Benefit-risk assessment 
The main benefits and risks related to participation in the study are described in the below sections. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of semaglutide may be found in the investigator’s brochure.69 
2.3.1 
Risk assessment 
Table 2-1 
Risk assessment 
Potential risk of clinical 
significance 
 
 
Summary of data/rationale for risk 
 
 
Mitigation strategy 
 
Study intervention (semaglutide 2.4 mg) 
Gastrointestinal adverse 
events 
Consistent with findings with other GLP-1 RAs, 
the most frequently reported AEs in clinical 
studies with semaglutide were gastrointestinal 
AEs (such as nausea, vomiting and diarrhoea). In 
general, these reactions are mild or moderate in 
severity, of short duration, and dose-dependent.   
 
In participants treated with GLP-1 RAs, nausea, 
vomiting and diarrhoea may lead to significant 
dehydration. This should be considered when 
treating participants with impaired renal function 
as it may cause a deterioration of renal function.  
Clinical studies have shown that a 
low starting dose and gradual dose 
escalation mitigates the risk of 
developing gastrointestinal 
symptoms. 
Participants with GI symptoms are 
recommended to drink plenty of 
fluids to avoid volume depletion. 
Cholelithiasis 
Events of cholelithiasis were the most frequently 
reported gallbladder events in the clinical 
development programme for semaglutide 2.4 mg 
for weight management.  
In the phase 3a studies cholelithiasis was 
reported in 1.6% and led to cholecystitis in 0.6% 
of participants treated with semaglutide 2.4 mg. 
If cholelithiasis is suspected, 
appropriate clinical follow-up is to 
be initiated at the investigator’s 
discretion. 
Acute pancreatitis 
 
 
 
Acute pancreatitis has been observed with the 
use of GLP-1 RA drug class. 
The frequency of adjudication-confirmed acute 
pancreatitis reported in phase 3a clinical studies 
was 0.2% for semaglutide 2.4 mg and <0.1% for 
placebo, respectively. 
Participants should be informed of 
the characteristic symptoms of acute 
pancreatitis and if pancreatitis is 
suspected, semaglutide should be 
discontinued. If confirmed, 
semaglutide should not be restarted. 
Medullary thyroid cancer 
(MTC) (based on non-
clinical data) 
Thyroid C-cell tumours were seen in the mouse 
and rat carcinogenicity studies after daily 
exposure to semaglutide for 2 years. The rodent 
C-cell tumours are caused by a non-genotoxic, 
specific GLP-1 receptor mediated mechanism to 
which rodents are particularly sensitive. No 
hyperplasia was observed in monkeys after 
52 weeks exposure up to 13-fold above the 
clinical plasma exposure at 2.4 mg/week.  
The GLP-1 receptor is not expressed in the 
normal human thyroid, and therefore the clinical 
relevance of the findings is considered to be low. 
To mitigate this risk, participants 
with a family or personal history of 
medullary thyroid carcinoma or 
multiple endocrine neoplasia type 2 
(MEN2) are excluded from clinical 
studies with semaglutide. 
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Pancreatic cancer  
There is currently no support from non-clinical 
studies, clinical studies, or post-marketing data 
that GLP-1 RA-based therapies increase the risk 
of pancreatic cancer.  However, pancreatic 
cancer has been classified as a potential class 
risk for all marketed GLP-1 RAs by regulatory 
agencies.  
Participants with a history of 
malignant neoplasms within the past 
5 years prior to screening will be 
excluded from the study.  
Neoplasms (malignant 
and non-malignant)
 
 
 
People with overweight or obesity as well as 
people with T2D, have an increased risk of 
certain types of cancer.  
There is no evidence from clinical trials that 
GLP-1-based therapies increase the risk of 
neoplasms.  
No imbalance was observed in the semaglutide 
2.4 mg for weight management phase 3a trials 
with regards to the proportions of participants 
with neoplasms (malignant and non-malignant).  
However, in the semaglutide s.c. as well as oral 
semaglutide phase 3a trials for T2D, the 
proportion of participants with neoplasms 
(malignant and non-malignant) were slightly 
higher with semaglutide than with comparator. 
The number of participants exposed to 
semaglutide s.c. or oral semaglutide for a longer 
period is considered insufficient for a thorough 
assessment of the risk of neoplasms.  
Participants with a history of 
malignant neoplasms within the past 
5 years prior to screening will not be 
enrolled in this study. Basal 
and squamous cell skin cancer and 
any carcinoma in situ is allowed. 
Allergic reactions 
As is the case with all protein-based 
pharmaceuticals, treatment with semaglutide 
may evoke allergic reactions, including serious 
allergic reactions such as angioedema and 
anaphylactic reactions.   
As a precaution, participants with 
known or suspected hypersensitivity 
to semaglutide or related products 
will not be enrolled in this study. In 
addition, participants will be 
instructed to contact the site staff as 
soon as possible for further guidance 
if suspicion of a hypersensitivity 
reaction to the study product occurs. 
Risk of COVID-19 
infection in relation to 
study intervention 
Available data does not suggest an increased risk 
of infection or a more severe progression of 
infection when treated with s.c. semaglutide. 
Detailed information about the 
known risks for s.c. semaglutide can 
be found in the investigator’s 
brochure and summary of product 
characteristics.  
Study procedures 
Venous laboratory 
samples drawn at 
screening and selected 
visits may be associated 
with slight discomfort 
and complicated by 
bruising in the region.  
 
 
Risk of COVID-19 
infection in relation to 
study participation 
Participants may be exposed to the risk of 
COVID-19 transmission and infection in relation 
to site visits if an outbreak is ongoing in the 
given country. 
To minimize the risk as much as 
possible, local guidelines must be 
followed. 
Other 
Pregnancy and fertility 
(based on non-clinical 
data) 
Studies in animals have shown reproductive 
toxicity. There is limited data from the use of 
semaglutide in pregnant women. 
Semaglutide should not be used 
during pregnancy.  
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Women of childbearing potential are 
required to use highly effective 
contraceptive methods when 
participating in this study 
(Appendix 4, Table 10-2). If a 
participant wishes to become 
pregnant, or pregnancy occurs, 
semaglutide should be discontinued 
(please refer to protocol Section 7 
for further guidance).  
The effect of semaglutide on fertility 
in humans is unknown.  
 
Risk assessment has been conducted for PDS290 for semaglutide 2.4 mg in compliance with ISO 
14971: 2019. A study-specific device risk assessment has been performed to ensure safe and 
accurate handling and dosing of semaglutide 2.4 mg when using PDS290 in participants with 
overweight and obesity. 
All identified risks (see Table 2-1) associated with using PDS290 for semaglutide 2.4 mg according 
to the clinical procedures specified in this protocol have been reduced as far as possible and are 
acceptable, taking into account the current state of the art. The use of PDS290 for 
semaglutide 2.4 mg 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 68-week phase 3a weight 
management studies, STEP 1 (NN9536-4373) and STEP 2 (NN9536-4374), have demonstrated 
clinically significant weight loss with semaglutide s.c. 2.4 mg once weekly. In both studies, 
semaglutide s.c. 2.4 mg once weekly appeared to have a safe and well-tolerated profile, consistent 
with previous findings. 
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 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 safety profile for 
semaglutide generated from the clinical and non-clinical development programme has not revealed 
any safety issues that would prohibit administration of semaglutide s.c. 2.4 mg once-weekly. The 
results of the phase 3a studies (NN9536-4373, NN9536-4374, NN9536-4375 and NN9536-4376) 
indicate that semaglutide will provide a clinically meaningful weight loss. The anticipated benefits 
from diet and physical activity counselling will include all participants participating in this study. 
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Taking into account the measures taken to minimise risk to participants participating in this study, 
the potential risks identified in association with semaglutide s.c. 2.4 mg once-weekly 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 IB69 and any updates hereof. 
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3 
Objectives, endpoints and estimands 
The study endpoints are listed in Table 3-1 by their association to the objectives.  
Table 3-1 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
 To demonstrate the superiority 
of semaglutide s.c. 2.4 mg 
once weekly versus placebo as 
an adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI ≥ 
25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand on: 
 Body weight 
 ≥5% weight reduction 
Co-primary: 
Change in body weight 
From baseline (week 0) to end 
of treatment (week 44) 
% 
≥5% body weight reduction 
(yes/no) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant  
Confirmatory secondary: 
≥10% body weight reduction 
(yes/no)  
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
 ≥15% body weight reduction 
(yes/no) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in waist circumference 
From baseline (week 0) to end 
of treatment (week 44) 
cm 
Supportive secondary:  
≥20% body weight reduction 
(yes/no)  
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in body weight 
From baseline (week 0) to end 
of treatment (week 44) 
kg 
Change in body mass index 
From baseline (week 0) to end 
of treatment (week 44) 
kg/m2 
Secondary 
Title 
Time frame 
Unit 
 To compare the efficacy of 
semaglutide s.c. 2.4 mg once 
weekly versus placebo, as an 
adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI 
≥ 25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand, on 
cardiovascular risk factors  
Supportive secondary: 
Change in systolic blood 
pressure 
From baseline (week 0) to end 
of treatment (week 44) 
mmHg 
Change in diastolic blood 
pressure 
From baseline (week 0) to end 
of treatment (week 44) 
mmHg 
Change in total cholesterol 
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in high-density 
lipoprotein (HDL) cholesterol  
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in low-density 
lipoprotein (LDL) cholesterol  
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in triglycerides 
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in high-sensitivity 
c-reactive protein (hsCRP) 
From baseline (week 0) to end 
of treatment (week 44) 
mg/L 
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Objectives 
Endpoints 
Exploratory: 
Change in use of 
antihypertensive medication 
(decrease/no change/increase) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in use of lipid-lowering 
medication (decrease/no 
change/increase) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
 To compare the efficacy of 
semaglutide s.c. 2.4 mg once 
weekly versus placebo, as an 
adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI 
≥ 25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand, on 
glucose metabolism 
Supportive: 
Change in HbA1c 
From baseline (week 0) to end 
of treatment (week 44) 
% and 
mmol/mol 
Exploratory:  
Shift in glycaemic status 
(normo-glycaemic/pre-
diabetes/T2D) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
End of treatment (week 44) corresponds to end of study intervention. 
Co-primary estimands 
The primary clinical question of interest is: What is the treatment effect of semaglutide s.c. 2.4 mg 
once weekly as an adjunct to a reduced-calorie diet and increased physical activity in participants 
with obesity defined according to local guidelines in Republic of Korea and Thailand, measured by 
relative change from baseline (week 0) to week 44 in body weight and ≥ 5% body weight reduction 
at week 44, 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: People of Asian descent with obesity defined as BMI ≥ 25.0 kg/m2.   
Endpoint: 1) relative change from baseline to week 44 in body weight and 2) ≥ 5% body weight 
reduction at week 44. 
Treatment condition: the randomised treatment regardless of discontinuation or dose reduction of 
randomised trial product, and regardless of initiating other anti-obesity therapies (as defined above) 
 
Remaining intercurrent events: none, all intercurrent events (discontinuation or dose reduction of 
randomised trial product 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  
 
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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 estimand 
The secondary estimands for both the confirmatory secondary and supportive secondary endpoints 
are similar to the co-primary estimands except for the endpoint attribute. For continuous endpoints, 
the secondary estimands for primary and secondary objectives are similar to the co-primary 
estimand for % weight change. For binary endpoints, the secondary estimands for primary and 
secondary objectives are similar to the co-primary estimand for ≥ 5% body weight reduction.   
Additional estimand 
An additional clinical question of interest for the primary objective is: what is the treatment effect 
of semaglutide s.c. 2.4 mg once weekly as an adjunct to a reduced-calorie diet and increased 
physical activity in participants with obesity defined according to local guidelines in Republic of 
Korea and Thailand, measured by relative change from baseline (week 0) to week 44 in body 
weight and ≥ 5% body weight reduction at week 44, had they remained on their randomised 
treatment 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:  People of Asian descent with obesity defined as BMI ≥ 25.0 kg/m2 
Endpoint: 1) relative change from baseline to week 44 in body weight and 2) ≥ 5% body weight 
reduction at week 44. 
Treatment condition: the randomised treatment if participants had adhered to the randomised trial 
product (regardless of dose reduction) for the entire duration of the study and not initiated any other 
anti-obesity therapies (as defined above). Further details on study interventions and concomitant 
medication can be found in Section 6.  
 
Remaining intercurrent events: none, all intercurrent events (discontinuation or initiation of other 
anti-obesity therapies and dose reduction) are captured by the treatment condition attribute. 
Discontinuation or initiation of other anti-obesity therapies are handled by the hypothetical strategy. 
Dose reduction of randomised trial product 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 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 endpoints 
addressing the primary objective in the population. 
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4 
Study design 
4.1 
Overall design 
This is an interventional, multi-national, multi-centre, randomised, double-blind, placebo-
controlled, two-armed, parallel group clinical study.   
Approximately 150 eligible participants will be randomised in a 2:1 manner to receive either 
semaglutide s.c. 2.4 mg once weekly or placebo once weekly as an adjunct to a reduced-calorie diet 
and increased physical activity. The study population is participants of Asian descent with obesity, 
diagnosed according to local guidelines in Republic of Korea and Thailand. 
The study consists of: 
 a 1-week screening period 
 a 16-week dose escalation period 
 a 28-week maintenance period 
 a 5-week follow-up period 
The duration of the study intervention is 44 weeks with an additional 5 weeks follow-up (without 
trial product) (Figure 4-1).   
Figure 4-1 
Study design 
 
Note: ‘end of study intervention’ (week 44) corresponds to both end of IMP treatment and end of lifestyle intervention.  
4.2 
Scientific rationale for study design 
A 44-week study intervention duration (including 28 weeks on target dose) is considered sufficient 
to assess weight loss, safety, and tolerability. Results from STEP 1 has shown clinically significant 
weight loss with semaglutide s.c. 2.4 mg once weekly, already at 44 weeks.74 The 5-week follow-up 
period is included to account for the exposure and long half-life of semaglutide.  
A randomised, double-blind, placebo-controlled, multi-centre study design is chosen to minimise 
bias in the assessment of the efficacy and safety of semaglutide 2.4 mg once weekly versus placebo, 
as an adjunct to a reduced-calorie diet and increased physical activity. 
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The BMI inclusion criterion of ≥ 25.0 kg/m2 is selected because it aligns with the recommended 
guidelines for the diagnosis and management of obesity in Republic of Korea59 and the local 
practices in Thailand75. These Asian-specific BMI cut-offs for the diagnosis of obesity reflect 
recommendations from the WHO Western Pacific Region and evidence indicating that Asian 
individuals experience co-morbidities relating to obesity at a lower BMI compared to people of 
other ethnic origins.55, 56, 70-73  
4.3 
Justification for dose 
Results from the phase 2 dose-finding study (NN9536-4153) showed that the semaglutide 0.4 mg 
once-daily dose was most effective in terms of weight loss while displaying an acceptable 
tolerability profile. Using population PK modelling, it was estimated that a once-weekly 
maintenance dose of 2.4 mg semaglutide will result in similar Cmax at steady state as that obtained 
by the once-daily 0.4 mg semaglutide dose in study NN9536-4153. 
A maintenance dose of semaglutide s.c. 2.4 mg once weekly has been chosen for the phase 3 weight 
management development programme. The 68-week phase 3a weight management studies, STEP 1 
(NN9536-4373) and STEP 2 (NN9536-4374), have demonstrated clinically significant weight loss 
with semaglutide s.c. 2.4 mg once weekly. In STEP 1, 1,961 participants with overweight or obesity 
were included. At week 68, participants in the semaglutide s.c. 2.4 mg once-weekly group achieved 
an average weight loss of 14.85% compared to 2.41% in the placebo group. In STEP 2, 
1,210 participants with overweight or obesity and T2D were included. At week 68, participants in 
the semaglutide s.c. 2.4 mg once-weekly group achieved an average weight loss of 9.6% compared 
to 3.4% in the placebo group. In both studies, semaglutide s.c. 2.4 mg once weekly appeared to 
have a safe and well-tolerated profile, consistent with previous findings. A maintenance dose of 
semaglutide s.c. 2.4 mg once weekly in the Asian population is supported by the results from 
STEP 6 (NN9536-4382) with East Asian participants. With a mean baseline body weight of 
87.5 kg, 86.9% of participants who were assigned semaglutide s.c. 2.4 mg, tolerated 2.4 mg at 
52 weeks.   
It is well known that to mitigate gastrointestinal side effects with GLP-1 RA treatment, dose 
escalation to the target dose is required. Based on experience from the semaglutide T2D 
development programme, a fixed-dose escalation regimen is selected, with dose escalation every 
4 weeks until the target dose is reached. 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), until the target dose is reached after 16 weeks. 
Please refer to Section 6.1 for more details on trial product doses. See Section 6.5 for dose 
modification.  
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). 
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The primary endpoint is evaluated at visit 17 (week 44). The primary completion date (PCD) is 
defined as the date of visit 17 (week 44) 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 17.  
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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 participant 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. BMI1 ≥ 25.0 kg/m2 at screening. 
5. Both parents of Asian descent.a 
6. History of at least one self-reported unsuccessful dietary effort to lose body weight.a 
1BMI as calculated in the eCRF  
For country-specific requirements, see Section 10.7. 
5.2 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening. 
2. History of type 1 or type 2 diabetes mellitus. 
3. Treatment with glucose-lowering agent(s) within 90 days before screening. 
4. Vaccination with approved COVID-19 vaccine within 30 days before screening.  
5. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
6. Treatment with any medication for the indication of obesity within the past 90 days before 
screening. 
7. Any participant where a substantial weight loss, in the investigator’s opinion, might jeopardise 
the participant’s safety. 
8. Uncontrolled thyroid disease as per investigator’s discretion. 
9. History of major depressive disorder within 2 years prior to screening.a 
10. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder).a 
11. Previous or planned (during the study period) obesity treatment with surgery or a weight loss 
device. However, the following are allowed:  
a. Liposuction and/or abdominoplasty, if performed > 1 year before screening 
b. Adjustable gastric banding if the band has been removed > 1 year before screening 
c. Intragastric balloon if the balloon has been removed > 1 year before screening 
d. Duodenal-jejunal bypass liner (e.g. Endobarrier), if the liner has been removed > 1 year 
before screening. 
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12. History or presence of chronic pancreatitis.a  
13. Presence of acute pancreatitis within 180 days prior to screening.a 
14. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma.a 
15. Renal impairment with estimated Glomerular Filtration Rate (eGFR) < 15 mL/min/1.73 m2 at 
screening. 
16. Presence or history of malignant neoplasms (other than basal and squamous cell skin cancer, in 
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years before screening.a 
17. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 60 days prior to the day of screening. 
18. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
19. Surgery scheduled for the duration of the study, except for minor surgical procedures, in the 
opinion of the investigator. 
20. Known or suspected abuse of alcohol or recreational drugs. 
21. Use of any medication with unknown or unspecified content within 90 days before screening. 
22. Known or suspected hypersensitivity to study intervention(s) or related products. 
23. Previous participation in this study. Participation is defined as signed informed consent. 
24. 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). 
25. Participation (i.e., signed informed consent) in any interventional, clinical study within 90 days 
before screening. 
26. Other individual(s) from the same household participating in any semaglutide study. 
27. Any disorder which in the investigator’s opinion might jeopardise participant’s safety or 
compliance with the protocol. 
a As declared by the participant or reported in the medical records. 
5.3 
Lifestyle considerations 
To ensure alignment of performance of assessments across participants and study sites, the below 
restrictions apply.  
5.3.1 
Meals and dietary restrictions 
Not Applicable 
5.3.2 
Caffeine, alcohol, and tobacco 
Participants should avoid caffeine and tobacco use at least 30 minutes prior to measuring the blood 
pressure. 
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
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 
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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 session must be made in the randomisation and trial supplies management system 
(RTSM). 
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 samples), re-sampling is allowed for the affected parameter(s). 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
Not applicable for this study. 
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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 medical 
devices. 
6.1 
Study intervention(s) administered 
Table 6-1 provides an overview of the study interventions. 
Table 6-1 
Study interventions 
Intervention/Arm name 
Semaglutide  
Placebo 
Any other interventions 
Intervention name 
 
Semaglutide B 
 
Placebo 
 
Diet and physical activity 
counselling 
Intervention type 
IMP 
IMP, reference therapy 
Background intervention 
Pharmaceutical form 
Solution for injection 
Solution for injection 
 
Route of administration  
Subcutaneous 
Subcutaneous 
 
Trial product strength 
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 
 
Dosing instructions and 
administration  
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. 
 
Packaging and labelling 
 Labelled and packaged 
by Novo Nordisk A/S 
 Labelled in accordance 
with Annex 13,76 local 
regulations and study 
requirements 
 IMP is provided in a 
PDS290 pen-injector 
(device constituent of 
non-approved drug-
device combination 
product76) (see 
Table 6-2).  
 Labelled and packaged 
by Novo Nordisk A/S 
 Labelled in accordance 
with Annex 13,76 local 
regulations and study 
requirements 
 IMP is provided in a 
PDS290 pen-injector 
(see Table 6-2).  
 
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The investigator must document that directions for use was given to the participant verbally and in 
writing as a direction 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.  
Table 6-2 
Investigational medicinal products 
Trial product name 
Dose 
Volume  
Value shown 
in dose 
counter* 
Duration 
 
Dose escalation period 
Semaglutide  0.68 mg/mL or 
placebo, PDS290 
0.25 mg 
0.37 mL 
37* 
4 weeks 
Semaglutide  1.34 mg/mL or 
placebo, PDS290  
0.5 mg 
0.37 mL 
37* 
4 weeks 
Semaglutide  1.34 mg/mL or 
placebo, PDS290  
1.0 mg 
0.75 mL 
75* 
4 weeks 
Semaglutide  2.27 mg/mL or 
placebo, PDS290  
1.7 mg 
0.75 mL 
75* 
4 weeks 
 
Maintenance period 
Semaglutide  3.2 mg/mL or placebo, 
PDS290  
2.4 mg 
0.75 mL  
75* 
28 weeks 
* Conversion to dose is calculated based on 0.01 mL/value for all strengths of semaglutide. 
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), until the target dose is reached after 16 weeks (Table 6-2). All participants should 
aim at reaching the recommended target dose of semaglutide 2.4 mg once weekly, or placebo. 
 If a participant does not tolerate the recommended target dose of 2.4 mg once weekly, the 
participant may stay at a lower dose level. 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 to the recommended target dose of 2.4 mg once weekly, as per the 
investigator’s discretion. 
 It is recommended that the investigator consults Novo Nordisk in case of persistent deviations 
from the planned escalation regimen.  
 A dose reminder card will be handed out to the participants at each site visit during the 
escalation period. Once the target dose has been reached, the dose reminder card is only handed 
out as needed. 
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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 re-
commence the trial product if considered safe as per the 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. 
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 healthcare 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 1.3.77 
TEE = BMR x 1.3 
Table 6-3 
Equation for estimated BMR 
Sex 
Age  
BMR (kcal/day) 
Men 
18–30 years 
31–60 years 
> 60 years 
15.057 × weight at randomisation in kg + 692.2 
11.472 × weight at randomisation in kg + 873.1 
11.711 × weight at randomisation in kg + 587.7 
Women 
18–30 years 
31–60 years 
> 60 years 
14.818 × weight at randomisation in kg + 486.6 
8.126 × weight at randomisation in kg + 845.6 
9.082 × weight at randomisation in kg + 658.5 
 
Dose adjustment 
If a participant with a  BMI1 within the lower normal range continues to lose weight, and there is a 
health concern, the investigator must consider reducing the dose of IMP. The investigator can 
contact Novo Nordisk for guidance. If the participant reaches a BMI1<18.5 kg/m2, the dose of IMP 
must be reduced and Novo Nordisk should be contacted for guidance. 
1BMI as calculated in the eCRF  
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Auxiliary supplies including medical device(s) not under investigation 
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 
Information about the PDS290 pen-injector may be found in the IB69 and any updates hereof. 
Information about the use of the drug-device combination products can be found in the DFU. 
Training in the PDS290 pen-injector 
Site staff will train participants according to the flowchart (Section 1.2). Novo Nordisk will train the 
site staff and only trained site staff can be allocated the task to train and supervise participants. All 
training must be documented. 
The following should be emphasised during training of participants: 
 use of the pen-injector (according to instruction guidelines given in the DFU) 
 long-term and in-use storage conditions of the pen-injector (as specified on the label and in the 
TMM). 
The investigator must document that directions for use are given to the participant verbally and in 
writing as a DFU document at the first dispensing visit (as specified in the flowchart [Section 1.2]) 
and that participants are trained. Training must be repeated as specified in the flowchart and, if 
needed, during the study at regular intervals in order to ensure correct use of the pen-injector and 
correct injection technique. Training is the responsibility of the investigator or a delegate. 
The first dose of trial product must be taken on the day of randomisation (visit 2) at the clinical site 
by self-administration under supervision by trained site staff.  
6.2 
Preparation, handling, storage and accountability 
Only participants enrolled in the study may use study intervention and only delegated site staff may 
supply or administer study intervention. 
Each site will be supplied with sufficient trial product for the study on an ongoing basis according 
to recruitment and randomisation. 
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product from the study site or pharmacy to the participant’s home by courier service. The process 
for sending trial product 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 
trial product, handover of trial product from the study site or pharmacy staff to the courier, required 
Auxiliary supply 
Details 
Direction for use (DFU) 
DFU for PDS290 pre-filled pen-injector.  
Not included in the dispensing unit and to be handed out separately.  
Needles 
Needles for pre-filled pen system. Details provided in the TMM. 
Only needles approved and provided by Novo Nordisk and with a maximum length of 
6 mm must be used for administration of trial product. 
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temperature monitoring of trial product, delivery to and receipt of trial product by the participant. 
The process for returning trial product 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 trial product 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. 
The investigator or designee must instruct the participant in what to return at next visit (see 
flowchart Section 1.2). The participant must return all used and unused trial product including 
empty packaging materials during the study as instructed by the investigator. Additional details 
regarding handling of drug accountability can be found in the Trial Materials Manual (TMM). 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. 
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. 
6.3 
Measures to minimise bias: Randomisation and blinding 
All participants will be screened and centrally randomised using the RTSM and assigned to the next 
available trial product according to the randomisation schedule. Trial product will be allocated by 
the RTSM 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. 
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The RTSM is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a participant’s study intervention 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, sign and date the document. If RTSM is 
not accessible at the time of blind break, the RTSM 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 
Trial product 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. 
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 information 
about missed doses, if any, and current treatment dose at every visit. Information on treatment dose 
and periods > 14 days without treatment 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.  
Trial product start and stop dates will be recorded in the CRF. 
6.5 
Dose modification 
Not applicable for this study. Please refer to Section 6.1 for description of missed dose(s) and for 
recommended action if participants’ BMI falls into the normal range. 
6.6 
Continued access to study intervention after end of study 
There is no intervention 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. 
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6.7 
Treatment of overdose 
Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in clinical 
studies. The most commonly reported AE was nausea. All participants recovered without 
complications. 
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to 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. 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 semaglutide investigator’s 
brochure (IB).69 
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 (unit) and dosing frequency 
 Primary indication  
 Dates of administration including start and stop dates 
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. 
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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 18) is scheduled approximately 5 weeks after end of study intervention 
to ensure the safety of the participant. If the participant has discontinued trial product > 5 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 trial product must be discontinued, if any of the following applies for the participant: 
1. Safety concern as judged by the investigator 
2. Suspicion of pancreatitis 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical study 
If acute pancreatitis is suspected, appropriate actions should be initiated, including local 
measurements of amylase and lipase (see Appendix 3 [Section 10.3.3] for reporting). 
Participants meeting trial product discontinuation criterion no. 2 are allowed to resume trial product 
at the investigator’s discretion if the Atlanta criteria78 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.  
Participants meeting trial product discontinuation criteria no. 1, 3 and 4 are allowed to resume trial 
product, if the criteria are no longer met (Section 7.1.1).  
See the flowchart for data to be collected at the time of trial product discontinuation (early 
discontinuation visit) and follow-up and for any further evaluations that need to be completed. 
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The primary reason for discontinuation of trial product must be specified in the CRF, and final trial 
product accountability must be performed. A treatment discontinuation must be made in the RTSM. 
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 6.1). 
In such cases a treatment discontinuation should not be made in the RTSM. 
If a treatment discontinuation previously has been made in RTSM to indicate discontinuation of 
trial product, a 'resume treatment' must be made to resume trial product.  
In case of suspicion of acute pancreatitis, the trial product should promptly be discontinued; 
however, treatment discontinuation should not be made in RTSM before diagnosis of acute 
pancreatitis is confirmed. If acute pancreatitis is confirmed, treatment with trial product should not 
be restarted, and a treatment discontinuation should be made in RTSM. 
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 17 (end of treatment). 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. A treatment discontinuation must be made in the RTSM. 
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. 
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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 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’. 
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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. 
The investigator will maintain a screening log to record details of all participants screened and 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 laboratory reports must be documented in the source documents or the participant’s 
medical record. If clarification of entries or discrepancies in the PK diary 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. Vital signs (see Section 8.2.2) and body measurements (see Section 8.1.1) 
2. Blood samples 
3. 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 
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 8.4.1 
for a description of the data to be entered in the PK diary.  
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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 
subjects who are unable or unwilling to comply with protocol procedures as per the exclusion 
criteria. In addition, the interview will ensure that any minor barriers are addressed during lifestyle 
counselling. The results of the interview will not be entered into the CRF. It will be at the 
investigator’s discretion to evaluate the motivation of the participant and related eligibility. 
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) using the same scale throughout the study. The scale must be calibrated 
according to manufacturer’s recommendation or local requirements – the strictest requirement must 
be followed. 
Height is measured without shoes in centimetres or inches (one decimal). 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. 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. 
8.1.2 
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. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
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. Findings of specific medical history should de described in designated forms.  
As part of the medical history, information related to history of gallbladder disease, breast 
neoplasm, colon neoplasm, skin cancer, and psychiatric disorder will be recorded. Information on 
weight related co-morbidities will be collected as part of medical history at screening (visit 1) and 
an evaluation will be done at the end of study intervention (visit 17). Follow-up questions related to 
the breast neoplasm and colon neoplasm will be asked at the end of study visit. 
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As part of the medical history, information on the following will be collected: 
 Weight-related comorbidities  
 Weight history (incl. previous weight, debut time of overweight, previous weight loss attempts, 
previous use of prescription medication for obesity, considerations regarding bariatric surgery, 
and family history of overweight/obesity) 
 History of weight disorder 
 History of breast neoplasm 
 History of cardiovascular disorder and procedure 
 History of gallbladder disease and procedure 
 History of gastrointestinal disorder and neoplasm 
 History of pancreatic disease 
 History of psychiatric disorder 
 History of skin cancer and skin disorder 
 Other relevant concomitant illness/medical history (also including COVID-19 illness, and 
including malignant neoplasms not covered by the above categories) 
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. 
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).  
8.2.1 
Physical examinations 
A physical examination will include assessments of the cardiovascular, respiratory, gastrointestinal, 
neurological system and skin. 
A physical examination will include assessments of: 
 general appearance  
 skin 
 head, ears, eyes, nose, throat, and neck  
 thyroid gland  
 cardiovascular and respiratory systems  
 abdomen  
 musculoskeletal system  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
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8.2.2 
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 (diastolic and systolic) 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 visit 1 (screening), visit 2 (week 0), visit week 4 
(week 4), visit 8 (week 12), visit 11 (week 20), visit 13 (week 28), visit 15 (week 36) and visit 17 
(week 44, end of treatment). 
8.2.3 
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. 
8.2.4 
Pregnancy testing  
Urine pregnancy tests provided by central laboratory must be performed for women of childbearing 
potential at screening and as specified in the flowchart.   
Woman of childbearing potential (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.  
Additional pregnancy testing should be performed during the treatment period, if required locally, 
refer to Appendix 7 (Section 10.7). 
8.2.5 
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 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. 
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Bariatric surgery – including bariatric gastric balloon insertion/removal, duodenal-jejunal bypass 
sleeve therapy, endoscopic sleeve gastroplasty, gastric binding (includes laparoscopic adjustable 
gastric band), gastric band repositioning, gastric band reversal, gastric bypass, gastric bypass 
reversal or duodenal switch. 
Knee surgery – including baker’s cyst excision, joint debridement, revision arthroplasty, partial 
knee replacement or total knee 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.  
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 error  
X 
Misuse and abuse 
X 
Acute pancreatitis 
X 
Acute gallbladder disease 
X 
Hepatic event 
X 
Malignant neoplasm 
X 
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 
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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 
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 visit. For details regarding collection and reporting of pregnancy information, 
please refer to Appendix 4 (Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
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). 
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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).  
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 the study.  Participant confidentiality will be 
maintained.  
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 
Not applicable for this study.  
8.6 
Biomarkers 
Not applicable for this study.  
8.7 
Immunogenicity assessments 
Not applicable for this study.  
8.8 
Health economics 
Not applicable for this study. 
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9 
Statistical considerations 
The statistical analysis plan (SAP) will be finalised prior to database lock, 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 endpoints including primary 
and confirmatory secondary endpoints. 
9.1 
Statistical hypotheses 
The tests of superiority of semaglutide s.c. 2.4 mg once weekly to placebo for the two primary and 
all confirmatory secondary endpoints are performed using a fixed-sequence statistical strategy and 
will be based only on analyses addressing the primary estimand. This strategy tests the endpoints 
using a predefined hierarchical order, all at the significance level of 5%, moving to test the next 
endpoint only after a statistically significant superiority result (p-value < 5%) on the previous 
endpoint. 
For the co-primary estimands with the primary endpoints, 1) change in body weight (%) from 
baseline to end of treatment (week 44) and 2) ≥ 5% body weight reduction (yes/no) from baseline 
(week 0) to end of treatment (week 44), the following confirmatory 1-sided hypotheses are planned 
to be tested for semaglutide s.c. 2.4 mg once weekly versus placebo. Let the mean difference in 1) 
be defined as: 
μ1 = ([semaglutide s.c. 2.4 mg] minus [placebo]) 
and let the odds ratio of 2) be defined as: 
OR = (odds[semaglutide s.c. 2.4 mg] divided by odds[placebo]) 
Superiority 
1) H01 : μ1 ≥ 0.0 percentage points against Ha1 : μ1 < 0.0 percentage points. 
and 
2) H02 : OR ≤ 1 against Ha2 : OR > 1 
Operationally, the hypotheses will be evaluated by 2-sided tests. 
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. For 
example, the second null hypothesis will only be tested if the first null hypothesis has been rejected 
in favour of semaglutide s.c. 2.4 mg. 
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The steps in the hierarchical testing procedure are as follows: 
 Step 1: change in body weight (%) from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
and 
≥ 5% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
 Step 2: ≥ 10% body weight reduction (yes/no) from baseline (week 0) to end of treatment 
(week 44) superiority of semaglutide s.c. 2.4 mg versus placebo 
 Step 3: ≥ 15% body weight reduction (yes/no) from baseline (week 0) to end of treatment 
(week 44) superiority of semaglutide s.c. 2.4 mg versus placebo 
 Step 4: Change in waist circumference from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
9.2 
Analysis sets 
For the purposes of analysis, the following analysis sets (Table 9-1) and observation periods 
(Table 9-2) are defined: 
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Table 9-1 
Analysis sets 
Participant Analysis Set Description 
Full analysis set (FAS) 
All randomised participants. Participants will be included in the analyses according to the 
randomised intervention. 
Safety analysis set (SAS) 
All participants who are exposed to at least one dose of randomised IMP. Participants will 
be included in the analyses according to the intervention they actually received. 
Table 9-2 
Defined data point sets 
Defined data point sets (DPS) 
Description 
In-trial (DPS1) 
The time period where the participant is assessed in the study. The in-trial 
observation period for a participant begins on the date of randomisation and ends 
at the first of the following dates (both inclusive): 
 ‘End of study’ visit 
 withdrawal of consent 
 last contact with participant (for participants lost to follow-up) 
 death 
On-treatment (DPS2) 
The time period where participants are treated with trial product. A time-point is 
considered as “on-treatment” if any dose of trial product has been administered 
within the prior 2 weeks (14 days). The participant is considered “on-treatment” 
regardless of dose reduction. The on-treatment period is defined as all times 
which are considered on-treatment. In general, the on-treatment period will 
therefore be from the date of first trial product administration to date of last trial 
product administration excluding potential off-treatment time intervals triggered 
by at least two consecutive missed doses. 
For the evaluation of AEs and potential pregnancies, the lag time for each on-
treatment time interval is 5 weeks (35 days). 
On-treatment until first 
discontinuation of trial product 
or initiation of other anti-obesity 
therapies (DPS3) 
The time period where participants are treated with trial product. A time-point is 
considered as “on-treatment” if any dose of trial product has been administered 
within the prior 2 weeks (14 days). The participant is considered “on-treatment” 
regardless of dose reduction. Observations after the first discontinuation of trial 
product or initiation of other anti-obesity therapies will not be included.  
FAS and DPS1 are used to estimate the co-primary estimands and the secondary estimands for the 
primary and secondary objectives. 
FAS and DPS3 are used to estimate the additional estimand for the primary objective and secondary 
objectives.  
SAS and either DPS1 or DPS2 are used to present safety data.  
The in-trial (DPS1) and on-treatment (DPS2) periods define the patient years of observation (PYO) 
and patient years of exposure (PYE), respectively, as the total time duration in the periods. 
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided.  
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9.3 
Statistical analyses 
9.3.1 
General considerations 
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all participants is used as 
the baseline value. 
All tests are tests of superiority of semaglutide s.c. 2.4 mg once weekly to placebo. All estimated 
treatment contrasts between semaglutide s.c. 2.4 mg and placebo 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:  
 Change in body weight (%) from baseline (week 0) to end of treatment (week 44) 
 ≥ 5% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
The two primary analyses are aligned with the two co-primary estimands defined in Section 3. 
The analysis model for change in body weight (%) will be a linear regression (ANCOVA) with 
randomised study intervention as factor and baseline body weight (kg) as covariate.  
The analysis model for the 5% responder endpoint is a logistic regression using randomised study 
intervention as factor and baseline body weight (kg) as covariate.  
All available data at week 44 are used and missing values at week 44 will be imputed and the 
endpoint will be derived from the imputed values. The imputation approach for the primary analysis 
is a multiple imputation similar to the one described by McEvoy et al.79. For participants in the 
semaglutide s.c. 2.4 mg once weekly and the placebo groups, missing measurements at week 44 for 
non-retrieved participants are imputed using assessments from retrieved participants in each 
intervention group. The timing of last available observation during the on-treatment period (LAO-
OT) will be included in the imputation model as a continuous covariate. Missing measurements at 
week 44 for participants on randomised study intervention (at week 44) are imputed by sampling 
from available measurements at week 44 from participants on randomised study intervention in the 
relevant randomised intervention group. Details of the multiple imputation approach are provided in 
the SAP.  
Sensitivity analyses 
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at 
week 44 for both the semaglutide 2.4 mg and placebo group are imputed by sampling among all 
available assessments at week 44 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. Details of the multiple imputation approach are provided in the SAP.  
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Second, for the semaglutide 2.4 mg treatment arm a 
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penalty will be added to the imputed values at week 44. The approach is to gradually increase this 
penalty until all confirmed conclusions from the primary analysis are reversed. For each hypothesis 
tested the specific value of the penalty that reverses the conclusion will be used to evaluate the 
robustness of the primary analysis results. This sensitivity analysis evaluates the robustness of the 
superiority conclusions. 
Non-retrieved participants as non-responders: For the 5% responder analysis an analysis using non-
retrieved participants as non-responders in the logistic regressions will be done. 
ANCOVA for unequal variances: An alternative analysis model for the change in body weight (%) 
similar to the primary analysis model (ANCOVA), but assuming unequal variances instead of equal 
variances. The analysis model includes randomised treatment as factor and baseline body weight 
(kg) as covariate.  
Supplementary analyses 
The following statistical analyses are designed to address the additional estimand for the primary 
endpoints. 
The analysis model for change in body weight (%) will be a mixed model for repeated 
measurements (MMRM). The MMRM will be fitted using randomised study intervention as factor 
and baseline body weight (kg) as covariate all nested within visit. An unstructured covariance 
matrix for measurements within the same participant will be employed, assuming that 
measurements for different participants are independent.  
The analysis model for the 5% responder endpoint is a logistic regression where any missing values 
at week 44 will be predicted from the MMRM. The predicted values will be used to classify each 
participant as 5% responder or not. This classification will then be analysed using a logistic 
regression model with randomised study intervention as factor and baseline body weight (kg) as 
covariate.  
Week 44 assessments for retrieved drop-outs are not used in these analyses. The MMRM will use 
assessments only from participants who are taking the randomised study intervention until end of 
treatment or until first discontinuing of randomised study intervention or initiation of other anti-
obesity therapies (weight management drugs or bariatric surgery).  
9.3.3 
Secondary estimands analysis 
9.3.3.1 
Confirmatory secondary estimands 
The confirmatory secondary endpoints are: 
 ≥10% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 ≥15% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 change in waist circumference from baseline (week 0) to end of treatment (week 44) 
All confirmatory secondary endpoints will be analysed using the same analysis model and 
imputation approach as used to address the primary estimand for the primary endpoints.  
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The analysis model for change in waist circumference will be a linear regression (ANCOVA) with 
randomised study intervention as factor and baseline waist circumference as covariate.  
The analysis model for the responder endpoints is a logistic regression using randomised study 
intervention as factor and baseline body weight (kg) as covariate. 
Sensitivity analysis  
For the change in waist circumference, a sensitivity analysis using jump to reference as imputation 
approach will be carried out. For both binary confirmatory secondary endpoints, a sensitivity 
analysis using non-retrieved participants as non-responders will be carried out. 
Supplementary analysis 
The confirmatory secondary endpoints will be analysed using the same analysis model as used to 
address the additional estimand for the primary endpoints.  
The analysis model for change in waist circumference will be a mixed model for repeated 
measurements (MMRM). The MMRM will be fitted using randomised study intervention as factor 
and baseline waist circumference as covariate all nested within visit. An unstructured covariance 
matrix for measurements within the same participants will be employed, assuming that 
measurements for different participants are independent.  
The analysis model for the responder endpoints is a logistic regression where any missing values at 
week 44 will be predicted from the MMRM. The predicted values will be used to classify each 
participant as a responder or not. This classification will then be analysed using a logistic regression 
model with randomised study intervention as factor and baseline body weight (kg) as covariate.  
9.3.3.2 
Supportive secondary estimands 
Supportive secondary endpoints are listed in Section 3. For details on analyses of supportive 
secondary endpoints, please refer to the SAP.  
9.3.4 
Exploratory endpoints analysis 
Exploratory endpoints are listed in Section 3. Exploratory endpoints will be summarised by 
descriptive statistics. For further details, please refer to the SAP. 
9.3.5 
Safety analyses 
Adverse events will be summarised by descriptive statistics using the SAS. For further details, 
please refer to the SAP. 
9.3.6 
Other analyses 
Please refer to the SAP for details.  
Pharmacokinetic and/or pharmacodynamic modelling 
Pop-PK and exposure-response analyses will be used as supportive evidence for the evaluation of 
efficacy and safety and further to support the recommended dose of semaglutide in people with 
obesity. First, plasma semaglutide concentrations will be analysed using a population 
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pharmacokinetic model, quantifying covariate (such as baseline body weight, age, gender, race, 
ethnicity and injection site) effects on semaglutide exposure. Second, model-based estimates of 
steady-state average concentrations will be derived for each participant 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. 
A modelling analysis plan will be prepared before first database lock. Individual drug concentration 
data will be tabulated in the CSR, and the results of the modelling will be included in a separate 
report.  
9.4 
Interim analysis 
Not applicable.  
9.5 
Sample size determination 
The study is designed with an effective power of > 95% to detect differences on the primary 
endpoints. 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 
equal variances, whereas those for the categorical endpoints are based on the Pearson chi-square 
test for two independent proportions. 
Assumptions for these power calculations are presented in Table 9-3 and are based on findings from 
NN9536-4382 (STEP 6 East Asian study). 
Based on the multinational study STEP 1, where 18.9% permanently discontinued trial product and 
on East Asian study STEP 6, where 6.0% permanently discontinued trial product, it is assumed that 
13% of participants will discontinue trial product permanently before week 44. It is assumed that 
approximately 75% will be retrieved at week 44 which is similar to that observed in STEP 6 which 
however was of longer duration (68 weeks). 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. 2.4 mg once-weekly arm are assumed to have an effect corresponding to half the 
treatment difference (compared to placebo) of participants who complete the study on semaglutide 
s.c. 2.4 mg once weekly. Non-retrieved participants in the semaglutide s.c. 2.4 mg once weekly arm 
are assumed to have an effect corresponding to placebo.  
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 expected to be comparable to the effect in STEP 6 which is 
included in the assumed mean and proportions in Table 9-3. 
Under these assumptions and a 2:1 randomisation ratio, a sample size of 150 participants 
randomised to either receive semaglutide s.c. 2.4 mg once weekly (100 participants) or placebo 
(50 participants) yields an effective power of > 95% for both primary endpoints and 81% power for 
all confirmatory endpoints. 
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Table 9-3 
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 150 randomised 
participants 
Order Endpoint 
Assumed mean (±SD) or 
proportion for completers 
Expected 
mean (±SD) 
or 
proportion 
Expected 
difference or 
proportion ratio 
Marginal 
power (%) 
Effective 
power (%) 
Semaglutide 
s.c. 2.4 mg 
once weekly 
Placebo 
Semaglutide 
s.c. 2.4 mg 
once weekly 
 
 
 
1 
% body 
weight change 
12.0 (±10) 
3.0 (±10) 
11.3 (±10) 
8.3%-points 
> 99 
> 99 
2 
5% responders 
75.8% 
42.1% 
73.2% 
1.7 
96 
96 
3 
10% 
responders 
57.9% 
24.2% 
55.1% 
2.3 
96 
92 
4 
15% 
responders 
38.2% 
11.5% 
35.9% 
3.1 
92 
85 
5 
Change in 
waist 
circumference 
10.0 (±10) 
3.0 (±10) 
9.4 (±10) 
6.4 
96 
81 
 
How the design assumptions in terms of the assumed mean and standard deviation of the % body 
weight change affect the power of the first four endpoints is shown in Table 9-4.  
Table 9-4 
Marginal and effective power by assumed mean and standard deviation in % 
body weight change with a sample size of 150 participants 
Endpoint 
Semaglutide 
s.c. 2.4 mg: 
10.0 (±10) 
Semaglutide 
s.c. 2.4 mg: 
12.0 (±10)* 
Semaglutide 
s.c. 2.4 mg: 
14.0 (±10) 
Semaglutide 
s.c. 2.4 mg: 
12.0 (±8) 
Semaglutide 
s.c. 2.4 mg: 
12.0 (±12) 
Marginal power 
(%) / Effective 
power (%) 
Marginal power 
(%) / Effective 
power (%) 
Marginal power 
(%) / Effective 
power (%) 
Marginal power 
(%) / Effective 
power (%) 
Marginal power 
(%) / Effective 
power (%) 
% body weight 
change 
96 / 96 
>99 / >99 
>99 / >99 
>99 / >99 
97 / 97 
5% responders 
85 / 81 
96 / 96 
>99 / >99 
>99 / >99 
88 / 86 
10% responders 
83 / 67 
96 / 92 
>99 / 99 
>99 / >99 
88 / 75 
15% responders 
71 / 48 
92 / 85 
99 / 98 
98 / 97 
82 / 62 
* Assumption used in the sample size calculation 
The effective power of the co-primary and all confirmatory tests versus total number of participants 
randomised in shown in Figure 9-1.  
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Figure 9-1 
Effective power including all confirmatory tests versus total number of 
participants randomised 
 
All above-outlined sample size and power considerations are based on the treatment policy strategy 
used in the co-primary and secondary estimands. It is assumed that up to 13% of participants 
discontinue permanently and 75% of these are retrieved at week 44, which amounts to around 3% 
expected missing data at week 44. This is similar to that observed in STEP 6, in which 2% missing 
in-trial body weight data were observed after both 44 and 68 weeks for the primary estimand. Any 
superiority conclusions will be based on the primary estimand. 
For the additional estimand however, data from retrieved participants are not used. Hence, it is 
expected that up to 13% of data will be missing at week 44. Based on STEP 6, approximately 6% 
on-treatment data were missing after 68 weeks for the additional estimand. This included missing 
data not only due to treatment discontinuation, but also due to initiation of other anti-obesity 
therapies. 
Finally, based on STEP 6 it is expected that approximately 95% of participants will attend the end 
of study visit at week 49. Therefore, a sample size of 150 randomised participants is expected to 
give 142 participants attending the end of study visit at week 49. 
50
100
150
200
250
Total number of subjects
0.5
0.6
0.7
0.8
0.9
1.0
Effective power
50
100
150
200
250
Total number of subjects
0.5
0.6
0.7
0.8
0.9
1.0
Effective power
All confirmatory tests
Test for co-primary endpoints
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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 
Helsinki80 and applicable ICH Good Clinical Practice (GCP) Guideline81 
 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. 
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. 
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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 
GCP81 guidelines, Declaration of Helsinki,80 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 like “dose reminder card” and “what is Semaglutide”. 
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 participant 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 
participant ID, visit number and study ID. Appropriate measures such as encryption or leaving out 
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. 
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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.  
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,80 the International Committee of Medical Journal Editors (ICMJE),82 the Food and Drug 
Administration Amendment Act (FDAAA),83 European Commission Requirements84-86 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. 
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. 
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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 GCP81, 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 
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. 
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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. 
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. 
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 15 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. 
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 
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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. 
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 
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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. 
One investigator will be appointed by Novo Nordisk to review and sign the CSR (signatory 
investigator) on behalf of all participating investigators. 
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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 participant 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.87 
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. 
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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. 
 
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10.2 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 10-1 will be performed by the central 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. 
Laboratory samples will be destroyed no later than at end of study or no later than at finalisation of 
the CSR. 
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Table 10-1 
Protocol-required efficacy and safety laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
Visit 1, 2, 11, 17 
 HbA1c 
Lipids 
Visit 2, 11, 17 
 Total cholesterol 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 Triglycerides 
Biomarkers 
Visit 2, 11, 17 
 High-sensitive C-Reactive Protein (hsCRP) 
Haematology 
Visit 2, 11, 17 
 Haemoglobin 
 Thrombocytes 
 Leukocytes 
 Neutrophils 
 Lymphocytes 
 Basophils 
 Eosinophils 
 Monocytes 
Biochemistrya 
Visit 2, 11, 17 
 Alanine Aminotransferase (ALT) 
 Alkaline phosphatase 
 Aspartate Aminotransferase (AST) 
 Amylase 
 Lipase 
 Bilirubin 
 Creatinine 
 Potassium 
 Sodium 
Pregnancy Testingb 
Visit 1, 2, 4, 6, 8, 10, 11, 13, 
15, 17, 18 
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test  
Other tests 
Visit 1, 11, 17 
 eGFR calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation 
Notes: 
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) and Section 7.1. 
bFor women of childbearing potential, as needed, local urine testing will be standard unless serum testing is required 
by local regulation or IRB/IEC, see Appendix 4 (Section 10.4). 
Laboratory results that could unblind the study will not be reported to the sites until the study has 
been unblinded.  
 
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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 
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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: 
 Suspicion of transmission of infectious agents via IMP 
 Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 3x UNL and total bilirubin > 2x UNL where no 
alternative aetiology exists (Hy’s law) 
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. 
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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 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. 
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., 
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. 
Acute gallbladder disease: Events of symptomatic acute gallbladder disease (including gallstones 
and cholecystitis) 
Acute pancreatitis. The diagnosis of acute pancreatitis requires two of the following three features: 
 Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric 
pain often radiating to the back) 
 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 
Malignant neoplasm: Malignant neoplasm by histopathology or other substantial clinical evidence 
Hepatic event defined as: 
 Disorders of the liver including cholestatic conditions and liver related signs and symptoms 
 ALT or AST > 3x UNL and total bilirubin > 2x UNL or INR > 1.5a 
 ALT or AST > 3x UNL with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
a Please note that in case of a hepatic event defined as ALT or AST > 3x UNL and total bilirubin 
> 2x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using 
the important medical event criterion if no other seriousness criteria are applicable. 
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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 
participant 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 
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 adverse 
event 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.  
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. 
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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 brochure for the assessment. For each AE/SAE, the 
investigator must document in the medical records that he/she has reviewed the AE/SAE and has 
provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator always 
makes an assessment of causality for every event before the initial transmission of the SAE 
data. 
The investigator may change his/her opinion of causality, in light of follow-up information, and 
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 
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. 
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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. 
 
 
 
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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. 
 
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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 hormone replacement therapy (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. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use methods 
of contraception consistently and correctly. Table 10-2 lists the highly effective methods of 
contraception allowed. Local regulations may apply, see Appendix 7 (Section 10.7). 
Highly effective contraception should be utilised until the end of study. 
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Table 10-2 
Highly effective contraceptive methods allowed88 
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, acceptable 
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). 
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 Figure 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. 
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 adverse event in connection with 
pregnancy or elective termination of a pregnancy for medical reasons will be reported as an AE or 
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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 
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female participants requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female participants
 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention.  
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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 (e.g., to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and needle) 
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. 
2. For products without DUN: One technical complaint form must be completed for each batch, 
code or lot number. 
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 days calendar 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. 
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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. 
10.5.3 
Reporting of technical complaints from products not included in the technical 
complaint form 
Technical complaints on products not included in the technical complaint form should be reported 
to manufacturing holder. 
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10.6 
Appendix 6: Mitigations to ensure participant safety and data integrity during an 
emergency situation 
10.6.1 
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. 
Table 10-3 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. 
10.6.2 
Visits 
Screening (Visit 1) and randomisation/baseline (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 11 and 17 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 4, 6, 8, 10, 13, and 15) 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. 
10.6.3 
Assessments 
Assessments used for safety or the confirmatory endpoints (i.e., body weight and waist 
circumference) should be prioritised. The preferred order for the method of assessment is: on-site, 
video, phone, home visit. Specifications regarding how to perform these assessments using remote 
visits or as home visits will be provided by Novo Nordisk. Specifications will include training for 
raters performing remote assessments and adoption of modifications for equivalent administration 
of assessments using remote visits (video, phone or similar). 
Local laboratories or diagnostic facilities can be used for glucose metabolism, lipids, biomarkers, 
haematology, biochemistry at the investigator’s discretion if on-site visits are not possible or in case 
of temporary lockdown of the central laboratory. Only findings meeting the definition for an AE 
(refer to Appendix 3 [Section 10.3]) should be reported in the CRF.  
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Home measurements of body weight can be performed if on-site visits are not possible and if 
deemed feasible for the participant. This is applicable only for emergency situations, and in this 
instance, Novo Nordisk will be in contact with the sites to provide further instructions.  
If the assessments indicated in Table 10-3 cannot be performed as on-site visits, remote visits or be 
analysed at a local laboratory or diagnostic facility, they should be performed at the first possible 
timepoint following the originally scheduled visit in agreement with Novo Nordisk. 
10.6.4 
Study intervention 
Alternative dispensing methods of study intervention may be implemented, and details will be 
communicated and documented. The dispensing options will be provided by Novo Nordisk A/S and 
will be based on options and requirements at country level and if permitted by local regulations.  
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Table 10-3 Minimum assessments following randomisation 
 
Screening Randomisation 
Intervention period 
End of study 
interventiona 
End of 
study 
Visit 
V1 
V2 
P3 V4 P5 V6 P7 V8 P9 V10 V11 P12 V13 P14 V15 P16 
V17 
P18 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
40 
44 
49 
Visit Window (Days) 
-7 
0 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
Informed Consent and Demographyb (10.1.3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Concomitant Illness (8.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility Criteria (5.1 and 5.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation (6.3) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication (6.8) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Childbearing Potentialc (10.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Used (5.3.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  (8.2.4) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Evaluation of Antihypertensive Treatment  (8) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Evaluation of Glycaemic Status (8) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Evaluation of Lipid-lowering Treatment (8) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Discontinuation Criteria (7) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Surgical Procedures Form (8.2.5) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Height (8.1.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight (8.1.1) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Waist Circumference (8.1.1) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical Examination (8.2.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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Screening Randomisation 
Intervention period 
End of study 
interventiona 
End of 
study 
Visit 
V1 
V2 
P3 V4 P5 V6 P7 V8 P9 V10 V11 P12 V13 P14 V15 P16 
V17 
P18 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
40 
44 
49 
Visit Window (Days) 
-7 
0 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
Vital Signs  (8.2.2) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Laboratory Assessments (10.2) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Adverse Event (8.3 and 10.3) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
PK Sampling (8.4.1) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Breast Neoplasms Follow-upc (8.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Colon Neoplasms Follow-up (8.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug Dispensing (6.2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug Accountability (6.2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Training in Trial Product, Pen-handling (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment (4.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hand Out Direction for Use (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand Out Dose Reminder Card 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand Out and Instruct in PK Diary (8) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet and Physical Activity Counselling (6.1) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Barriers and Motivation Interview (8) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. End of study intervention includes both end of IMP treatment (‘end of treatment’) and end of lifestyle intervention b. Demography consists of date of birth, sex, ethnicity, and race 
(according to local regulation); c. For all female participants; d. Smoking is defined as smoking at least one cigarette or equivalent daily 
 


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10.7 
Appendix 7: Country-specific requirements 
Republic of Korea: 
Section 5.1, Inclusion criteria 
3.  Age above or equal to 19 years at the time of signing informed consent. 
 
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10.8 
Appendix 8: Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BMR 
basic metabolic rate 
hCG 
human chorionic gonadotropin 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-
19 
coronavirus disease 
CRF 
case report form 
CSR 
clinical study report 
DFU 
directions for use 
DPS 
defined data point sets  
DUN 
dispensing unit number 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GLP-1 
glucagon-like protein-1  
GLP-1 
RA 
glucagon-like protein-1 receptor agonist 
HDL 
high-density lipoprotein 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator's Brochure 
ICH 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
institutional review board 
LAO-OT 
last available observation during the on-treatment period  
LDL 
low-density lipoprotein 
MEN2 
multiple endocrine neoplasia type 2  
MMRM 
mixed model for repeated measurements 
MTC 
medullary thyroid cancer  
NIMP 
non-investigational medicinal product 
NN 
Novo Nordisk 
NYHA 
New York Heart Association 
OR 
odds ratio 
PCD 
primary completion date 
PK 
pharmacokinetics 
PYE 
patient-years of exposure 
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PYO 
patient-years of observation 
QTL 
quality tolerance limit 
RTSM 
randomisation and trial supplies management system  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
standard deviation 
SOP 
standard operating procedure 
STEP 
Semaglutide Treatment Effect in People with obesity 
SUSAR 
suspected unexpected serious adverse reaction 
TEE 
total daily energy expenditure  
TMM 
trial materials manual  
TP-MI 
tipping-point multiple imputation analysis 
UNL 
upper normal limit 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
 
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10.9 
Appendix 9: 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, including version 1.0: 25 June 2021, global 
This amendment is considered to be non-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, because 
it neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall rationale for preparing protocol version 2.0 
Section # and name 
Description of change 
Brief rationale 
Section 8.2 Safety assessment 
Under Medical History, the 
sentence ”Information on weight 
related co-morbidities will be 
collected as part of medical history at 
screening (visit 1) and an evaluation 
will be done at the end of study 
intervention (visit 17).” has been 
added.  
Added to clarify the procedure related 
to evaluation of weight-related 
comorbidities.  
 
Protocol version 3.0: 15 September 2021, global 
This amendment is considered to be non-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, because 
it neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall rationale for preparing protocol, version 3.0: 
The randomisation system to be used in this study has been changed from the IWRS (interactive 
web response system) to the RTSM (randomisation and trial supplies management system).  
Section # and name 
Description of change 
Brief rationale 
Section 5.4 Screen failures 
Section 6 Study intervention(s) and 
concomitant therapy 
Section 7 Discontinuation of study 
intervention and participant 
discontinuation/withdrawal 
Appendix 8 Abbreviations 
Throughout the protocol, the IWRS 
(interactive web response system) has 
been updated to the RTSM 
(randomisation and trial supplies 
management system). 
 
 
 
 
 
The randomisation system for the trial 
has been updated to the RTSM instead 
of the IWRS. 
 
 
 
 
 
 
 
Section 6.2 Preparation, handling, 
storage and accountability 
 
Sentence with reference to 
Appendix 7 has been deleted. 
Wrong reference to Appendix 7. 
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Section # and name 
Description of change 
Brief rationale 
Section 9.3 Statistical analyses 
Minor change of wording: subjects 
updated to participants. 
Align wording  
 
Protocol version 4.0 (09 February 2022) 
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, because 
the change of device impacts the conduct of the study.  
Overall rationale for preparing protocol, version 4.0: 
The device used for administration of semaglutide 2.4 mg or placebo was changed from DV3396 
single-dose pen-injector to a PDS290 pen-injector. In addition, the editorial changes were made to 
the statistic sections and it was specified that PK samples will not be stored after end of study. 
Additional minor editorial changes have been made throughout the document.  
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
 
Section 6.1 Study intervention(s) 
administered 
Throughout the protocol the device 
for administration of 
semaglutide 2.4 mg and placebo has 
been changed from DV3396 single-
dose pen-injector to PDS290 pen-
injector. 
The device used for administration of 
semaglutide 2.4 mg and placebo in 
this study has been changed from 
DV3396 single-dose pen-injector to 
PDS290 pen-injector. The reason for 
change was to reflect the devices 
expected to be marketed in the 
involved countries.  
Section 1.1 Synopsis 
Editorial changes to objectives, 
endpoints and estimands. 
Editorial changes were made to reflect 
the intention of the statistical analyses 
more accurately. The planned 
statistical analyses and the conduct of 
the study has not been changed.  
Section 3 Objectives, endpoints and 
estimands 
Editorial changes to objectives, 
endpoints and estimands and 
additional information added to the 
secondary estimand, treatment 
condition, remaining intercurrent 
events and rationale for estimand.  
Section 9 Statistical considerations 
‘Breaking the blind to trials product 
assignment’ was changed to ‘database 
lock.’  
Section 9.2 Analysis sets 
Definition of Safety analysis set 
(SAS) specified. 
Use of FAS and DPS1 amended to 
include primary objectives. 
Section 1.1 Synopsis 
 
Section 2.1 Study rationale 
 
Section 2.2.1 Semaglutide 
 
Section 3 Objectives, endpoints and 
estimands 
 
Section 4.1 Overall design 
The term Asians was changed to 
people, participants or deleted. 
Alignment of wording. 
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Section # and name 
Description of change 
Brief rationale 
Section 1.2 Flowchart 
Actions related to drug dispensing and 
accountability were updated. 
The flowchart was updated to reflect 
the change in device. 
Section 2.3.1 Risk assessment 
Risk assessment statement added. 
To comply with template and change 
in device. 
Section 5.2 Exclusion criteria 
‘adequate’ changed to ‘highly 
effective’ 
To align with Section 10.4 Appendix 
4 
Section 8.4.1 Pharmacokinetics 
Text specified: additional analyses 
will only be conducted during the 
study. Sentence about residual 
samples has been deleted. 
Sentence on genetic analyses has been 
deleted. 
Change was made to clarify the use of 
PK samples and that genetic analyses 
will not be performed. 
Section 9.3.2 Primary estimands 
analysis 
Week 68 corrected to week 44. 
Wrong week number stated. 
Section 10.2 
Additional haematology parameters 
added. 
To align with previous studies. 
Section 10.5.1 Definition of technical 
complaint 
List of examples amended. 
Examples updated to reflect the 
PDS290 device. 
Section 10.5.3 Reporting of technical 
complaints from products not 
included in the technical complaint 
form 
New section added. 
New section added to align with 
requirements for the PDS290 device. 
Throughout the protocol 
Minor editorial changes. 
Updated IB reference to ed. 7 
General update of the document with 
no impact on the conduct of the study. 
Protocol version 5.0 (20 June 2022) 
This amendment is considered to be non-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, because 
it neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. 
Overall rationale for preparing protocol, version 5.0: 
Fasting requirements are not required in this study and have been removed throughout the protocol. 
Body Mass Index (BMI) is calculated via the electronic Case Report Form (eCRF), this has been 
specified in the protocol. Dose adjustment guidance has been revised for clarity. 
Section # and name 
Description of change 
Brief rationale 
1.2 Flowchart 
 
5.3.1 Meals and dietary restrictions 
Removal of description of fasting 
requirements. 
Fasting is not required at any visit 
during the study.  
5.1 Inclusion Criteria,  
 
6.1 Study intervention(s) administered  
 
8.1.1 Body measurements 
Description of BMI calculation via the 
eCRF has been added throughout the 
protocol. 
To avoid incorrect calculation of BMI, 
protocol has been updated to clarify 
how BMI is calculated via the eCRF.  
6.1 Study intervention(s) administered Revised dose adjustment procedure 
for participants with BMI within 
lower normal range. 
To ensure participant safety, dose 
adjustment guidance has been revised 
for clarity. 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04998136 
Sponsor trial ID: 
NN9536-4707 
Official title of study: 
Efficacy and safety of semaglutide 2.4 mg once-weekly in 
Asians with obesity diagnosed as BMI ≥ 25 kg/m2 according 
to local guidelines. 
Document date*: 
28 November 2023 
 
*Document date refers to the date on which the document was most recently updated. 


Statistical Analysis Plan 
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Statistical Analysis Plan 
Efficacy and safety of semaglutide 2.4 mg once-weekly in Asians 
with obesity diagnosed as BMI 
≥ 25 kg/m2 according to local guidelines. 
Substance: semaglutide 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 4 
Version History ................................................................................................................................................. 5 
List of abbreviations ......................................................................................................................................... 6 
1 Introduction ................................................................................................................................................. 7 
1.1 
Objectives, endpoints and estimands .................................................................................................. 7 
1.2 
Study Design ..................................................................................................................................... 10 
2 Statistical Hypotheses ............................................................................................................................... 11 
2.1 
Multiplicity Adjustment .................................................................................................................... 11 
3 Analysis Sets .............................................................................................................................................. 13 
4 Statistical Analyses .................................................................................................................................... 15 
4.1 
General Considerations ..................................................................................................................... 15 
4.2 
Co-primary estimands analyses ........................................................................................................ 15 
4.2.1 
Definition of Endpoints ..................................................................................................... 15 
4.2.2 
Main Analytical Approach ................................................................................................ 15 
4.2.3 
Sensitivity Analyses .......................................................................................................... 17 
4.2.4 
Supplementary Analyses ................................................................................................... 17 
4.3 
Secondary Estimands Analyses ........................................................................................................ 18 
4.3.1 
Confirmatory Secondary Estimands .................................................................................. 18 
4.3.1.1 
Definition of Endpoints .................................................................................. 18 
4.3.1.2 
Main Analytical Approach ............................................................................. 18 
4.3.1.3 
Sensitivity Analyses ....................................................................................... 19 
4.3.1.4 
Supplementary Analyses ................................................................................ 19 
4.3.2 
Supportive Secondary Endpoints Analyses ....................................................................... 19 
4.4 
Exploratory Endpoints Analyses ....................................................................................................... 21 
4.5 
Other Safety Analysis ....................................................................................................................... 21 
4.6 
Other Analysis .................................................................................................................................. 21 
4.7 
Subgroup Analysis ............................................................................................................................ 21 
4.8 
Interim Analysis ................................................................................................................................ 21 
4.9 
Changes to Protocol-planned Analysis ............................................................................................. 21 
5 Sample size determination ........................................................................................................................ 23 
6 References .................................................................................................................................................. 24 
 
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Table of figures 
 
Page 
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Table of tables 
 
Page 
Table 1-1 
Objectives and endpoints ............................................................................................................. 7 
Table 3-1 
Analysis sets .............................................................................................................................. 13 
Table 3-2 
Defined data point sets ............................................................................................................... 13 
Table 4-1 
Analyses and imputation methods to address the efficacy estimands for the co-primary 
endpoints .................................................................................................................................... 18 
Table 4-2 
Analyses and imputation methods to address the secondary estimands for the 
confirmatory secondary endpoints ............................................................................................. 19 
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Version History 
This Statistical Analysis Plan (SAP) for trial NN9536-4707 is based on the protocol version 6.0 
dated 16DEC2022. 
SAP Version 
Date 
Change 
Rationale 
1.0 
28 Nov 2023 
Not Applicable 
Original version 
 
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List of abbreviations 
 
AD 
available but discontinued  
AE 
adverse event 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
cm 
centimetre 
FAS  
full analysis set 
HbA1c  
glycated haemoglobin 
HDL 
high density lipoprotein  
hsCRP          high-sensitivity C-reactive protein 
J2R-MI         Jump to reference multiple imputation approach  
kg 
kilogram 
LAO-OT  
last available observation during the on-treatment period 
LDL 
low density lipoprotein  
LR 
logistic regression 
MedDRA 
medical dictionary for regulatory activities 
mg 
milligrams 
mg/dL 
milligrams per decilitre 
MI 
multiple imputation 
mmHg 
millimetre of mercury 
mmol/mol 
millimoles per mol 
MMRM  
mixed model for repeated measurements 
OR 
odds ratio 
RD-MI 
multiple imputation using retrieved participants 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
TFL  
tables, figures and listings 
WO-MI 
wash-out multiple imputation 
 
 
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1 
Introduction 
This SAP is based on protocol version 6.0 dated 16DEC2022. 
1.1 
Objectives, endpoints and estimands 
The trial endpoints are listed in Table 1-1 by their association to the objectives.  
Table 1-1 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
 To demonstrate the superiority 
of semaglutide s.c. 2.4 mg 
once weekly versus placebo as 
an adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI ≥ 
25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand on: 
 Body weight 
 ≥5% weight reduction 
Co-primary: 
Change in body weight 
From baseline (week 0) to end 
of treatment (week 44) 
% 
≥5% body weight reduction 
(yes/no) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant  
Confirmatory secondary: 
≥10% body weight reduction 
(yes/no)  
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
 ≥15% body weight reduction 
(yes/no) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in waist circumference 
From baseline (week 0) to end 
of treatment (week 44) 
cm 
Supportive secondary:  
≥20% body weight reduction 
(yes/no)  
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in body weight 
From baseline (week 0) to end 
of treatment (week 44) 
kg 
Change in body mass index 
From baseline (week 0) to end 
of treatment (week 44) 
kg/m2 
Secondary 
Title 
Time frame 
Unit 
 To compare the efficacy of 
semaglutide s.c. 2.4 mg once 
weekly versus placebo, as an 
adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI 
≥ 25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand, on 
cardiovascular risk factors  
Supportive secondary: 
Change in systolic blood 
pressure 
From baseline (week 0) to end 
of treatment (week 44) 
mmHg 
Change in diastolic blood 
pressure 
From baseline (week 0) to end 
of treatment (week 44) 
mmHg 
Change in total cholesterol 
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in high-density 
lipoprotein (HDL) cholesterol  
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in low-density 
lipoprotein (LDL) cholesterol  
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in triglycerides 
From baseline (week 0) to end 
of treatment (week 44) 
mg/dL and 
mmol/L 
Change in high-sensitivity 
c-reactive protein (hsCRP) 
From baseline (week 0) to end 
of treatment (week 44) 
mg/L 
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Objectives 
Endpoints 
Exploratory: 
Change in use of 
antihypertensive medication 
(decrease/no change/increase) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
Change in use of lipid-lowering 
medication (decrease/no 
change/increase) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
 To compare the efficacy of 
semaglutide s.c. 2.4 mg once 
weekly versus placebo, as an 
adjunct to a reduced-calorie 
diet and increased physical 
activity in participants with 
obesity, classified as BMI 
≥ 25 kg/m2 according to local 
guidelines in Republic of 
Korea and Thailand, on 
glucose metabolism 
Supportive: 
Change in HbA1c 
From baseline (week 0) to end 
of treatment (week 44) 
% and 
mmol/mol 
Exploratory:  
Shift in glycaemic status 
(normo-glycaemic/pre-
diabetes/T2D) 
From baseline (week 0) to end 
of treatment (week 44) 
Count of 
participant 
End of treatment (week 44) corresponds to end of trial intervention. 
Co-primary estimands 
The primary clinical question of interest is: What is the treatment effect of semaglutide s.c. 2.4 mg 
once weekly as an adjunct to a reduced-calorie diet and increased physical activity in participants 
with obesity defined according to local guidelines in Republic of Korea and Thailand, measured by 
relative change from baseline (week 0) to week 44 in body weight and ≥ 5% body weight reduction 
at week 44, 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: People of Asian descent with obesity defined as BMI ≥ 25.0 kg/m2.   
 Endpoint: 1) relative change from baseline to week 44 in body weight and 2) ≥ 5% body 
weight reduction at week 44. 
 Treatment condition: the randomised treatment regardless of discontinuation or dose 
reduction of randomised trial product, and regardless of initiating other anti-obesity 
therapies (as defined above) 
 
 Remaining intercurrent events: none, all intercurrent events (discontinuation or dose 
reduction of randomised trial product 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  
 
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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 trial. The co-primary estimands are thus 
relevant to support regulatory decision-making. 
Secondary estimand 
The secondary estimands for both the confirmatory secondary and supportive secondary endpoints 
are similar to the co-primary estimands except for the endpoint attribute. For continuous endpoints, 
the secondary estimands for primary and secondary objectives are similar to the co-primary 
estimand for % weight change. For binary endpoints, the secondary estimands for primary and 
secondary objectives are similar to the co-primary estimand for ≥ 5% body weight reduction.   
Additional estimand 
An additional clinical question of interest for the primary objective is: what is the treatment effect 
of semaglutide s.c. 2.4 mg once weekly as an adjunct to a reduced-calorie diet and increased 
physical activity in participants with obesity defined according to local guidelines in Republic of 
Korea and Thailand, measured by relative change from baseline (week 0) to week 44 in body 
weight and ≥ 5% body weight reduction at week 44, had they remained on their randomised 
treatment for the entire planned duration of the trial 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:  People of Asian descent with obesity defined as BMI ≥ 25.0 kg/m2 
 Endpoint: 1) relative change from baseline to week 44 in body weight and 2) ≥ 5% body 
weight reduction at week 44. 
 Treatment condition: the randomised treatment if participants had adhered to the 
randomised trial product (regardless of dose reduction) for the entire duration of the trial and 
not initiated any other anti-obesity therapies (as defined above).  
 
 Remaining intercurrent events: none, all intercurrent events (discontinuation or initiation 
of other anti-obesity therapies and dose reduction) are captured by the treatment condition 
attribute. Discontinuation or initiation of other anti-obesity therapies are handled by the 
hypothetical strategy. Dose reduction of randomised trial product 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 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 endpoints 
addressing the primary and secondary objective in the population. 
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1.2 
Study Design 
The study design is provided in the protocol section 4.1. 
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2 
Statistical Hypotheses 
The tests of superiority of semaglutide s.c. 2.4 mg once weekly to placebo for the two primary and 
all confirmatory secondary endpoints are performed using a fixed-sequence statistical strategy and 
will be based only on analyses addressing the primary estimand. This strategy tests the endpoints 
using a predefined hierarchical order, all at the significance level of 5%, moving to test the next 
endpoint only after a statistically significant superiority result (p-value < 5%) on the previous 
endpoint. 
For the co-primary estimands with the primary endpoints, 1) change in body weight (%) from 
baseline to end of treatment (week 44) and 2) ≥ 5% body weight reduction (yes/no) from baseline 
(week 0) to end of treatment (week 44), the following confirmatory 1-sided hypotheses are planned 
to be tested for semaglutide s.c. 2.4 mg once weekly versus placebo. Let the mean difference in 1) 
be defined as: 
μ1 = ([semaglutide s.c. 2.4 mg] minus [placebo]) 
and let the odds ratio of 2) be defined as: 
OR = (odds[semaglutide s.c. 2.4 mg] divided by odds[placebo]) 
Superiority 
1) H01 : μ1 ≥ 0.0 percentage points against Ha1 : μ1 < 0.0 percentage points. 
and 
2) H02 : OR ≤ 1 against Ha2 : OR > 1 
Operationally, the hypotheses will be evaluated by 2-sided tests. 
2.1 
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. For 
example, the second null hypothesis will only be tested if the first null hypothesis has been rejected 
in favour of semaglutide s.c. 2.4 mg. 
The steps in the hierarchical testing procedure are as follows: 
 Step 1: change in body weight (%) from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
and 
≥ 5% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
 Step 2: ≥ 10% body weight reduction (yes/no) from baseline (week 0) to end of treatment 
(week 44) superiority of semaglutide s.c. 2.4 mg versus placebo 
 Step 3: ≥ 15% body weight reduction (yes/no) from baseline (week 0) to end of treatment 
(week 44) superiority of semaglutide s.c. 2.4 mg versus placebo 
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 Step 4: Change in waist circumference from baseline (week 0) to end of treatment (week 44) 
superiority of semaglutide s.c. 2.4 mg versus placebo 
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3 
Analysis Sets 
For the purposes of analysis, the following analysis sets (Table 3-1) and observation periods 
(Table 3-2) are defined: 
Table 3-1 
Analysis sets 
Participant Analysis Set Description 
Full analysis set (FAS) 
All randomised participants. Participants will be included in the analyses according to the 
randomised intervention. 
Safety analysis set (SAS) 
All participants who are exposed to at least one dose of randomised IMP. Participants will 
be included in the analyses according to the intervention they actually received. 
Table 3-2 
Defined data point sets 
Defined data point sets (DPS) 
Description 
In-trial (DPS1) 
The time period where the participant is assessed in the trial. The in-trial 
observation period for a participant begins on the date of randomisation and 
ends at the first of the following dates (both inclusive): 
 ‘End of trial’ visit 
 withdrawal of consent 
 last contact with participant (for participants lost to follow-up) 
 death 
On-treatment (DPS2) 
The time period where participants are treated with trial product. A time-point 
is considered as “on-treatment” if any dose of trial product has been 
administered within the prior 2 weeks (14 days). The participant is considered 
“on-treatment” regardless of dose reduction. The on-treatment period is defined 
as all times which are considered on-treatment. In general, the on-treatment 
period will therefore be from the date of first trial product administration to date 
of last trial product administration (+14 days) excluding potential off-treatment 
time intervals triggered by at least two consecutive missed doses. 
For the evaluation of AEs and potential pregnancies, the lag time for each on-
treatment time interval is 5 weeks (35 days). 
On-treatment until first 
discontinuation of trial product 
or initiation of other anti-
obesity therapies (DPS3) 
The time period where participants are treated with trial product. A time-point 
is considered as “on-treatment” if any dose of trial product has been 
administered within the prior 2 weeks (14 days). The participant is considered 
“on-treatment” regardless of dose reduction. Observations after the first 
discontinuation of trial product or initiation of other anti-obesity therapies will 
not be included.  
FAS and DPS1 are used to estimate the co-primary estimands and the secondary estimands for the 
primary and secondary objectives. 
FAS and DPS3 are used to estimate the additional estimand for the primary objective and secondary 
objectives.  
SAS and either DPS1 or DPS2 are used to present safety data.  
The in-trial (DPS1) and on-treatment (DPS2) periods define the patient years of observation (PYO) 
and patient years of exposure (PYE), respectively, as the total time duration in the periods. 
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Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided.  
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4 
Statistical Analyses 
4.1 
General Considerations 
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all participants is used as 
the baseline value. 
All tests are tests of superiority of semaglutide s.c. 2.4 mg once weekly to placebo. All estimated 
treatment contrasts between semaglutide s.c. 2.4 mg and placebo will be reported together with the 
associated two-sided 95% confidence interval (CI) and corresponding p-value. 
4.2 
Co-primary estimands analyses 
The two primary analyses are aligned with the two co-primary estimands defined in Section 1.1. 
4.2.1 
Definition of Endpoints 
The co-primary endpoints are:  
 Change in body weight (%) from baseline (week 0) to end of treatment (week 44) 
 ≥ 5% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
4.2.2 
Main Analytical Approach 
The analysis model for change in body weight (%) will be a linear regression (ANCOVA) with 
randomised trial intervention as factor and baseline body weight (kg) as covariate.  
The analysis model for the 5% responder endpoint will be a logistic regression using randomised 
trial intervention as factor and baseline body weight (kg) as covariate.  
Multiple imputation approach using retrieved subjects (RD-MI): All available data at week 44 are 
used and missing values at week 44 will be imputed and the endpoint will be derived from the 
imputed values. The imputation approach for the primary analysis is a multiple imputation similar 
to the one described by McEvoy et al.1 For participants in the semaglutide s.c. 2.4 mg once weekly 
and the placebo groups, missing measurements at week 44 for non-retrieved participants are 
imputed using assessments from retrieved participants in each intervention group. The timing of last 
available observation during the on-treatment period (LAO-OT) will be included in the imputation 
model as a continuous covariate. Missing measurements at week 44 for participants on randomised 
trial intervention (at week 44) are imputed by sampling from available measurements at week 44 
from participants on randomised trial intervention in the relevant randomised intervention group.  
1. Imputation: Defines an imputation model using retrieved participants from FAS and done within 
groups defined by randomised treatment. The model will be a linear regression of body weight at 
week 44 with gender (male/female) and baseline BMI (kg/m2) (in categories <35, 35-<40, ≥40) as 
factors and baseline body weight (kg), timing of the LAO-OT and LAO-OT of body weight (kg) as 
covariates. No interactions will be included. If no LAO-OT exists post-baseline then the LAO-OT 
will be the baseline value of body weight and the timing will be 0. If any participants are on-
treatment with missing values at week 44, an imputation model for missing body weight at week 44 
will be defined using participants on-treatment and with available observations at week 44 in a 
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similar way. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 44 body weight values 
for each randomised treatment arm. This will be done 1,000 times and results in 1,000 complete 
data sets. If the imputation model cannot be fit due to small group size, the wash-out multiple 
imputation approach (WO-MI) will be used instead as described below.   
2. Analysis: Analysis of each of the 1,000 complete data sets, using the analysis models (ANCOVA 
and logistic regression) results in 1,000 times 2 estimations. 
3. Pooling: Integrates the 1,000 times 2 estimation results into two final results using Rubin’s 
formula. 
Wash-out multiple imputation approach (WO-MI): Missing values of body weight at week 44 are 
imputed using the same framework (Imputation, Analysis, Pooling) as described above with the 
first step replaced by:  
 Imputation: Defines an imputation step procedure utilizing different imputation models 
depending on randomised treatment group and end of treatment status as described in the 
following steps: 
1. For on-drug participants in the semaglutide s.c. 2.4 mg arm, missing week 44 values of body 
weight are imputed based on observed data from the on-drug participants in the semaglutide 
2.4 mg arm and according to the RD-MI procedure described above. This will result in 
1,000 complete data sets for on-drug participants in the semaglutide s.c. 2.4 mg arm.  
2. For the participants in semaglutide placebo arm, missing week 44 values of body weight are 
imputed based on all observed data at all time points in the semaglutide placebo arm, and 
using an MMRM model with gender (male/female), baseline BMI (kg/m2) (in categories 
<35, 35-<40, ≥40) as factors and baseline body weight (kg) as a covariate – all nested within 
visit. An unstructured covariance matrix for measurements within the same subject will be 
employed. Each missing value of body weight at week 44 is imputed 1,000 times by random 
sampling from normal distribution with the MMRM-predicted value at week 44 as mean and 
variance as a sum of prediction variance and residual variance. 
3. For off-drug participants in the semaglutide s.c. 2.4 mg arm, missing week 44 values of 
body weight are imputed from the semaglutide placebo arm assuming that all drug effect 
will be washed out and gone before the landmark visit. The imputation procedure will be 
similar to jump to reference multiple imputation as described in the sensitivity analyses 
section below. An imputation model will be fitted to each of 1,000 complete data sets 
resulting from MMRM imputation for the semaglutide placebo arm in the previous step. The 
estimated posterior distribution for the parameters (regression coefficients and variances) in 
the imputation model from each of 1,000 fits is then used to impute missing week 44 body 
weight values once, ultimately resulting in 1,000 complete data sets for off-drug participants 
in semaglutide s.c. 2.4 mg arm. 
Data sets obtained in steps 1-3 are combined resulting in 1,000 complete data sets for all 
randomised participants. 
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Based on NN9536-4153 phase 2 results 1,000 copies should be sufficient to establish stable results. 
The multiple imputations will be generated using Novo Nordisk trial number 95364707 as seed 
number. In addition to the seed number, it is specified that the dataset is sorted by participant ID. 
4.2.3 
Sensitivity Analyses 
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at 
week 44 for both the semaglutide 2.4 mg and placebo group are imputed by sampling among all 
available assessments at week 44 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 multiple imputation approach is done as above with the first step replaced by:  
 
1. Imputation: Defines an imputation model using semaglutide placebo participants from FAS with 
a week 44 measurement. The model will be a linear regression of body weight (kg) at week 44 with 
gender (male/female) and BMI (kg/m2) (in categories <35, 35-<40, ≥40) as factors and baseline 
body weight (kg) as covariate. No interactions will be included. If the imputation model cannot be 
fit due to inadequate numbers of retrieved participants in one or more groups, then the imputation 
model will be reduced until the model can be fit. Reduction will be done in a fixed order by first 
removing gender, then collapsing the two highest baseline BMI-groups into one (≥35) and finally 
removing baseline BMI-group. The estimated posterior distribution for the parameters (regression 
coefficients and variances) in the imputation models are then used to impute missing week 44 body 
weight values for each randomised treatment arm. This will be done 1,000 times and results in 
1,000 complete data sets.  
 
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Second, for both treatment arms a penalty will be added 
to the imputed values at week 44. The approach is to explore a range of penalties for both treatment 
groups, and the impact these would have on the trial conclusions. The 2-dimensional space of 
penalties covering the range from -30% to 30% will be explored for both treatment groups. This 
sensitivity analysis evaluates the robustness of the superiority conclusions. 
Non-retrieved participants as non-responders: For the 5% responder analysis an analysis using 
participants with missing week 44 assessment as non-responders in the logistic regressions will be 
done.  
ANCOVA for unequal variances: An alternative analysis model for the change in body weight (%) 
similar to the primary analysis model (ANCOVA), but assuming unequal variances instead of equal 
variances. The analysis model includes randomised treatment as factor and baseline body weight 
(kg) as covariate.  
4.2.4 
Supplementary Analyses 
The following statistical analyses are designed to address the additional estimand for the primary 
endpoints. 
The analysis model for change in body weight (%) will be a mixed model for repeated 
measurements (MMRM). The MMRM will use assessments only from participants who are taking 
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the randomised trial intervention until end of treatment or until first discontinuing of randomised 
trial intervention. For participants who experience other intercurrent events (weight management 
drugs or bariatric surgery) before completion or first discontinuing of randomised treatment, the 
date of initiating other anti-obesity therapies will be used as latest date for using assessments in this 
MMRM. The MMRM will be fitted using randomised trial intervention as factor and baseline body 
weight (kg) as covariate all nested within visit. An unstructured covariance matrix for 
measurements within the same participant will be employed, assuming that measurements for 
different participants are independent.  
The analysis model for the 5% responder endpoint is a logistic regression where any missing values 
at week 44 will be predicted from the MMRM. The predicted values will be used to classify each 
participant as 5% responder or not. This classification will then be analysed using a logistic 
regression model with randomised trial intervention as factor and baseline body weight (kg) as 
covariate.  
Table 4-1 
Analyses and imputation methods to address the efficacy estimands for the co-
primary endpoints 
Endpoint 
Endpoint type 
Analysis 
Set 
Estimand 
Statistical 
model  
Imputation 
model 
Sensitivity 
Analysis 
Co-primary endpoints 
Change in 
body weight 
(%) from 
week 0 to 
week 44 
Continuous 
FAS 
 
Treatment 
policy 
ANCOVA 
RD-MI/ 
WO-MI 
J2R-MI, TP-MI, 
ANCOVA for 
unequal variances 
Hypothetical 
MMRM 
- 
- 
≥5% body 
weight 
reduction 
from week 0 
to week 44 
Binary 
FAS 
 
Treatment 
policy 
LR 
RD-MI/ 
WO-MI 
J2R-MI, TP-MI, 
Non-responder 
Hypothetical 
LR 
MMRM 
- 
 
4.3 
Secondary Estimands Analyses 
4.3.1 
Confirmatory Secondary Estimands 
The confirmatory secondary estimands are defined in Section 1.1. 
4.3.1.1 
Definition of Endpoints 
The confirmatory secondary endpoints are: 
 ≥10% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 ≥15% body weight reduction (yes/no) from baseline (week 0) to end of treatment (week 44) 
 Change in waist circumference from baseline (week 0) to end of treatment (week 44) 
4.3.1.2 
Main Analytical Approach 
All confirmatory secondary endpoints will be analysed using the same analysis model and 
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imputation approach as used to address the co-primary estimand for the primary endpoints. 
 
The analysis model for change in waist circumference will be a linear regression (ANCOVA) with 
randomised trial intervention as factor and baseline waist circumference as covariate. 
 
The analysis model for the responder endpoints will be a logistic regression using randomised trial 
intervention as factor and baseline body weight (kg) as covariate.   
4.3.1.3 
Sensitivity Analyses 
For the change in waist circumference, a sensitivity analysis using jump to reference as imputation 
approach will be carried out. For both binary confirmatory secondary endpoints, a sensitivity 
analysis using non-retrieved participants as non-responders will be carried out. 
4.3.1.4 
Supplementary Analyses 
The confirmatory secondary endpoints will be analysed using the same analysis model as used to 
address the additional estimand for the primary endpoints. 
 
The analysis model for change in waist circumference will be a mixed model for repeated 
measurements (MMRM). The MMRM will be fitted using randomised trial intervention as factor 
and baseline waist circumference as covariate all nested within visit. An unstructured covariance 
matrix for measurements within the same participants will be employed, assuming that 
measurements for different participants are independent. 
 
The analysis model for the responder endpoints will be a logistic regression where any missing 
values at week 44 will be predicted from the MMRM. The predicted values will be used to classify 
each participant as a responder or not. This classification will then be analysed using a logistic 
regression model with randomised trial intervention as factor and baseline body weight (kg) as 
covariate. 
Table 4-2 
Analyses and imputation methods to address the secondary estimands for the 
confirmatory secondary endpoints 
Endpoint 
Unit 
Endpoint 
type 
Strategy 
Analysis 
set 
Statistical 
model 
Imputation 
approach 
Sensitivity 
analysis 
≥10% body 
weight reduction 
from week 0 to 
week 44 
Count of 
participant 
Binary 
Treatment 
policy 
FAS 
LR 
RD-MI/ 
WO-MI 
non-
responder 
Hypothetical 
FAS 
LR 
MMRM 
 
≥15% body 
weight reduction 
from week 0 to 
week 44 
Count of 
participant 
Binary 
Treatment 
policy 
FAS 
LR 
RD-MI/ 
WO-MI 
non-
responder 
Hypothetical 
FAS 
LR 
MMRM 
 
Change in waist 
circumference 
from week 0 to 
week 44 
cm 
Continuous 
Treatment 
policy 
FAS 
ANCOVA 
RD-MI/ 
WO-MI 
J2R-MI 
Hypothetical 
FAS 
MMRM 
 
 
4.3.2 
Supportive Secondary Endpoints Analyses 
Analyses addressing the supportive secondary estimand 
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The supportive secondary endpoints will be analysed using the same imputation approach as used 
for the primary endpoints to address the primary estimand. The statistical model for continuous 
endpoints will be the same linear regression as for the primary continuous endpoint (ANCOVA) 
with treatment as a factor and baseline value of the endpoint as covariate. The statistical model for 
responder endpoints will be the same logistic regression as for the primary binary endpoint using 
treatment as a factor and baseline value of the endpoint as covariate.   
Analyses addressing the additional estimand 
The supportive secondary endpoints will be analysed using the same approach as used for the 
primary endpoints to address the additional estimand. 
Table 4-3  
Analyses and imputation methods to address the secondary and additional 
estimands for supportive secondary endpoints 
Endpoint 
Unit 
Endpoint 
type 
Strategy 
Analysis 
set 
Statistical 
model 
Imputation 
approach 
Change in body weight 
from week 0 to week 44 
kg 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
Change in body mass 
index from week 0 to 
week 44 
kg/m2 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
≥20% body weight 
reduction from week 0 to 
week 44 
Count of 
participant 
Binary 
Treatment policy 
FAS 
LR 
RD-MI/WO-MI 
Hypothetical 
FAS 
LR 
MMRM 
Change in systolic blood 
pressure from week 0 to 
week 44 
mmHg 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
Change in diastolic 
blood pressure from 
week 0 to week 44 
mmHg 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
Change in lipids 
 
Triglycerides 
 
Total cholesterol 
 
High density 
lipoprotein (HDL) 
cholesterol 
 
Low density 
lipoprotein (LDL) 
cholesterol 
from week 0 to week 44 
mg/dL 
mmol/L 
 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
Change in hsCRP from 
week 0 to week 44 
mg/dL 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
Change in HbA1c from 
week 0 to week 44 
%-point  
mmol/mol 
Continuous 
Treatment policy 
FAS 
ANCOVA 
RD-MI/WO-MI 
Hypothetical 
FAS 
MMRM 
 
 
Analyses addressing the primary, secondary and additional estimands for responder 
endpoints 
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For all analyses of responder endpoints including both primary and secondary responder endpoints 
(≥5%, ≥10%, ≥15%, ≥20% body weight reduction from week 0 to week 44), in addition to the 
estimated odds ratio, the estimated treatment differences (ETDs) will be provided by calculating the 
responder probabilities and treatment differences between responder probabilities based on the 
logistic regression model, with confidence intervals for treatment differences obtained using the 
delta method. 
Analyses corrected to address the situation if no responder for ≥5%, ≥10%, ≥15%, ≥20% 
body weight reduction from week 0 to week 44 in one treatment group 
If no responder for   ≥5%, ≥10%, ≥15%, ≥20% body weight reduction at week 44 for one treatment 
group, the logistic regression will not fit. Thus, Firth’s approximation will be implemented in order 
to provide valid inference in this situation. 
4.4 
Exploratory Endpoints Analyses 
Exploratory endpoints are listed in Section 1.1. Exploratory endpoints will be summarised by 
descriptive statistics. 
4.5 
Other Safety Analysis 
Adverse events will be defined as “treatment-emergent” (TEAE), if the onset of the event occurs in 
the on-treatment period. TEAEs and SAEs will be summarised by descriptive statistics using the 
SAS, such as frequencies and rates. No formal statistical inference will be carried out based on the 
number of TEAEs and SAEs. All AEs will be coded using the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). 
4.6 
Other Analysis 
All collected data that were not defined as endpoints will be summarised by descriptive statistics. 
4.7 
Subgroup Analysis 
Not applicable for this trial. 
4.8 
Interim Analysis 
Not applicable for this trial. 
4.9 
Changes to Protocol-planned Analysis 
 
The WO-MI model has been specified for the main imputation model if the full RD-MI model 
cannot be fit.  
 
Firth’s approximation has been specified for the situation of no responders in either treatment 
group for ≥5%, ≥10%, ≥15%, ≥20% body weight reduction 
 
In the text describing that “In general, the on-treatment period will therefore be from the date of 
first trial product administration to date of last trial product administration” the following has 
been added “(+14 days)” to emphasize that the lag-time after last trial product administration is 
included in the on-treatment period.  
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CONFIDENTIAL 
Date: 
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Study ID: NN9536-4707 
Version: 
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Status: 
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 
It is clarified that TP-MI imputation is performed with penalties applied to both treatment 
groups. 
 
In the J2R-MI imputation model, the model reduction steps have been pre-specified in case the 
model cannot run.  
 
It is clarified that, in addition to OR, ETD will be reported for logistic regression analyses. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
28 Nov 2023 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
1.0 
 
Status: 
Final 
 
Page: 
23 of 24 
 
 
5 
Sample size determination 
See protocol section 9.5. 
 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
28 Nov 2023 Novo Nordisk 
Study ID: NN9536-4707 
Version: 
1.0 
 
Status: 
Final 
 
Page: 
24 of 24 
 
 
6 
References 
1. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6. 
 
 
 
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