Effect of Subcutaneous Semaglutide 2.4 mg Once-weekly Compared to Placebo in Subjects With Obesity and Knee Osteoarthritis
Phase: PHASE3
Conditions: Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05064735 
Sponsor trial ID: 
NN9536-4578 
Official title of study: 
Effect of subcutaneous semaglutide 2.4 mg once-weekly 
compared to placebo in subjects with obesity and knee 
osteoarthritis 
Document date*: 
21 April 2021 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 and 94 is the date of compilation of the documents and not of an update to 
content. 

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Protocol ...............................................................................................................................................
Protocol attachment ...........................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly 
Study ID: NN9536-4578 (Knee OA) 
Clinical Study Report
Appendix 9.1.1
12 January 2024 
1.0
Final
9.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 

Protocol 
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Date: 
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Trial ID: NN9536-4578 
Version: 
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Protocol
Protocol title: Effect of subcutaneous semaglutide 2.4 mg once-weekly compared to placebo 
in subjects with obesity and knee osteoarthritis 
Substance name: semaglutide 
Universal Trial Number: U1111-1246-5824 
EudraCT Number: 2020-000204-11 
IND Number:126,360 
Trial phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol 
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Date: 
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Trial ID: NN9536-4578 
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Protocol amendment summary of changes table  
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 3.0 
21 April 2021 
CA, CO, DK, FR, NO, RU, SA, ZA, 
ES, SE, US  
Protocol version 2.0 
23 Sep 2020 
CA, CO, DK, FR, NO, RU, SA, ZA, 
ES, SE, US  
Original protocol version 1.0 
 24 July 2020 
CA, CO, DK, FR, NO, RU, SA, ZA, 
ES, SE, US  
 
Protocol version 3.0 (21 April 2021) 
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 Union1 for the 
countries participating in the NN9536-4578 trial.  
Overall rationale for preparing protocol, version 3.0: 
The overall rationale for preparing protocol version 3.0 is to include a pain and pain medication diary, to 
update supportive secondary endpoints and adjust WOMAC assessments with respect to frequency and 
recall period. This is to ensure interpretability of treatment effect. Furthermore, this version of the 
protocol includes an appendix to ensure subject safety and data integrity during COVID-19 and allows 
for co-participation in COVID-19 related trials.  
Co-participation in other clinical trials is generally not allowed while participating in a Novo Nordisk 
trial. However, given the large societal impact of the COVID-19 pandemic, Novo Nordisk will allow for 
co-participation in trials with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious 
conditions. For the current trial it has been evaluated that the safety profile of semaglutide is well 
established and based on current knowledge it is expected that co-participation in COVID-19 trials will 
not lead to unreasonable unforeseen risks for trial subjects. Exclusion criterion 25 and discontinuation 
criterion 5 regarding simultaneous participation in other trials has thus been amended, and changes have 
been made to registration of concomitant illness and handling of AEs. 
Section # and name 
Description of change 
Brief rationale 
Section 1.2 Flowchart 
Addition of WOMAC assessments at 
V3, V5, V6, V8, V10, V12. 
To have a more adequate frequency 
of time points for pain assessment to 
capture pain intensity change over 
the entire treatment course. 
Section 1.2 Flowchart 
PGI-S will not be assessed at V4 and 
V9. 
Assessment removed as it will not be 
used in the analysis. 
Section 1.2 Flowchart 
PGI-C will not be assessed at V2, 
V4, and V9. 
Assessment removed as it will not be 
used in the analysis. 
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Section 1.2 Flowchart 
Addition of a pain and pain 
medication diary (training and 
review). 
Daily pain scores are included as 
complementary evidence and permits 
averaging pain intensity by week to 
reduce the effect of daily variability. 
Recording pain medication enables a 
comparison of change in use of pain 
medication and grouping according 
to type of pain medication used. 
Section 2.3 Benefit-risk assessment 
Addition of risk of COVID-19 
infection and overall neoplasms, and 
minor updates of text to reflect most 
recent data. Updated text on benefits. 
To include the current risk of 
COVID-19 infection, overall 
neoplasms and allergic reactions as 
well as reflect the newest efficacy 
data in the benefit risk section. 
Section 3.2 Primary, secondary and 
exploratory endpoint(s) 
Addition and reorganisation of 
secondary and exploratory 
endpoints. 
To include endpoints which reflect 
the data obtained in the pain and pain 
medication diary  
Section 5.2 Exclusion criteria 
Rephrased exclusion criteria 4 and 5. 
Rephrased to avoid 
misinterpretation. 
Section 5.2 Exclusion criteria 
Amending the exclusion criterion 25, 
so that subjects are allowed to be 
included in the trial, while also 
participating in a COVID-19 trial. 
To allow for simultaneous 
participation in current trial and a 
COVID-19 trial.  
Section 6.5 Concomitant medication 
Amending the use of a pain and pain 
medication diary and specifying that 
all pain medication is allowed. 
Daily pain scores are included as 
complementary evidence and the use 
of pain medication will be used to 
analyse treatment effect in subjects 
grouped according to the pain 
medication they use. 
Section 7.1 Discontinuation of trial 
treatment 
Amending the discontinuation 
criterion 5, so that subjects are 
allowed to continue in the trial, while 
also participating in a COVID-19 
trial. 
To allow for simultaneous 
participation in current trial and a 
COVID-19 trial.  
Section 8.1 Efficacy assessments 
Rephrased the WOMAC description. 
Recall period is changed to 24-hours. 
Addition of a description of the pain 
and pain medication diary. 
To have a more adequate pain 
outcome assessment recall period. 
The pain and pain medication diary 
is added to capture changes in pain 
and pain medication. 
Section 8.2 Safety assessments 
Inclusion of Cardiovascular Disorder 
and Procedure as part of the 
concomitant illness/medical history 
to be recorded in the eCRF. 
To reflect the most updated eCRF. 
Section 8.2 Safety assessments 
Inclusion of COVID-19 as part of 
the concomitant illness/medical 
history to be recorded in the eCRF 
When participation in a COVID-19 
trial is allowed, the registration of 
any COVID-19 infections in the 
subjects is relevant. 
Section 8.3 Adverse events and 
serious adverse events 
Addition of COVID-19 related AEs 
to the list of AEs that the investigator 
is responsible for detecting, 
documenting, recording and 
following up on. 
When participation in a COVID-19 
trial is allowed, the handling of 
COVID-19 related AEs is relevant. 
Section 9.4.2 Primary endpoint(s) 
Addition of WOMAC pain score to 
be taken into account when imputing 
missing data. 
To reflect both primary endpoints in 
the imputation. 
Section 10.3.5 Reporting of SAEs 
Inclusion of COVID-19 related AEs 
in the Figure 10-1 “Decision tree for 
determining the event type and the 
respective forms to complete with 
associated timelines”. 
When participation in a COVID-19 
trial is allowed, the handling of 
COVID-19 related AEs is relevant to 
ensure alignment between 
Figure 10-1 and Section 8.3 
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Section 10.6 Appendix 6 
Amending the appendix: Mitigations 
to ensure subject safety and data 
integrity during COVID-19 
To have mitigations in place in case 
local restrictions due to a COVID-19 
outbreak lead to lock-down of a site. 
Section 10.7 Appendix 7 
Deletion of country requirements for 
Russia 
The text is included in the 
Agreement with sites. 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 5 
1 Protocol summary ....................................................................................................................................... 8 
1.1 
Synopsis .............................................................................................................................................. 8 
1.2 
Flowchart .......................................................................................................................................... 11 
2 Introduction ............................................................................................................................................... 14 
2.1 
Trial rationale .................................................................................................................................... 14 
2.2 
Background ....................................................................................................................................... 15 
2.2.1 
Semaglutide ....................................................................................................................... 15 
2.3 
Benefit-risk assessment ..................................................................................................................... 15 
2.3.1 
Risk assessment ................................................................................................................. 16 
2.3.2 
Benefit assessment ............................................................................................................. 18 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 19 
3 Objectives and endpoints .......................................................................................................................... 20 
3.1 
Primary, secondary and exploratory objective(s) and estimand(s) ................................................... 20 
3.2 
Primary, secondary and exploratory endpoint(s) .............................................................................. 22 
3.2.1 
Primary endpoints .............................................................................................................. 22 
3.2.2 
Secondary endpoints .......................................................................................................... 22 
3.2.2.1 
Confirmatory secondary endpoints ................................................................ 22 
3.2.2.2 
Supportive secondary endpoints .................................................................... 22 
3.2.3 
Exploratory endpoint(s) ..................................................................................................... 23 
4 Trial design ................................................................................................................................................ 24 
4.1 
Overall design ................................................................................................................................... 24 
4.2 
Scientific rationale for trial design .................................................................................................... 24 
4.3 
Justification for dose ......................................................................................................................... 25 
4.4 
End of trial definition ........................................................................................................................ 25 
5 Trial population ......................................................................................................................................... 26 
5.1 
Inclusion criteria ............................................................................................................................... 26 
5.2 
Exclusion criteria .............................................................................................................................. 26 
5.3 
Lifestyle considerations .................................................................................................................... 27 
5.3.1 
Caffeine and tobacco ......................................................................................................... 28 
5.4 
Screen failures ................................................................................................................................... 28 
5.5 
Randomisation criteria ...................................................................................................................... 28 
5.5.1 
Randomisation criteria ....................................................................................................... 28 
6 Treatments ................................................................................................................................................. 29 
6.1 
Treatments administered ................................................................................................................... 29 
6.1.1 
Medical devices ................................................................................................................. 31 
6.1.2 
Diet and Physical Activity counselling ............................................................................. 31 
6.1.2.1 
Non-investigational medical device(s) ........................................................... 31 
6.2 
Preparation/handling/storage/accountability ..................................................................................... 31 
6.2.1 
Shipment of trial product to subject’s home ...................................................................... 32 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 33 
6.4 
Treatment compliance ....................................................................................................................... 33 
6.5 
Concomitant medication ................................................................................................................... 33 
6.5.1 
Rescue medication ............................................................................................................. 34 
6.6 
Dose modification ............................................................................................................................. 34 
6.7 
Treatment after end of trial ............................................................................................................... 34 
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7 Discontinuation of trial treatment and subject discontinuation/withdrawal ....................................... 35 
7.1 
Discontinuation of trial treatment ..................................................................................................... 35 
7.1.1 
Temporary discontinuation of trial treatment .................................................................... 36 
7.1.2 
Rescue criteria ................................................................................................................... 36 
7.2 
Subject discontinuation/withdrawal from the trial ............................................................................ 36 
7.2.1 
Replacement of subjects .................................................................................................... 36 
7.3 
Lost to follow-up............................................................................................................................... 37 
8 Trial assessments and procedures............................................................................................................ 38 
8.1 
Efficacy assessments ......................................................................................................................... 38 
8.1.1 
Western Ontario and McMaster Universities Osteoarthritis Index ................................... 38 
8.1.2 
Body measurements ........................................................................................................... 39 
8.1.3 
Pain and pain medication diary ......................................................................................... 39 
8.1.4 
Clinical outcome assessments ........................................................................................... 40 
8.2 
Safety assessments ............................................................................................................................ 41 
8.2.1 
Radiographic examinations ............................................................................................... 42 
8.2.2 
Physical examinations ....................................................................................................... 42 
8.2.3 
Vital signs .......................................................................................................................... 42 
8.2.4 
Clinical safety laboratory assessments .............................................................................. 42 
8.3 
Adverse events and serious adverse events ....................................................................................... 42 
8.3.1 
Time period and frequency for collecting AE and SAE information ................................ 43 
8.3.2 
Method of detecting AEs and SAEs .................................................................................. 44 
8.3.3 
Follow-up of AEs and SAEs ............................................................................................. 44 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 44 
8.3.5 
Pregnancy .......................................................................................................................... 44 
8.3.6 
Cardiovascular and death events ....................................................................................... 44 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE.................................................................................................................................... 44 
8.3.8 
Adverse event of special interest ....................................................................................... 45 
8.3.9 
Technical complaints ......................................................................................................... 45 
8.4 
Treatment of overdose ...................................................................................................................... 45 
8.5 
Pharmacokinetics .............................................................................................................................. 45 
8.6 
Pharmacodynamics ........................................................................................................................... 45 
8.7 
Genetics ............................................................................................................................................ 45 
8.8 
Biomarkers ........................................................................................................................................ 45 
8.9 
Immunogenicity assessments ............................................................................................................ 46 
8.10 Health economics .............................................................................................................................. 46 
9 Statistical considerations .......................................................................................................................... 47 
9.1 
Statistical hypotheses ........................................................................................................................ 47 
9.2 
Sample size determination ................................................................................................................ 47 
9.3 
Populations for analyses ................................................................................................................... 50 
9.4 
Statistical analyses ............................................................................................................................ 51 
9.4.1 
General considerations ...................................................................................................... 51 
9.4.2 
Primary endpoint(s) ........................................................................................................... 51 
9.4.3 
Secondary endpoints .......................................................................................................... 52 
9.4.3.1 
Confirmatory secondary endpoints ................................................................ 52 
9.4.3.2 
Supportive secondary endpoints .................................................................... 53 
9.4.4 
Exploratory endpoints........................................................................................................ 53 
9.4.5 
Other safety analyses ......................................................................................................... 53 
9.4.6 
Other analyse(s) ................................................................................................................. 53 
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling .................................. 53 
9.5 
Interim analyses ................................................................................................................................ 54 
9.6 
Data monitoring committee .............................................................................................................. 54 
9.7 
Reporting of the main part of the trial ............................................................................................... 54 
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10 Supporting documentation and operational considerations.................................................................. 55 
10.1 Appendix 1: Regulatory, ethical, and trial oversight considerations ................................................ 55 
10.1.1 
Regulatory and ethical considerations ............................................................................... 55 
10.1.2 
Financial disclosure ........................................................................................................... 55 
10.1.3 
Informed consent process .................................................................................................. 55 
10.1.4 
Information to subjects during trial ................................................................................... 56 
10.1.5 
Data protection .................................................................................................................. 56 
10.1.6 
Committees structure ......................................................................................................... 57 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 57 
10.1.6.2 
Trial safety group ........................................................................................... 57 
10.1.6.3 
Data monitoring committee............................................................................ 57 
10.1.6.4 
Event adjudication committee ........................................................................ 57 
10.1.7 
Dissemination of clinical trial data .................................................................................... 57 
10.1.8 
Data quality assurance ....................................................................................................... 58 
10.1.8.1 
Case report forms ........................................................................................... 58 
10.1.8.2 
Monitoring ..................................................................................................... 58 
10.1.8.3 
Protocol compliance ....................................................................................... 59 
10.1.9 
Source documents. ............................................................................................................. 59 
10.1.10 Retention of clinical trial documentation .......................................................................... 59 
10.1.11 Trial and site closure.......................................................................................................... 60 
10.1.12 Responsibilities .................................................................................................................. 60 
10.1.13 Indemnity statement .......................................................................................................... 61 
10.1.14 Publication policy .............................................................................................................. 61 
10.1.14.1 
Communication of results .............................................................................. 61 
10.1.14.2 
Authorship ...................................................................................................... 62 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 62 
10.1.14.4 
Investigator access to data and review of results ........................................... 62 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 63 
10.3 Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 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 ..................................................................... 66 
10.3.5 
Reporting of SAEs ............................................................................................................. 68 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 70 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 73 
10.5.1 
Definition of technical complaint ...................................................................................... 73 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 73 
10.5.3 
Reporting of technical complaints ..................................................................................... 74 
10.6 Appendix 6: Mitigations to ensure subject safety and data integrity during COVID-19 .................. 75 
10.6.1 
Visits .................................................................................................................................. 75 
10.6.2 
Assessments ....................................................................................................................... 75 
10.6.3 
Minimum assessments following randomisation to be performed during lockdown ........ 76 
10.7 Appendix 7: Country-specific requirements ..................................................................................... 78 
10.8 Appendix 8: Abbreviations ............................................................................................................... 82 
10.9 Appendix 9: Protocol amendment history ........................................................................................ 84 
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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1 
Protocol summary 
1.1 
Synopsis 
The prevalence of obesity has reached epidemic proportions in most countries around the world and the 
prevalence is still increasing at an alarming rate. The medical and societal impacts are extensive, and 
obesity is one of the most significant public health challenges worldwide2-8. 
 
Obesity is associated with an increased risk of a variety of complications, including osteoarthritis (OA), 
affects physical and mental health and reduces health-related quality of life9-23.  
With the increasing prevalence of obesity, the health issues related to knee OA will intensify with 
huge consequence for society and the individual patient. Due to the pivotal role of the knee in basic 
mobility and locomotion, knee OA is associated with significant impairments and limitations to 
basic activities of daily living. The physical disability of knee OA arising from pain and loss of 
functional capacity reduces health-related quality of life and increases the risk of further morbidity. 
Rationale: 
Weight loss is strongly recommended as a primary management strategy in subjects with knee OA 
and obesity24. However, no specific guidance on how to achieve this is given, and no widely 
available and feasible means to sustain weight loss in subjects with knee OA and obesity have been 
presented. 
There is a clear association between obesity and knee OA with obesity being a major risk factor for 
the incidence and progression of OA, and negatively influences disease outcomes25, 26. 
In accordance, American College of Rheumatology (ACR) guidelines strongly recommend weight 
loss in subjects with knee OA and obesity as first line treatment24.  
A significant relationship between weight loss above 10% of body weight and improvement in pain 
and function has been demonstrated in subjects with knee OA and obesity27,28, 29. Pharmacotherapy 
may therefore serve as a valuable adjunct to lifestyle intervention for individuals with knee OA and 
obesity in order to achieve a sufficient and sustainable weight loss. In a recent phase 3a study 
(NN9536-4373) semaglutide s.c. 2.4 mg once-weekly led to a weight loss of 14.9% in subjects with 
overweight and obesity. 
Objectives and endpoints: 
Primary objective 
To confirm superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in change from baseline to week 68 in body weight and knee OA-related pain. 
Secondary objectives  
To confirm superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in achieving body weight response criteria after 68 weeks from baseline as well as change from 
baseline to week 68 in knee OA-related and general physical function. 
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To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in change from baseline to week 68 in waist circumference, knee OA-related stiffness, overall 
knee OA-related physical limitations, general health-related quality of life, and in use of analgesics. 
Primary estimand 
The primary estimand is the average treatment effect of semaglutide s.c. 2.4 mg once-weekly 
relative to semaglutide placebo as an adjunct to a reduced-calorie diet and increased physical 
activity, in patients with obesity and knee OA, measured by change from baseline to week 68 in 
body weight and knee OA-related pain, regardless of adherence to randomised treatment, regardless 
of initiating other anti-obesity therapies (weight management drugs or bariatric surgery) or other 
knee OA interventions (joint replacement or steroid injection or opioid medication or medical 
marijuana) and regardless of compliance with washout period for pain medication (the latter only 
relevant in this context for knee OA-related pain) (“treatment policy” strategy). 
Primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline (week 0) to end of 
treatment (week 68) 
% 
Change in WOMAC pain score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
WOMAC; Western Ontario and McMaster Universities Osteoarthritis Index 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Achieving body weight reduction 
≥5% (yes/no) 
From baseline (week 0) to end of 
treatment (week 68) 
Count of subject 
Achieving body weight reduction 
≥10% (yes/no) 
From baseline (week 0) to end of 
treatment (week 68) 
Count of subject 
Change in WOMAC physical 
function score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 physical 
functioning score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Overall design: 
This is a 68-week, randomised, two-arm, double-blinded, multi-centre clinical trial comparing 
semaglutide s.c. 2.4 mg once-weekly with semaglutide placebo in subjects with moderate OA of 
one or both knees, pain due to knee OA, and obesity (BMI ≥30.0 kg/m2). 
Eligible subjects fulfilling all randomisation criteria at visit 2 will be randomised in a 2:1 manner to 
receive either semaglutide s.c. 2.4 mg or semaglutide placebo once-weekly as adjunct to a reduced-
calorie diet and increased physical activity.  
Key inclusion criteria: 
• Male or female, age above or equal to 18 years at the time of signing informed consent 
• Body Mass Index (BMI) ≥30.0 kg/m2 
• Clinical diagnosis of knee OA (American College of Rheumatology (ACR) criteria) with 
moderate radiographic changes (Kellgren-Lawrence (KL) grades 2 or 3 as per central 
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reading) in target knee. Target knee joint is defined as most symptomatic knee at screening. 
If pain in knees are equal target knee joint will be in the most dominant leg.  
• Pain due to knee OA  
Key exclusion criteria:  
• Joint replacement in target knee 
• Arthroscopy or injections into target knee within last 3 months prior to enrolment 
• Any other joint disease in the target knee 
Number of subjects: 
Approximately 420 subjects will be screened to achieve 375 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
• The total trial duration for the individual subject will be approximately 76 weeks. The trial 
includes a screening period of approximately 2 weeks followed by randomisation. Dose 
escalation of semaglutide/semaglutide placebo will take place every 4 weeks during the first 
16 weeks after randomisation. All subjects should aim at reaching the target dose of 
semaglutide 2.4 mg once-weekly. Following randomisation, visits are scheduled every 8th 
week until end-of-treatment (week 68). Follow-up period is 7 weeks after end-of-treatment.     
• The following trial products will be supplied by Novo Nordisk A/S for the duration of the 
trial:  
o Semaglutide B 3.0 mg/mL PDS290 and semaglutide placebo, solution for injection, 
3 mL PDS290 pre-filled injector  
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1.2 
Flowchart 
 
Screening 
Randomisation 
Dose escalation period 
Treatment period 
End of 
treatment 
End of 
trial 
Visit (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Timing of Visit (Weeks) 
-1 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
60 
68 
75 
Visit Window (Days) 
-7 to 0 
±0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
SUBJECT RELATED INFORMATION AND 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent and Demographya (Appendix 
1, Section 10.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria (5.1) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation Criteria & Randomisation (5.5) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History/Concomitant Illness (8.2 /6.5) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco Useb (5.3.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Childbearing Potential (Appendix 4, Section 
10.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc (8.3.5) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Knee Radiography (8.2.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Measurements (8.1.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Body Weight 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
     Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Waist Circumference 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Clinical Outcome Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Western Ontario and McMaster Universities   
Osteoarthritis Index (WOMAC) (8.1.1) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening 
Randomisation 
Dose escalation period 
Treatment period 
End of 
treatment 
End of 
trial 
Visit (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Timing of Visit (Weeks) 
-1 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
60 
68 
75 
Visit Window (Days) 
-7 to 0 
±0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
     Patient Global Impression of Status (PGI-S) 
Pain 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
    Patient Global Impression of Change (PGI-C) 
Pain 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     Short Form 36 V2.0 acute (SF-36) (8.1.4) 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
     PGI-S Physical Function 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     PGI-C Physical Function 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     Six-Minute Walking Test (8.1.4) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (8.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Technical Complaint (8.3.9) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (8.2.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Systolic Blood Pressure 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
     Diastolic Blood Pressure 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
     Pulse 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical Examination (8.2.2) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Assessments (Appendix 2, Section 
10.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Hemoglobin A1c (HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TRIAL MATERIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     IWRS Session 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of Trial Product (6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
Randomisation 
Dose escalation period 
Treatment period 
End of 
treatment 
End of 
trial 
Visit (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Timing of Visit (Weeks) 
-1 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
60 
68 
75 
Visit Window (Days) 
-7 to 0 
±0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
     Dispensing Visit 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
     Drug Accountability 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
REMINDERS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria for discontinuation (7.1)  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Barriers and motivation interview (8) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet and physical activity counselling (6.1.2) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Training in the use of the pain and pain 
medication diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of the pain and pain medication diaryd 
(8.1.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hand out direction for use (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Training in trial product, pen-handling 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Hand out dose reminder card (6.1) 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Hand out ID card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Demography consists of date of birth, sex, ethnicity, and race (according to local regulation). 
b Smoking is defined as smoking at least one cigarette or equivalent daily. 
c For all female subjects of child-bearing potential. 
d The pain and pain medication diary should be filled in on a daily basis by the subject
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2 
Introduction 
Knee osteoarthritis and obesity 
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate. The medical and societal impacts are extensive, 
and obesity is one of the most significant public health challenges worldwide2-8. 
Obesity is associated with an increased risk of a variety of complications including osteoarthritis 
(OA), type 2 diabetes (T2D), dyslipidaemia, hypertension, cardiovascular disease, obstructive sleep 
apnoea, non-alcoholic fatty liver disease, urinary incontinence, several types of cancers, and 
increased mortality.9-23 
The risk of obesity-related complications increases with increasing body mass index (BMI) and 
body weight loss has been shown to have significant health benefits on many obesity-related 
complications as well as physical symptoms and health-related quality of life30-37. 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 loss38-47.  
With the increasing prevalence of obesity, the health issues related to knee OA will intensify with 
huge consequence for society and the individual patient. Obesity and the increased weight bearing 
are attributable to development and progressions of knee OA being a highly disabling degenerative 
joint disease22, 25. Due to the pivotal role of the knee in basic mobility and locomotion, knee OA is 
associated with significant impairments and limitations to basic activities of daily living. The 
physical disability of knee OA arising from pain and loss of functional capacity reduces quality of 
life and increases the risk of further morbidity26.  
Weight loss is associated with a reduced risk of knee OA progression and improvement in pain and 
function regardless of the extent of radiological changes and knee OA grading27, 48, 49. However, in 
the IDEA trial only a reduction in baseline body weight of above 10% significantly reduced pain 
and improved function in subjects with knee OA and obesity27.  
Based on a systematic literature review, the ACR guidelines strongly recommends as primary 
management strategy that subjects with knee OA and obesity lose weight and participate in physical 
activity programme commensurate with their ability to perform these activities24. Furthermore, as 
obesity is an additional limiting factor in participating in physical activity programmes, weight loss 
will have both direct and indirect positive effect on management strategy and symptom relief in 
knee OA.   
2.1 
Trial rationale 
Weight loss is strongly recommended as a primary management strategy in subjects with knee OA 
and obesity24. However, no specific guidance on how to achieve this is given, and no widely 
available and feasible means to sustain weight loss in subjects with knee OA and obesity have been 
presented. 
Subjects with knee OA and obesity show a very specific pathophysiological profile compared to the 
population with knee OA without obesity. Subjects with knee OA and obesity have decreased 
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quality of life, more pain and limited physical function compared to subjects with knee OA without 
obesity24.  
A reduction in baseline body weight loss above 10% significantly improves function and reduce 
pain in subjects with knee OA and obesity27. Semaglutide is a glucagon-like-peptide 1 (GLP-1) 
receptor agonist (RA) currently under development by Novo Nordisk A/S for weight management 
and treatment of obesity. Semaglutide is expected to provide a body weight loss of up to 10-15%50. 
The aim of the present trial is to investigate the effects of semaglutide s.c. 2.4 mg once-weekly on 
weight loss, knee OA-related pain and physical function, and health-related quality of life in a 
patient population with obesity and knee OA. 
2.2 
Background 
2.2.1 
Semaglutide 
Semaglutide is a long-acting GLP-1 RA currently under development by Novo Nordisk A/S for 
weight management. Semaglutide has a half-life of approximately 160 hours, making it suitable for 
once-weekly dosing51. GLP-1 is a physiological regulator of appetite, and a postprandial GLP-1 
response is present in several areas of the brain involved in appetite regulation52. 
Clinical53-58 and non-clinical58 data indicate that the body weight reducing effect of semaglutide is 
mainly mediated by a reduced energy intake.  
A 52-week phase 2 dose-finding trial within weight management (NN9536-4153) has been 
completed. An overall monotone dose-dependent weight loss was observed across the 5 
semaglutide doses tested (0.05 to 0.4 mg once-daily). The estimated weight loss at week 52 was 
13.8% at the highest dose tested (0.4 mg once-daily) compared to the weight loss of 2.3% achieved 
by diet, exercise and placebo alone50 . Based on results from this trial, a target dose of 2.4 mg of 
semaglutide s.c. once-weekly was used for the clinical phase 3a and 3b programme50.   
The 68-week phase 3a weight management trial, STEP 1 (NN9536-4373) has demonstrated clinical 
significant weight loss with semaglutide and is currently in the reporting phase. A total of 1,961 
subjects were included in the trial: 1,306 randomised to semaglutide s.c. 2.4 mg once-weekly and 
655 to placebo. At week 68, subjects 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.  
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)50 and any updates hereof.  
2.3 
Benefit-risk assessment 
Main benefits and risks 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 IB50 or any updates hereof.   
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2.3.1 
Risk assessment 
Potential risk of clinical 
significance 
 
Summary of data/rationale for 
risk 
 
Mitigation strategy 
 
Trial treatment(s)  
Gastrointestinal AE 
 
Consistent with findings with other 
GLP-1 RAs, the most frequently 
reported adverse events (AE) in 
clinical trials 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 subjects treated with GLP-1 RAs, 
nausea, vomiting and diarrhoea may 
lead to significant dehydration. This 
should be considered when treating 
subjects with impaired renal function 
as it may cause a deterioration of 
renal function. 
 
A low starting dose and dose 
escalation steps will be implemented 
to mitigate the risk of developing 
gastrointestinal symptoms.  
 
Subjects 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 trials cholelithiasis was reported 
in 1.6% and led to cholecystitis in 
0.6% of patients 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 trials was 0.2% 
for semaglutide 2.4 mg and <0.1% 
for placebo, respectively. 
Subjects with a history of chronic 
pancreatitis or recent acute 
pancreatitis will not be enrolled in 
the trial. In addition, trial product 
should be discontinued in case of 
suspicion of acute pancreatitis in 
accordance to Section 7.1 
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Medullary thyroid cancer (MTC) 
(based on non-clinical data) 
Proliferative thyroid C-cell changes 
were seen in the mouse and rat 
carcinogenicity studies after daily 
exposure to semaglutide for 2 years. 
No hyperplasia was observed in 
monkeys after 52 weeks exposure up 
to 13-fold above the clinical plasma 
exposure at 2.4 mg/week. In clinical 
trials with semaglutide, there have 
been no clinically relevant changes 
in calcitonin levels. The C-cell 
changes in rodents are mediated by 
the GLP-1 receptor, which is not 
expressed in the normal human 
thyroid. Accordingly, the risk of 
GLP-1 receptor-mediated C-cell 
changes in humans is considered to 
be low.  
Exclusion criteria related to medical 
history of multiple endocrine 
neoplasia type 2 (MEN2) or MTC 
have been implemented.  
Pancreatic cancer 
There is currently no support from 
non-clinical studies, clinical trials or 
post-marketing data that GLP-1 RA 
based therapies increase the risk of 
pancreatic cancer, but pancreatic 
cancer has been classified as a 
potential class risk of GLP-1 RAs by 
European Medicines Agency.  
Subjects with a history of malignant 
neoplasms within the past 5 years 
prior to screening will be excluded 
from the trial.  
Allergic reactions 
As is the case with all protein-based 
pharmaceuticals, treatment with 
semaglutide may evoke allergic 
reactions, including serious allergic 
reactions such as angioedema and 
anaphylactic reactions.   
As a precaution, subjects with 
known or suspected hypersensitivity 
to semaglutide or related products 
will not be enrolled in this trial. In 
addition, subjects will be instructed 
to contact the site staff as soon as 
possible for further guidance if 
suspicion of a hypersensitivity 
reaction to the trial product occurs. 
Neoplasms (malignant and non-
malignant) 
Patients with overweight or obesity, 
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. However, in the 
semaglutide s.c. as well as oral 
semaglutide phase 3a trials for T2D, 
the proportion of subjects with 
neoplasms (malignant and non-
malignant) were slightly higher with 
semaglutide than with comparator. 
The number of subjects exposed to 
semaglutide s.c. or oral semaglutide 
for a longer period is considered 
insufficient for a thorough 
assessment of the risk of neoplasms. 
Subjects with a history of malignant 
neoplasms within the past 5 years 
prior to screening will not be 
enrolled in this trial. Basal 
and squamous cell skin cancer and 
any carcinoma in-situ is allowed 
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Risk of COVID-19 infection in 
relation to participation in study 
Available data does not suggest an 
increased risk of infection or a more 
severe progression of infection when 
treated with semaglutide. 
Detailed information about the 
known risks for semaglutide can be 
found in the investigator’s brochure. 
Trial procedures 
Pain analgesics washout period  
 
There is a potential risk of increased 
pain  
Washout period is short in duration. 
Use of rescue medication 
(acetaminophen) is allowed during 
wash out until 24 hours before visit 
Risk of COVID-19 infection in 
relation to participation in study 
Patients 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 
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however this 
may vary between geographical 
areas. 
To minimize the risk as much as 
possible, the following measures 
have been taken: 
Cautious patient recruitment 
planning ensures controlled patient 
enrolment in countries where the 
COVID-19 pandemic is evaluated to 
be sufficiently under control, and at 
sites where health care resources are 
evaluated to be adequate 
Study procedures including the 
number and frequency of study 
procedures and assessments have 
already during the protocol 
development been evaluated to limit 
the number of on-site visits. 
Additionally, we allow subjects that 
are treatment discontinued to convert 
on-site visits to phone (see Section 
7.1). 
Physical contact between subjects 
and site staff will be limited to the 
extent possible, and protective 
measures will be implemented 
according to local practice. 
Appendix 6 (Section 10.6) includes 
mitigations that can be implemented 
to ensure subject safety and data 
integrity in case a COVID-19 
outbreak leads to lock-down of sites 
which affects the ability to perform 
trial related procedures.  
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. Exclusion and 
discontinuation criteria related to 
pregnancy have been implemented. 
AE, adverse events; GLP-1 RA, Glucagon-like-peptide-1 receptor agonist; MTC, medullary thyroid cancer; MEN2, 
multiple endocrine neoplasia type 2 
2.3.2 
Benefit assessment 
Subjects will be treated with a regimen anticipated to be better than or equal to the weight 
management they receive at the time of entry into the trial. The 68-week phase 3a weight 
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management trials, STEP 1 (NN9536-4373), have demonstrated clinically significant weight loss 
with semaglutide s.c. 2.4 mg once-weekly. Semaglutide s.c. 2.4 mg once-weekly was overall well-
tolerated, and the safety and tolerability profile was consistent with other GLP-1 RAs.  
In addition, it is expected that subjects will benefit from participation through close contact with the 
trial site and counselling by a dietician or a similar qualified healthcare professional, all of which 
will most likely result in intensified weight management. In addition, subjects will benefit from 
physical activity counselling and from improved physical function and knee pain reduction with 
body weight lowering. It is anticipated that all subjects will benefit from participation, but the effect 
will be greater in subjects 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 trial in 
order to minimise the risks (including the risk of transmission of infectious diseases such as 
COVID-19) and inconveniences of participation in the trial. The safety profile for semaglutide 
generated from the clinical and non-clinical development programmes has not revealed any safety 
issues that would prohibit administration of semaglutide s.c. 2.4 mg once-weekly. Results from four 
phase 3a trials with semaglutide s.c. 2.4 mg once-weekly (NN9536-4373, -4374, -4375 and -4376) 
have demonstrated that semaglutide s.c. 2.4 mg once-weekly can provide a clinically meaningful 
weight loss. The anticipated benefits from diet and physical activity counselling will include all 
subjects participating in this trial. 
Taking into account the measures taken to minimise risk to subjects participating in this trial, the 
potential risks identified in association with semaglutide are justified by the anticipated benefits that 
may be afforded to subjects with obesity and knee OA. 
 
 
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3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objective(s) and estimand(s) 
Primary objectives 
To confirm superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in change from baseline to week 68 in body weight and knee OA-related pain. 
Secondary objectives 
To confirm superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in achieving body weight response criteria after 68 weeks from baseline as well as change from 
baseline to week 68 in knee OA-related and general physical function. 
To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in change from baseline to week 68 in waist circumference, knee OA-related stiffness, overall 
knee OA-related physical limitations, general health-related quality of life, and in use of analgesics. 
Exploratory objectives 
To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as 
adjunct to a reduced-calorie diet and increased physical activity in subjects with obesity and knee 
OA in change from baseline to week 68 in selected SF-36 domain scores and on walking distance. 
Primary estimand 
The primary clinical question of interest is: what is the average treatment effect of semaglutide s.c. 
2.4 mg once-weekly relative to semaglutide placebo as an adjunct to a reduced-calorie diet and 
increased physical activity, in patients with obesity and knee OA, measured by change from 
baseline to week 68 in body weight and knee OA-related pain, regardless of adherence to 
randomised treatment, regardless of initiating other anti-obesity therapies (weight management 
drugs or bariatric surgery) or other knee OA interventions (joint replacement or steroid injection or 
opioid medication or medical marijuana) and regardless of compliance with washout period for pain 
medication (the latter only relevant in this context for knee OA-related pain) (“treatment policy” 
strategy).  
The estimand is described by the following attributes (according to ICH E9(R1)): 
• Treatment condition: The randomised treatment regardless of adherence or initiation of other 
anti-obesity therapies (as defined above) or other knee OA interventions (as defined above) 
• Population: Patients with obesity and knee OA 
• Endpoints: The two primary endpoints relative change in body weight and change in Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score both from 
baseline to week 68 
• Remaining intercurrent events: The intercurrent events “treatment discontinuation for any 
reason”, “initiation of other anti-obesity therapies” and “initiation of other knee OA 
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interventions” are addressed by the treatment condition attribute. The remaining intercurrent 
event is “compliance with washout period for pain medication” (in general only applicable to 
WOMAC endpoints), which is handled by the treatment policy strategy. 
• Population-level summary: Difference in mean changes between treatment conditions 
A similar estimand applies to all secondary endpoints (confirmatory and supportive), which is 
called secondary estimand. The population-level summary for body weight response endpoints is 
the ratio of odds between treatment conditions. 
Rationale for estimand: The primary (and secondary) estimand was requested by different 
regulatory authorities and it aims at reflecting how patients with obesity are treated in clinical 
practice. 
Additional estimand 
An additional clinical question of interest is: what is the average treatment effect of semaglutide s.c. 
2.4 mg once-weekly relative to semaglutide placebo as an adjunct to a reduced-calorie diet and 
increased physical activity, in patients with obesity and knee OA, measured by change from 
baseline to week 68 in body weight and knee OA-related pain, had they remained on their 
randomised treatment for the entire planned duration of the trial, not initiated other anti-obesity 
therapies (weight management drugs or bariatric surgery) or other knee OA interventions (joint 
replacement or steroid injection or opioid medication or medical marijuana) and had they 
additionally complied with the washout period for pain medication (the latter only relevant in this 
context for knee OA-related pain) (“hypothetical” strategy).  
The estimand is described by the following attributes (according to ICH E9(R1)): 
• Treatment condition: The randomised treatment if patients had adhered for the entire duration of 
the trial, not initiated other anti-obesity therapies (as defined above) or other knee OA 
interventions (as defined above) 
• Population: Patients with obesity and knee OA 
• Endpoints: The two primary endpoints relative change in body weight and change in WOMAC 
pain score both from baseline to week 68 
• Remaining intercurrent events: The intercurrent events “treatment discontinuation for any 
reason”, “initiation of other anti-obesity therapies” and “initiation of other knee OA 
interventions” are addressed by the treatment condition attribute. The remaining intercurrent 
event is “compliance with washout period for pain medication” (in general only applicable to 
WOMAC endpoints), which is handled by the hypothetical strategy. 
• Population-level summary: Difference in mean changes between treatment conditions 
A similar additional estimand also applies to all secondary body weight endpoints as well as all 
secondary WOMAC endpoints (both confirmatory and supportive). The population-level summary 
for body weight response endpoints is the ratio of odds between treatment conditions. 
Rationale for estimand: The additional estimand was requested by few regulatory authorities and 
aims at reflecting the treatment effect in the absence of intercurrent events. 
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3.2 
Primary, secondary and exploratory endpoint(s) 
3.2.1 
Primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline (week 0) to end of 
treatment (week 68) 
% 
Change in WOMAC pain score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
WOMAC; Western Ontario and McMaster Universities Osteoarthritis Index 
3.2.2 
Secondary endpoints 
The confirmatory and supportive secondary endpoints addressing the primary and secondary 
objectives are listed in Sections 3.2.2.1 and 3.2.2.2. 
3.2.2.1 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Achieving body weight reduction 
≥5% (yes/no) 
From baseline (week 0) to end of 
treatment (week 68) 
Count of subject 
Achieving body weight reduction 
≥10% (yes/no) 
From baseline (week 0) to end of 
treatment (week 68) 
Count of subject 
Change in WOMAC physical 
function score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 physical 
functioning score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
WOMAC; Western Ontario and McMaster Universities Osteoarthritis Index, SF-36; Short Form (36) Health Survey 
3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in waist circumference 
From baseline (week 0) to end of 
treatment (week 68) 
cm 
Change in WOMAC stiffness score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in WOMAC total score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 bodily pain score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 physical 
component summary 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 mental 
component summary 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Use of allowed rescue analgesics 
during wash out 
From baseline (week 0) to end of 
treatment (week 68) 
Count of subjects 
Amount of allowed rescue 
analgesics used during wash out 
From baseline (week 0) to end of 
treatment (week 68) 
Dose 
Change in pain medication 
From baseline (week 0) to end of 
treatment (week 68) 
Dose 
Change in pain intensity (NRS) 
From baseline (week 0) to end of 
treatment (week 68)   
Score points 
WOMAC; Western Ontario and McMaster Universities Osteoarthritis Index, SF-36; Short Form (36) Health Survey 
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3.2.3 
Exploratory endpoint(s) 
Endpoint title 
Time frame 
Unit 
Change in 6 minutes walking 
distance 
From baseline (week 0) to end of 
treatment (week 68)   
Meters 
Change in SF-36 role-physical 
score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 general health 
score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 vitality score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 social functioning 
score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 role-emotional 
score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
Change in SF-36 mental health 
score 
From baseline (week 0) to end of 
treatment (week 68) 
Score points 
 
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4 
Trial design 
This trial is designed to evaluate weight loss and knee OA-related outcomes and will apply a 
targeted approach to collection of safety data focusing on serious adverse events (SAEs), adverse 
events (AEs) leading to discontinuation of trial product and other selected AEs. An adequate 
characterisation of the less serious and more common AEs is evaluated in the phase 3a trials 
(Section 2.2.1).  
4.1 
Overall design 
This is a 68-week, randomised, two-arm, double-blinded, multi-centre clinical trial comparing 
semaglutide s.c. 2.4 mg once-weekly with semaglutide placebo in subjects with moderate OA of 
one or both knees, pain due to knee OA, and obesity (BMI ≥30.0 kg/m2). 
Eligible subjects will be randomised in a 2:1 manner to receive either semaglutide s.c. 2.4 mg once-
weekly or semaglutide placebo once-weekly as adjunct to a reduced-calorie diet and increased 
physical activity (Figure 4-1).  
 
The trial includes a screening visit to assess the subject’s eligibility followed by visits  
every 8th week until end-of-treatment (week 68). Follow-up period is 7 weeks after end-of-treatment 
(week 75).  
mg; milligram 
Figure 4-1 
A schematic diagram of the trial design 
4.2 
Scientific rationale for trial design 
The trial population will consist of subjects with obesity (≥ BMI 30.0 kg/m2) and knee OA 
((primary knee OA according to the ACR criteria), ≥ 40 point in the WOMAC pain subscale, and 
radiological KL grade 2 or 3)59. The trial population is chosen to optimise the likelihood of 
achieving a clinical benefit with weight loss (reduction in knee OA-related pain and improved 
physical function) by including subjects with a clear medical need (obesity and knee OA). Although 
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T2D is prevalent in the obesity population, it has been decided to exclude this group of subjects 
from the trial in order to get a homogenous study population. 
The treatment duration of the trial is 68 weeks with an additional 7 weeks follow-up (without 
treatment). A 68-week treatment duration (including 52 weeks on target dose) is considered 
sufficient to realise the weight loss potential of the intervention as well as downstream effects on 
symptoms and function related to knee OA. The 7 weeks follow-up period is included to account 
for the exposure and long half-life of semaglutide.  
A randomised, double-blinded, placebo-controlled, multi-centre trial design is chosen to minimise 
bias in the assessment of the effect and safety of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo, as an adjunct to a reduced calorie diet and increased physical activity.  
In accordance with guideline for Clinical investigation of medicinal products used in the treatment 
of OA by the European Medicines Agency (EMA) pain medication required during the trial period 
is discontinued 72 hours in advance of assessment of symptomatic endpoints to avoid confounding 
effects60. During the washout rescue medication with acetaminophen is allowed as analgesic until 
24 hours before visit if needed.  
4.3 
Justification for dose 
Results from the phase 2 dose-finding trial for semaglutide in weight management (NN9536-4153) 
showed that the semaglutide s.c. 0.4 mg once-daily dose was most effective in terms of weight loss 
while displaying an acceptable tolerability profile. Using population pharmacokinetic modelling, it 
was estimated that a once-weekly maintenance dose of semaglutide s.c. 2.4 mg will result in similar 
Cmax at steady-state as that obtained by the once-daily 0.4 mg semaglutide dose in trial 
NN9536-4153. 
A maintenance dose of semaglutide s.c. 2.4 mg once-weekly was chosen for the phase 3 weight 
management development programme. The once-weekly dosing is anticipated to ease the burden of 
drug administration in clinical practice. Subjects will be initiated at a once-weekly dose of 0.24 mg 
and follow a fixed-dose escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 
1.7 and 2.4 mg/week), until the target dose is reached after 16 weeks. 
It is well known that to mitigate gastrointestinal side effects with GLP-1 RA treatment, dose 
escalation to the target dose is required. Based on experience from the semaglutide T2D 
development programme, a fixed dose escalation regimen was selected, with dose escalation every 
4 weeks until the target dose is reached. 
4.4 
End of trial definition 
The end of trial is defined as the date of the last visit of the last subject in the trial globally. 
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5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial 
2. Male or female, age above or equal to 18 years at the time of signing informed consent 
3. Body Mass Index (BMI) ≥30.0 kg/m2  
4. Clinical diagnosis of knee OA (ACR criteria) with moderate radiographic changes (KL 
grades 2 or 3 as per central reading) in target knee. Target knee joint is defined as most 
symptomatic knee at screening. If pain in knees are equal target knee joint will be in the most 
dominant leg.  
5. Pain due to knee OA (Section 5.5.1) 
6. Willingness to complete 72-hour washout period of analgesics before all visits involving 
WOMAC questionnaire (acetaminophen is allowed as rescue medication).  
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
 
Knee OA-related: 
1. Joint replacement in target knee 
2. Arthroscopy or injections into target knee within the last 3 months prior to enrolment 
3. Elective surgery scheduled during the trial duration period, except for minor surgical 
procedures 
4. Any other joint disease in the target knee 
5. Current use of medical marijuana or opioids  
6. Symptomatic hip OA unless treated with hip replacement 
7. Primary localisation of pain is not within target knee  
8. Chronic widespread pain, including neuropathic pain 
 
Obesity-related: 
9. Previous or planned (during the trial period) obesity treatment with surgery or a weight loss 
device, except for: (1) liposuction and/or abdominoplasty, if performed > 1 year before 
screening, (2) lap banding, if the band has been removed >1 year before screening, (3) 
intragastric balloon, if the balloon has been removed >1 year before screening or (4) 
duodenal-jejunal bypass sleeve, if the sleeve has been removed >1 year before screening.  
10. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records 
11. Uncontrolled thyroid disease 
12. Treatment with any medication for the indication of obesity within the past 90 days before 
screening 
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Glycemia-related: 
13. HbA1c ≥ 48 mmol/mol (6.5%) as measured by local laboratory at screening 
14. History or presence of type 1 or type 2 diabetes (history of gestational diabetes is allowed) 
15. Treatment with any GLP-1 RA within 90 days prior to the day of screening 
 
General health and safety: 
16. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma 
17. Presence of acute pancreatitis within the last 180 days prior to screening  
18. History or presence of chronic pancreatitis  
19. End-stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis 
20. Presence or history of malignant neoplasm within 5 years prior to the day of screening. 
Basal and squamous cell cancer and any carcinoma in-situ are allowed  
21. Any of the following in the past 60 days prior to screening: myocardial infarction, stroke, 
hospitalisation for unstable angina or transient ischaemic attack  
22. Subjects presently classified with heart failure New York Heart Association: Class IV 
23. Known or suspected hypersensitivity to trial product(s) or related products  
24. Previous participation in this trial. Participation is defined as signed informed consent 
25. Participation in another clinical trial within 90 days before screeninga  
26. Other subject(s) from the same household participating in any semaglutide trial  
27. Female who is pregnant, breast feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method (highly effective 
contraceptive measures as required by local regulation or practice)  
28. History of major depressive disorder within 2 years before screening 
29. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder) 
30. History of a suicide attempt 
31. Suicidal behaviour within 30 days before screening  
32. Known or suspected abuse of alcohol or recreational drugs 
33. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, 
which in the investigator’s opinion, might jeopardise the subject’s safety or compliance with 
the protocol 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed if the last dose of the investigational medicinal product has been received more than 30 days before screening. 
 
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
 
For country specific requirements, see Appendix 7 (Section 10.7)  and for contraceptive 
requirements, see Appendix 4 (Section 10.4). 
5.3 
Lifestyle considerations 
To ensure alignment regarding performance of assessments across subjects and trial sites, the below 
restrictions apply.  
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5.3.1 
Caffeine and tobacco 
Subject should avoid caffeine and smoking at least 30 minutes prior to measuring their blood 
pressure.  
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, eligibility criteria, and any SAEs. A screen failure session must 
be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to the 
laboratory parameter, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. If the subject has failed 
inclusion criteria no. 4 due to incorrect position of the knee during the radiographic examination a 
reassessment is allowed.  
5.5 
Randomisation criteria  
First dose must only be administered after assessments related to primary and secondary endpoints 
are completed. 
5.5.1 
Randomisation criteria 
1. A score of at least 40 on the WOMAC version 3.1 pain subscale (range 0-100 normalised 
Numerical Rating Scale (NRS)) 
2. For subjects taking analgesics, attend randomisation visit after 72-hour washout period 
(rescue medication with acetaminophen allowed until 24 hours before visit) (Section 8.1.1)  
To be randomised, all relevant randomisation criteria must be answered "yes".  
A subject not fulfilling the randomisation criteria will be considered a randomisation failure, see 
Section 5.4 regarding screen failures. 
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6 
Treatments 
6.1 
Treatments administered 
• 
All trial products listed in Table 6-1 are considered investigational medicinal products 
(IMP). 
• 
Trial product must only be used, if it appears clear and colourless. 
 
Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Trial product name: 
Semaglutide B 3.0 mg/mL PDS290   
Semaglutide Placebo  
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous 
Subcutaneous 
Dosing instruction: 
Once-weekly 
Once-weekly 
Delivery device 
3 mL PDS290 pre-filled pen-injector 
3 mL PDS290 pre-filled pen-injector 
• Dose escalation of semaglutide/semaglutide placebo should take place during the first 16 weeks 
after randomisation as described in Table 6-2. All subjects should aim at reaching the 
recommended target dose of 2.4 mg semaglutide s.c. once-weekly or the corresponding volume 
of semaglutide placebo. 
• If a subject does not tolerate the recommended target dose of 2.4 mg once-weekly, the subject 
may stay at a lower dose level of 1.7 mg semaglutide s.c. once-weekly. This should only be 
allowed if the subject 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 
subject makes at least one attempt to re-escalate to the recommended target dose of 2.4 mg 
semaglutide s.c. 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. 
• The investigator must document that directions for use are given to the subject verbally and in 
writing at the first dispensing visit (as specified in the flowchart). 
• A dose reminder card will be handed out to the subjects at each site visit during the dose 
escalation period. This is to remind the subjects of the dose to be taken until next site visit and 
provide a conversion of the dose to value shown in the dose counter. Once the target dose has 
been reached, the dose reminder card is only handed out as needed. 
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Table 6-2 
Dose escalation and maintenance of semaglutide s.c. 2.4 mg /semaglutide placebo 
once-weekly  
Trial product name 
Dose 
Value shown in dose counter 
Duration 
Dose escalation period 
Semaglutide B 3.0 mg/mL 
PDS290 or semaglutide placebo 
0.24 mg 
8* 
4 weeks 
Semaglutide B 3.0 mg/mL 
PDS290 or semaglutide placebo 
0.5 mg 
17* 
4 weeks 
Semaglutide B 3.0 mg/mL 
PDS290 or semaglutide placebo 
1.0 mg 
34* 
4 weeks 
Semaglutide B 3.0 mg/mL 
PDS290 or semaglutide placebo 
1.7 mg 
57* 
4 weeks 
Maintenance period 
Semaglutide B 3.0 mg/mL 
PDS290 or semaglutide placebo 
2.4 mg 
80* 
52 weeks 
*Conversion to dose is calculated based on 0.01 ml/value  
• Subjects will be instructed to inject semaglutide/semaglutide placebo once-weekly at the same 
day of the week (to the extent possible) throughout the trial. 
• Injections may be administered in the thigh, abdomen or upper arm, at any time of day 
irrespective of meals. 
• If a single dose of trial product is missed, it should be administered as soon as noticed, provided 
the time to the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next 
scheduled dose is less than 2 days (48 hours) away, the subject should not administer a dose 
until the next scheduled dose. A missed dose should not affect the scheduled dosing day of the 
week.  
• If ≥ 2 consecutive doses of trial product are missed, the subject should be encouraged to 
recommence the treatment if considered safe as per the investigator’s discretion and if the 
subject does not meet any of the discontinuation criteria (Section 7.1). The trial product should 
be continued as early as the situation allows. The missed doses should not affect the scheduled 
dosing day of the week. The start dose for re-initiation of trial product is at the investigator’s 
discretion. In case of questions related to re-initiation of trial product, the investigator should 
consult Novo Nordisk global medical expert.  
Auxiliary supplies 
• Auxiliary supplies will be provided in accordance with the trial materials manual (TMM) please 
see Table 6-3. 
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Table 6-3 
Auxiliary supplies provided by Novo Nordisk A/S 
Auxiliary supply 
Details 
Needles 
Needles for pre-filled pen system. Details provided in the 
TMM 
Only needles provided and approved by Novo Nordisk 
must be used for administration of trial product. 
Directions for use (DFU) 
DFU for 3 ml PDS290 pre-filled pen-injector.  
Not included in the dispensing unit and to be handed out 
separately.  
 
6.1.1 
Medical devices 
Information about the PDS290 pre-filled pen-injector may be found in the IB50 and any updates 
hereof.  
Information about the use of the PDS290 pre-filled pen-injector for semaglutide 3.0 mg/mL and 
semaglutide placebo can be found in the DFU.  
Training in the PDS290 pre-filled pen-injector 
The investigator must document that training in the DFU has been given to the subjects verbally and 
in writing at the first dispensing visit. Training must be repeated, during the trial at regular intervals 
in order to ensure correct use of the medical device. Training is the responsibility of the investigator 
or a delegate.  
6.1.2 
Diet and Physical Activity counselling 
All subjects in both treatment arms will receive counselling with regards to reduced calorie diet and 
physical activity taking subjects knee OA into consideration. Counselling should be done by a 
dietician or a similar qualified healthcare professional 
6.1.2.1 
Non-investigational medical device(s) 
Non-investigational medical devices are listed in Section 6.1 as auxiliary supplies. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply or administer trial product. 
Table 6-4 
Trial product storage conditions 
Trial product name 
Storage conditions  
(not-in-use) 
In-use conditions 
In-use time 
Semaglutide B 3.0 mg/mL 
PDS290   
Store in refrigerator (2°C-
8°C/36°F-46°F)  
Do not freeze  
Protect from light 
In-use conditions will be 
available on the trial 
product label 
In-use timea will be 
available on the trial 
product label 
Semaglutide placebo 
aIn-use time starts when the product is taken out of the refrigerator in the subject’s home  
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• Each site will be supplied with enough trial products for the trial on an ongoing basis. Trial 
product will be distributed to the sites according to screening and randomisation. 
• 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 subject 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 TMM. 
• The investigator or designee is responsible for drug accountability and record maintenance 
(i.e. receipt, accountability and final disposition records). 
• The investigator or designee must instruct the subject in what to return at next visit. 
• Drug accountability should be performed on a pen level and must be documented in the 
IWRS.  
• The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator.  
• Destruction of trial products can be performed on an ongoing basis and will be done 
according to local procedures after accountability is finalised by the site and reconciled by 
the monitor. 
• All returned, un-used, expired or damaged trial products (for technical complaint samples, 
see 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. 
6.2.1 
Shipment of trial product to subject’s home 
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product and auxiliaries from the trial site or pharmacy to the subject’s home by courier service.  
The process for sending trial product from the trial site or pharmacy to a subject’s home is 
described in the “Trial site/pharmacy instruction for shipment of trial product to patients’ homes” 
document. The document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
patient. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document.  
Investigators, trial site/pharmacy staff and patients who will be involved in shipment of trial product 
to the subject’s home will be adequately trained in this process. 
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6.3 
Measures to minimise bias: Randomisation and blinding 
Randomisation 
• All subjects will be centrally screened and randomised using an IWRS and assigned to the 
next available treatment according to randomisation schedule. Trial product will be 
dispensed at the trial visits summarised in the flowchart. 
Blinding 
• The active drug and placebo are visually identical for the following trial products: 
o Semaglutide B 3.0 mg/mL PDS290/Semaglutide placebo 
• The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a subjects’ treatment is warranted. Subject 
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 subjects’ treatment unless this could delay 
emergency treatment of the subject. If a subject’s treatment 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 “code break confirmation” notification 
generated by the IWRS, sign and date the document. If IWRS is not accessible at the time of 
the blind break, the IWRS helpdesk should be contacted. Contact details are listed in 
Attachment 1. The subject will continue on trial product.  
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product(s) at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. If any suspicion of non-compliance arises, the site must enter into a 
dialogue with the subject, re-emphasizing the importance of compliance and uncover barriers to 
compliance. This dialogue must be documented. Treatment compliance of trial product will be 
assessed by asking the subject about missed doses and current treatment dose at every visit. 
Information on treatment dose and periods > 14 days without treatment will be recorded in the case 
report form (CRF).  
6.5 
Concomitant medication 
Any medication other than the trial product that the subject is receiving at the time of the first visit 
or receives during the trial must be recorded along with: 
• Trade name or generic name 
• Indication 
• Dates of administration including start and stop dates 
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•
For analgesics, subjects must record dose and frequency in the pain medication diary
provided
During the trial subjects should not initiate any anti-obesity treatment (e.g. medication) which is not 
part of the trial procedures. If such treatment is initiated, the subject should be instructed to stop the 
anti-obesity treatment. 
All pain medications are allowed during the trial, except for the use of opioids and medical 
marijuana at inclusion (Section 5.2). Initiation of opioids is discouraged during the trial. If such 
treatment is initiated, the subject should be instructed to stop the opioid treatment, and all other 
options must be tried before starting opioid medication. During the washout period (24 – 72 h 
before visits), subjects should not use any pain medication, with the exception of acetaminophen, 
and should not use any pain medication <24 h before visits. 
Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 8.3. 
6.5.1 
Rescue medication 
During the washout period, use of acetaminophen for rescue medication (maximum of 4 g/day) is 
allowed until 24 hours before visit. Use of acetaminophen (dose and frequency) has to be recorded 
by the subjects in the pain medication diary. 
Rescue medication will not be supplied or reimbursed by Novo Nordisk. 
6.6 
Dose modification 
Not applicable for this trial. Please refer to Section 6.1 for description of missed dose(s). 
6.7 
Treatment after end of trial 
•
There is no treatment following the end of trial.
•
When discontinuing trial products, the subject should be transferred to a suitable marketed
product at the discretion of the investigator.
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7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have subjects, who discontinue trial product, to continue in the trial. 
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial.  
7.1 
Discontinuation of trial treatment 
• Discontinuation of treatment can be decided by both the investigator and the subject. 
• Subjects who discontinue trial product should continue with the scheduled visits and 
assessments to ensure continued counselling and data collection.  
o If the subject does not wish to attend the scheduled clinic visits efforts should be 
made to have the visits converted to phone contacts. However, all effort should be 
made to have the subject attend at least the ‘end of treatment’ clinic visit containing 
the final data collection of primary and confirmatory secondary efficacy endpoints, 
and the ‘end of trial’ visit.  
• The 'end of trial' visit is scheduled approximately 7 weeks after the final data collection, to 
ensure the safety of the subject. If the subject has discontinued trial product > 7 weeks prior 
to the 'end of treatment' visit, and the requirements for the follow-up period prior to the 'end 
of trial' visit is fulfilled, then 'end of trial' visit can be performed in combination with 'end of 
treatment' visit.  
o If the subject refuses to attend the ‘end of treatment’ and/or ‘end of trial’ visit, 
information about the attempts to follow up with the subject must be documented in 
the subject’s medical record.  
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern as judged by the investigator 
2. Suspicion of acute pancreatitis 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous use of an approved or non-approved IMP in another clinical triala 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed at the investigator’s discretion without discontinuing trial product. 
If acute pancreatitis is suspected appropriate actions should be initiated, including local 
measurements of amylase and lipase (see Appendix 3 (Section 10.3) for reporting).  
 
Subjects meeting discontinuation of trial product criterion no. 2 are allowed to resume trial product 
if the Atlanta criteria61 are not fulfilled and thus, the suspicion of acute pancreatitis is not 
confirmed, at the discretion of the investigator. Trial product may be resumed for subjects with a 
gallstone-induced pancreatitis in case of cholecystectomy.  
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Subjects meeting discontinuation of trial product criteria no. 1, 3 and 4 are allowed to resume trial 
product, if the criteria are no longer met (Section 7.1.1).  
The primary reason for discontinuation of trial product must be specified in the end-of-treatment-
form in the CRF, and final drug accountability must be performed. A treatment discontinuation 
status session must be made in the IWRS to indicate discontinuation of trial product. 
7.1.1 
Temporary discontinuation of trial treatment 
If a subject has discontinued trial product due to temporary safety concern not related to trial 
product and is allowed to resume, the subject should follow the guide for missed doses 
(Section 6.1). Similarly, a subject who discontinues trial product on their own initiative should be 
encouraged to resume trial product (Section 6.1).  
If a ‘treatment’ status session previously has been made in IWRS to indicate discontinuation of trial 
product, a new ‘treatment status’ session must be made to resume trial product.  
7.1.2 
Rescue criteria 
Refer to Section 6.5.1 for description of rescue medication. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to the ‘end of treatment’ visit. See the flowchart 
for data to be collected. 
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment discontinuation status session must be made in the IWRS to indicate discontinuation of 
trial product. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
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7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of ‘lost to follow-up’. 
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8 
Trial 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 trial-related activity, see Section 10.1.3. 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion criteria and none of the exclusion criteria. 
• The investigator will maintain a screening log to record details of all subjects screened and 
to confirm eligibility or record reason for screen failure, as applicable. 
• At screening, subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant site staff that can be contacted in case of 
emergency.  
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
• Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit the bias between 
assessments.  
• Source data of clinical assessments performed and recorded in the CRF must be available 
and will usually be the subject’s medical records. Additional recording to be considered 
source data includes, but is not limited to laboratory reports, clinical outcome assessments.  
• The barriers and motivation interview identify barriers to and motivation for lifestyle change 
and compliance with the protocol. The interview must be conducted at screening to assist in 
identifying subjects who are unable or unwilling to comply with protocol procedures as per 
the exclusion criteria. In addition, the interview will ensure that any minor barriers are 
addressed during lifestyle counselling.  
o The results of the interview will not be entered into the CRF. It will be at the 
investigator’s discretion to evaluate the motivation of the subject and related 
eligibility.  
• Subject’s weight history must be recorded in the subject’s medical record. 
• Review of pain and pain medication diary, patient reported outcome (PRO) instruments, 
laboratory report etc. must be documented either on the documents or in the subject's source 
documents. If clarification of entries or discrepancies in the PRO instruments is needed, the 
subject must be questioned, and a conclusion made in the subject's source documents. Care 
must be taken not to bias the subject. 
• Repeat 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. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart. 
8.1.1 
Western Ontario and McMaster Universities Osteoarthritis Index   
Subjects should be given the opportunity to complete the questionnaire by themselves without 
interruption. The questionnaire takes approximately 5-10 minutes to complete62.  
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• The WOMAC Osteoarthritis Index is a tri-dimensional, disease-specific, patient-reported 
outcome (PRO) measure63. It probes clinically-important, patient-relevant symptoms in the 
area of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or 
knee. The index consists of 24 questions (5 pain, 2 stiffness, 17 physical function). 
• The version used is the WOMAC 3.1 NRS version, an 11-point numeric rating scale with 
responses ranging from no symptom/difficulty (0) to extreme symptom/difficulty (10). The 
version used has a 24-hour recall period.  
• Subscale scores for pain, stiffness and physical function and a total score will be calculated 
according to the guidelines provided in the WOMAC user manual. 
• For subjects taking analgesics, no analgesics with exception of acetaminophen until 
24 hours before visit, may be taken 72-hours prior to completing the questionnaires allowing 
for 72-hour washout.  
• WOMAC questionnaire will relate to target knee joint defined as most symptomatic knee at 
screening. If pain in knees are equal target knee joint will be in the most dominant leg.  
8.1.2 
Body measurements 
• Body weight should be measured without shoes, on an empty bladder and only wearing light 
clothing. It should be measured on a digital scale and recorded in kilograms or pounds (one 
decimal) using the same scale throughout the trial.  
• The scale must be calibrated yearly as a minimum. 
• Height is measured without shoes in centimetres or inches (one decimal). BMI will be 
calculated by the CRF from screening data and must agree with inclusion criterion no. 3. 
• Waist circumference is defined as: 
o abdominal circumference located midway between the lower rib margin and the iliac 
crest 
o Measures must be obtained in a standing position with a non-stretchable measuring 
tape and to the nearest cm or inch.  
o The tape should touch the skin but not compress soft tissue and twists in the tape 
should be avoided. The subject should be asked to breathe normally. The same 
measuring tape should be used throughout the trial. The measuring tape will be 
provided by Novo Nordisk to ensure standardisation.  
8.1.3 
Pain and pain medication diary  
At screening, the subjects will be instructed in using an electronic pain and pain medication diary. 
In the diary, the subjects should record their: 
• daily pain in the knee at its worst (NRS).  
• daily use of pain medication and rescue pain medication (acetaminophen), including dose and 
frequency.  
The investigator/site staff should review the diary for missing entries. The investigator should assist 
the subject in choosing the pain medication most often used and assist in choosing the correct 
category if the subject has chosen the category ‘Other’. If the subject has not taken any pain 
medication, this has to be recorded in the diary. Use of pain medication should also be reflected in 
EDC (standard concomitant medication form). 
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8.1.4 
Clinical outcome assessments 
Subject should be given the opportunity to complete the questionnaires by themselves without 
interruption. Each questionnaire takes approximately 10 minutes to complete.  
The following PROs will be used:  
• The WOMAC 3.1 NRS (Section 8.1.1)  
• Patient Global Impression of Status (PGI-S) for Pain 
• Patient Global Impression of Change (PGI-C) for Pain 
• Short Form 36 v2.0 acute (SF-36) 
The SF-36v2.0 is a 36-item commonly used generic PRO instrument measuring health-related 
quality of life and general health status across disease areas. The SF-36v2.0 for adults with a 
1 week recall period (i.e. acute version) measures the individual overall health-related quality of 
life in 8 health domains (physical functioning, role limitation due to physical health problems 
[role-physical], bodily pain, general health, social functioning, role limitations due to emotional 
problems [role-emotional], vitality and mental health). Furthermore, it includes 2 aggregated 
scores: a physical component summary score and a mental component summary score64.  
• PGI-S for physical function 
• PGI-C for physical function 
• Knee pain NRS item 
      This is a single item measuring knee pain at its worst in the last 24 hours. This item is the pain 
diary described in Section 8.1.3. The response scale is a 11-point numeric rating scale from 0 
(No knee pain) to 10 (Worst possible knee pain). The NRS item will relate to the target knee 
joint defined as the most symptomatic knee at screening. If pain in the knees are equal, the 
target knee joint will be in the most dominant leg.  
• 6 Minute Walk Test (6MWT) 
The 6MWT assesses the distance a subject can walk in 6 minutes. It is a direct and timed 
measure of walking ability, which is technically simple, reproducible, and when administrators 
are well trained, readily standardised. The goal is for the subject to walk as far as possible in six 
minutes without running. The subject is allowed to self-pace and rest as needed as they traverse 
back and forth along a marked walkway of 66 feet (20 m) (Figure 8-1). The primary outcome is 
the distance covered over 6 minutes65, 66. 
Specifically, all investigators and 6MWT clinical site administrators will receive a manual, 
providing details for administration of the 6MWT. In addition to the manual, each 6MWT 
clinical site administrator will have a checklist that must be completed prior to initiating each 
test administration to confirm and document that specific test administration criteria are met 
(e.g., the test is assessed along a flat, straight, undisturbed room that is at least 6 feet (1.8 m) 
wide; proper footwear as judged by the investigator is worn by the subject or otherwise noted)67. 
If the specific test administration criteria are not met, the 6MWT should not be performed. 
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Figure 8-1 
Walkway marking for the six-minute walk text 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
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 trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject 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 be described in the Medical 
History/Concomitant Illness form. 
The following concomitant illness/medical history should be recorded in the eCRF: 
• History of breast neoplasm 
• History of cardiovascular disorder and procedure 
• History of dyslipidemia 
• History of gallbladder disease and procedure 
• History of gastrointestinal disorder and neoplasm 
• History of musculoskeletal system disorder 
• History of pancreatic disease 
• History of psychiatric disorder 
• History of skin cancer and skin disorder 
• History of weight disorder 
• 
Other relevant concomitant illness/medical history including COVID-19 and malignant 
neoplasm 
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.  
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8.2.1 
Radiographic examinations 
• Results of a radiographic examination of the target knee, performed by a suitably qualified 
health care provider, will be evaluated by central reading. Results will be made available to 
the investigator before randomisation to assess eligibility.  
• If the subject has had a radiographic examination performed within 90 days prior to 
screening, these images may be sent to for evaluation by central reading. The examination 
must be repeated before randomisation if the subject has experienced worsening of physical 
function since the last examination.  
• The radiographs will be assessed using the KL grading system; a categorical grading scale 
of knee OA going from 0 to 4 by means of an evaluation of osteophytes, joint space 
narrowing, sclerosis and altered bone shapes68, 69.  
8.2.2 
Physical examinations 
• A physical examination will include assessments of the cardiovascular, musculoskeletal and 
respiratory system, general appearance, thyroid gland and abdomen.  
• Body measurements (e.g. height and weight) will also be measured and recorded as 
specified in the flowchart. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.3 
Vital signs 
• The method for measuring systolic and diastolic blood pressure needs to follow the standard 
clinical practice at site 
However, as a minimum:  
• Vital sign assessment should be preceded by at least 5 minutes of rest for the subject 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. 
• Pulse rate will be measured in connection to the blood pressure measurements. Record the 
pulse rate for the last 2 blood pressure measurements in the CRF. The pulse rate is to be 
recorded as the mean of the last 2 measurement. 
8.2.4 
Clinical safety laboratory assessments 
Not applicable for this trial. 
8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on all the 
events listed below: 
• SAEs 
• Following AEs irrespective of seriousness 
o AEs leading to permanent discontinuation of trial product 
o AEs requiring invasive knee procedures  
o AEs with additional data collection: 
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▪ medication error (including abuse/misuse of trial product) 
▪ acute pancreatitis  
o AEs of COVID-19a 
• Pregnancies and pregnancy-related AEs 
• Technical complaints 
a Suspected COVID-19 should be reported if the clinical presentation is suggestive of COVID-19, even in the absence 
of a COVID-19 test or without a positive COVID-19 test result. In the absence of clinical symptoms, a positive 
COVID-19 test (antigen or antibody) should be reported, if available. 
Note, that also events not allowed in accordance with the protocol e.g. bariatric surgery or knee 
replacement should, if they take place, be reported with both the procedure and medical condition 
specified.   
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. This always includes 
medication error, misuse and abuse of IMP. The relevant events are listed below in Table 8-1. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs)  
Event type  
AE requiring additional data collection 
Medication error* 
X 
Misuse or abuse of trial product* 
X 
Acute pancreatitis 
X 
*Additional data for Misuse or abuse of trial product is reported on the medication error event form. 
A detailed description of 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 and SAE information 
All events specified in Section 8.3 (for events related to pregnancy, see Appendix 4 (Section 10.4) 
must be collected and reported. The events must be collected from the first trial-related activity after 
obtaining informed consent until the end of trial visit, at the time points specified in the flowchart. 
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk or designee 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 trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
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8.3.2 
Method of detecting AEs and SAEs 
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 subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
subject 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 or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until the end of trial visit. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in 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 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE 
Not applicable for this trial.  
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8.3.8 
Adverse event of special interest 
Not applicable for this trial.  
8.3.9 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
• Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in 
clinical trials. The most commonly reported AE was nausea. All subjects recovered without 
complications.  
• There is no specific antidote for overdose with semaglutide. In the event of an overdose, 
appropriate supportive treatment should be initiated according to subject’s clinical signs and 
symptoms.  
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 subject for overdose-related 
AE/SAE. A prolonged period of observation and treatment may be necessary, taking into account 
the long half-life of semaglutide of approximately one week. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose, also consult the current version of the investigator's brochure50 
and any updates hereof. 
8.5 
Pharmacokinetics 
Not applicable for this trial.  
8.6 
Pharmacodynamics 
Not applicable for this trial. 
8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Not applicable for this trial. 
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8.9 
Immunogenicity assessments 
Not applicable for this trial. 
8.10 
Health economics  
Not applicable for this trial. 
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9 
Statistical considerations  
9.1 
Statistical hypotheses 
The tests of superiority of semaglutide s.c. 2.4 mg once-weekly to semaglutide placebo for the two 
primary and all confirmatory secondary endpoints are performed using a fixed-sequence statistical 
strategy and a weighted Holm-Bonferroni procedure (with weights one). For a detailed specification 
of statistical hypotheses for the two primary endpoints see Section 9.4.2. 
This strategy tests the endpoints using a predefined hierarchical order; first the two primary 
endpoints: body weight change (%) and change in WOMAC pain score are tested at the significance 
level of 5% where the alpha is split between the two endpoints using 1% for body weight 
change  (%) and 4% for change in WOMAC pain score. 
If superiority is not confirmed for both endpoints, then the testing will stop. If the test of superiority 
for one of the two primary endpoints is significant, then the alpha can be recycled for the other 
primary endpoint, which will be tested at the 5% significance level. If both hypotheses are rejected 
and superiority is confirmed, then the confirmatory secondary endpoints (starting with ≥5% body 
weight reduction) will be tested at the 5% level. Testing for superiority of confirmatory secondary 
endpoints can proceed only after a statistically significant result (p-value < 5%) on the previous 
endpoint. 
9.2 
Sample size determination  
The trial is designed with an effective power of 90% and 67% to detect differences on the two 
primary endpoints and confirmatory secondary endpoints, respectively. 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 calculations are presented in Table 9-1 and are based on findings from 
NN9536-4153 and NN9536 phase 3a program (STEP) as well as on relevant publications on body 
weight loss and knee OA outcome (using WOMAC). Two studies, Bliddal et al. and Christensen et 
al., found that weight loss treatment (average weight loss 7.5% and 6.8% respectively) could lead to 
improvements in knee OA symptoms like pain and physical function (pain score: -8.4 (-10.4 vs -
2.0) with baseline score 38.4 (SD=21.1) and -5.4 (-11.4 vs -6.0) with baseline score 36.7 (SD=21.3) 
respectively; function score: -3.7 (-10.2 vs -6.5) with baseline score 39.2 (SD=21.4) and -9.9 (-14.9 
vs -5.0) with baseline value 37.4 (SD=21.8) respectively) in obese subjects (average BMI at 
baseline 35.6 and 35.9 respectively)28, 70. Aforementioned score improvements were found in 
treatment completers. Item responses were collected using the VAS format of the questionnaire. 
Bliddal et al. reported normalised sum of scores (range 0-100) and Christensen et al. reported sum 
of scores, which were transformed to a 0-100 range for comparison purposes. Consequently, a 
treatment difference for the pain score was assumed to be -9 (-11 vs -2) with SD=20; for the 
function score it was assumed to be -9 (-15 vs -6) with SD=19 if treated with semaglutide s.c. 2.4 
mg once-weekly vs semaglutide placebo for 68 weeks. Clement et al. identified a minimum 
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clinically important difference of 11 for pain and 9 for function and a minimum important change of 
21 for pain and 16 for function for improvement in WOMAC after total knee arthroplasty.71 
Although, it is planned to use the NRS format of the questionnaire in this trial, it is known that VAS 
and NRS are highly correlated (r>0.93) and that VAS derived assumptions for sample size 
calculation are adequate and can be translated to a setting where NRS is used72. It is planned that 
the WOMAC scores (derived from NRS responses) will be transformed to a 0-100 range based on 
which the corresponding endpoints will be calculated. 
In relation to expected treatment effects it was assumed that 20% of subjects discontinue 
permanently and 60% of these are retrieved at week 68. All subjects in the placebo arm are assumed 
to have same effect as subjects who complete the trial on placebo. Retrieved subjects 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 subjects who complete the trial on semaglutide s.c. 
2.4 mg once-weekly. Non-retrieved subjects in the semaglutide s.c. 2.4 mg once-weekly arm are 
assumed to have an effect corresponding to placebo. 
Under these assumptions and a 2:1 randomisation ratio, the desired power of at least 90% for 
change in WOMAC pain score is obtained with 375 subjects randomised to either receive 
semaglutide s.c. 2.4 mg once-weekly (250) or placebo (125). 
Table 9-1 
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 375 randomised 
subjects 
Order Endpoint 
Assumed mean (±SD) or 
proportion for completers 
Expected 
mean (±SD) 
or 
proportion 
Expected 
difference 
or 
proportion 
ratio 
Marginal 
power 
(%) 
Two-sided 
significance 
level (%) * 
Effective 
power 
(%) 
Semaglutide 
s.c. 2.4 mg 
once-weekly 
Semaglutide  
placebo 
Semaglutide 
s.c. 2.4 mg 
once-weekly 
1 
% body 
weight 
change # 
14.0 (±10) 
3.0 (±10) 
12.5 (±11) 
9.5%-
points 
>99 
1 
99 
1 
WOMAC 
pain 
change # 
11.0 (±20) 
2.0 (±20) 
9.7 (±21) 
7.7 score-
points 
90 
4 
90 
2 
5% 
responders 
82% 
42% 
76% 
1.8 
>99 
5 
90 
3 
10% 
responders 
66% 
24% 
60% 
2.5 
>99 
5 
90 
4 
WOMAC 
function 
change # 
15.0 (±19) 
6.0 (±19) 
13.7 (±20) 
7.7 score-
points 
94 
5 
84 
5 
SF-36 
physical 
functioning 
change 
6.0 (±10) 
2.0 (±10) 
5.4 (±11) 
3.4 score-
points 
80 
5 
67 
SD: Standard deviation; WOMAC: Western Ontario McMasters Osteoarthritis Index ; SF-36: Short Form (36) Health 
Survey. 
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*Significance level for confirmatory secondary endpoints reflects local alpha if all superiority hypotheses for endpoints 
higher in the statistical hierarchy were rejected 
# Shown as a positive number 
 
As currently there are no NN trials utilizing WOMAC, see Table 9-2 for alternative power 
calculations to the main scenario assuming varying sample size, mean difference or standard 
deviation. 
 
Table 9-2 
Marginal power for WOMAC pain change (shown as a positive number) for 
alternative sample size, mean difference or standard deviation 
Sample size 
Expected mean 
for semaglutide  
placebo 
Expected mean 
for semaglutide 
s.c. 2.4 mg once-
weekly 
Expected 
difference  
Common SD 
Marginal 
power (%) 
Main scenario 
375 
2 
9.7 
7.7 
21 
0.900 
Varying sample size 
285 
2 
9.7 
7.7 
21 
0.803 
303 
2 
9.7 
7.7 
21 
0.828 
324 
2 
9.7 
7.7 
21 
0.853 
348 
2 
9.7 
7.7 
21 
0.877 
375 
2 
9.7 
7.7 
21 
0.900 
411 
2 
9.7 
7.7 
21 
0.925 
462 
2 
9.7 
7.7 
21 
0.951 
543 
2 
9.7 
7.7 
21 
0.975 
888 
2 
9.7 
7.7 
21 
>.999 
Varying mean difference 
375 
2 
5 
3 
21 
0.226 
375 
2 
6 
4 
21 
0.375 
375 
2 
7 
5 
21 
0.545 
375 
2 
8 
6 
21 
0.708 
375 
2 
9 
7 
21 
0.837 
375 
2 
10 
8 
21 
0.921 
375 
2 
11 
9 
21 
0.968 
375 
2 
12 
10 
21 
0.989 
375 
2 
13 
11 
21 
0.997 
375 
2 
14 
12 
21 
>.999 
375 
2 
15 
13 
21 
>.999 
Varying standard deviation 
375 
2 
9.7 
7.7 
10 
>.999 
375 
2 
9.7 
7.7 
11 
>.999 
375 
2 
9.7 
7.7 
12 
>.999 
375 
2 
9.7 
7.7 
13 
>.999 
375 
2 
9.7 
7.7 
14 
0.998 
375 
2 
9.7 
7.7 
15 
0.996 
375 
2 
9.7 
7.7 
16 
0.990 
375 
2 
9.7 
7.7 
17 
0.981 
375 
2 
9.7 
7.7 
18 
0.967 
375 
2 
9.7 
7.7 
19 
0.949 
375 
2 
9.7 
7.7 
20 
0.927 
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375 
2 
9.7 
7.7 
21 
0.900 
375 
2 
9.7 
7.7 
22 
0.871 
375 
2 
9.7 
7.7 
23 
0.840 
375 
2 
9.7 
7.7 
24 
0.807 
375 
2 
9.7 
7.7 
25 
0.773 
375 
2 
9.7 
7.7 
26 
0.740 
375 
2 
9.7 
7.7 
27 
0.706 
375 
2 
9.7 
7.7 
28 
0.673 
375 
2 
9.7 
7.7 
29 
0.642 
375 
2 
9.7 
7.7 
30 
0.611 
SD: Standard deviation. 
 
All above outlined sample size and power considerations are for the primary estimand for primary 
endpoints or the secondary estimand for confirmatory secondary endpoints (treatment policy 
strategy). It is assumed that up to 20% of subjects discontinue permanently and 60% of these are 
retrieved at week 68, which amounts to 8% expected missing data at week 68. Based on NN9536 
STEP 1 trial 8.8% missing in-trial data was observed after 68 weeks for the primary estimand. Any 
superiority conclusions will be based on the primary or secondary estimand. 
 
For the additional estimand (hypothetical strategy) however, data from retrieved subjects are not 
used. Hence, it is expected that up to 20% of data will be missing at week 68. Based on NN9536 
STEP 1 trial 20.6% missing on-treatment data was observed 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 (<1%). For trial NN9536 4578 slightly higher missing on-
treatment data is expected due to subjects initiating other knee OA interventions (<3%) and not 
complying with the washout period (<10%). In NN9536 STEP 1 trial it was seen that the treatment 
difference in mean changes for body weight was slightly higher and standard deviation was slightly 
lower for the additional estimand (using on-treatment data) than for the primary estimand (using in-
trial data). 
9.3 
Populations for analyses 
Two analysis sets are defined: 
The full analysis set (FAS) includes all randomised subjects according to the intention-to-treat 
principle. The subjects in the FAS contribute to the evaluation as randomised. 
The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of 
randomised treatment. The subjects in the SAS contribute to the evaluation as treated. 
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided. Efficacy endpoints will be analysed using the FAS; safety 
endpoints will be analysed using the SAS. 
Two observation periods are defined for each subject: 
In-trial: The in-trial period is defined as the uninterrupted time interval from date of randomisation 
to date of last contact with trial site. 
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On-treatment (with trial product): A time-point is considered as “on-treatment” if any dose of trial 
product has been administered within the prior 2 weeks (14 days). The on-treatment period is 
defined as all times which are considered on-treatment. 
In general, the on-treatment period will therefore be from the date of first trial product 
administration to date of last trial product administration excluding potential off-treatment time 
intervals triggered by at least two consecutive missed doses. 
For the evaluation of AEs, the lag time for each on-treatment time interval is 7 weeks (49 days). 
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods. 
9.4 
Statistical analyses 
9.4.1 
General considerations 
A statistical analysis plan (SAP) will be written, including a more technical and detailed elaboration 
of the statistical analyses. The SAP will be finalised before breaking the blind to treatment 
assignment. 
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all subjects is used as the 
baseline value. 
9.4.2 
Primary endpoint(s) 
The primary endpoints are change in body weight (%) and change in WOMAC pain score from 
baseline (week 0) to end-of-treatment (week 68) as listed in Section 3. 
Change from baseline to week 68 in body weight (%) is defined as 
% body weight change = (body weight at week 68 – body weight at baseline)
body weight at baseline
 ×100. 
Change from baseline to week 68 in WOMAC pain score is defined as 
WOMAC pain score change = WOMAC pain score at week 68 – WOMAC pain score at baseline. 
All tests are tests of superiority of semaglutide s.c. 2.4 mg once-weekly to semaglutide placebo. 
Let μsemaglutide and μsemaglutide placebo denote the true mean of % body weight change or WOMAC pain 
score change for semaglutide s.c. 2.4 mg once-weekly and semaglutide placebo, respectively. The 
null and alternative hypotheses tested are 
𝐻0: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒≥𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜 𝑣𝑠
𝐻𝐴: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒< 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜.  
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The null hypotheses will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0. 
Analyses addressing the primary estimand 
The following statistical analyses and imputation methods are designed to address the primary 
estimand. 
The analysis model for change in body weight (%) and change in WOMAC pain score will be a 
linear regression (ANCOVA) with randomised treatment as factor and either baseline body weight 
(kg) or baseline WOMAC pain score as covariate. The estimated treatment difference between 
semaglutide s.c. 2.4 mg once-weekly and semaglutide placebo will be reported together with the 
associated two-sided 95% confidence interval (CI) and corresponding p-value. 
All available data at week 68 are used and missing values at week 68 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 al73. For subjects in the 
semaglutide s.c. 2.4 mg once-weekly and the semaglutide placebo arms, missing measurements at 
week 68 for non-retrieved subjects are imputed using assessments from retrieved subjects in each 
randomised treatment arm. This will be done according to the timing of last available observation 
during the on-treatment period (LAO-OT) as well as by taking sex, baseline BMI and baseline body 
weight/WOMAC pain score into account. Missing measurements at week 68 for subjects on 
randomised treatment (at week 68) are imputed by sampling from available measurements at week 
68 from subjects on randomised treatment in the relevant randomised treatment arms. Details of the 
multiple imputation approach are provided in the SAP.  
Analysis addressing the additional estimand 
The additional estimand for change in body weight (%) and change in WOMAC pain score will be 
assessed using a mixed model for repeated measurements (MMRM) approach.  
Week 68 assessments for retrieved subjects are not used in this analysis. The MMRM will use 
assessments only from subjects who are taking the randomised treatment until end of treatment or 
until first discontinuation of randomised treatment. For subjects who experience other intercurrent 
events before completion or first discontinuing of randomised treatment, the date of initiating other 
anti-obesity therapies (weight management drugs or bariatric surgery) or other knee OA 
interventions (joint replacement or steroid injections) will be used as latest date for using 
assessments in this MMRM. Additionally, for the MMRM analysing change in WOMAC pain 
score, assessments from subjects incompliant with the washout period for pain medication will not 
be used. The MMRM will be fitted using the change (% body weight change or change in WOMAC 
pain score) and the same factor and covariate as for the primary analysis all nested within visit. An 
unstructured covariance matrix for measurements within the same subject will be employed, 
assuming that measurements for different subjects are independent. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Confirmatory secondary endpoints 
The confirmatory secondary endpoints are listed in Section 3. 
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All tests are tests of superiority of semaglutide s.c. 2.4 mg once-weekly to semaglutide placebo. 
Analyses addressing the secondary estimand 
The confirmatory secondary endpoints addressing the secondary estimand will be analysed in a 
similar way as the primary endpoints addressing the primary estimand.  
The statistical model for continuous confirmatory secondary endpoints will be the same linear 
regression as for the primary endpoints (ANCOVA) with treatment as a factor and the baseline 
value of the endpoint as covariate. The statistical model for confirmatory body weight responder 
endpoints is a logistic regression using randomised treatment as a factor and baseline body weight 
(kg) as covariate. The estimated odds ratio (OR) between semaglutide s.c. 2.4 mg once-weekly and 
semaglutide placebo will be reported together with the associated two-sided 95% confidence 
interval and corresponding p-value.  
The imputation approach is the same multiple imputation using retrieved subjects as described in 
Section 9.4.2 and taking the baseline value of the endpoint into account.  
Analyses addressing the additional estimand 
The confirmatory secondary endpoint change in WOMAC physical function score addressing the 
additional estimand will be analysed using the same MMRM as described for the primary endpoint 
change in WOMAC pain score addressing the additional estimand with randomised treatment as a 
factor and the baseline value of the endpoint as covariate.  
The confirmatory body weight responder endpoints addressing the additional estimand will be 
analysed using the same MMRM described for the primary endpoint change in body weight (%) 
addressing the additional estimand except that body weight (kg) will be used as response variable in 
the model. For subjects with missing body weight at week 68, individual values for body weight 
will be predicted from the MMRM and used to classify each subject as 5% or 10% responder or not. 
This classification will then be analysed using a logistic regression model with randomised 
treatment as a factor and baseline body weight (kg) as covariate. 
9.4.3.2 
Supportive secondary endpoints 
For details on analyses of supportive secondary endpoints, please see the SAP. 
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please see the SAP. 
9.4.5 
Other safety analyses 
For other safety analyse(s), please see the SAP.  
9.4.6 
Other analyse(s)  
Not applicable for this trial. 
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling 
Not applicable for this trial. 
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9.5 
Interim analyses  
Not applicable for this trial. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
9.7 
Reporting of the main part of the trial 
Not applicable for this trial. 
 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki74 and applicable ICH Good Clinical Practice (GCP) Guideline75 
• Applicable laws and regulations 
• The protocol, informed consent form, IB (as applicable) and other relevant documents (e.g. 
advertisements) must be submitted to an IRB/IEC and reviewed and approved by the 
IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the clinical trial report (CTR) according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial subjects. 
• Before a site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• The investigator will be responsible for: 
• providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
• notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• providing oversight of the conduct of the trial at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations 
• ensuring submission of the CTR 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 trial and one 
year after completion of the trial. 
Verification under disclosures per Code of Federal Regulations (CFR) of Financial Conflict of 
Interest. 
10.1.3 
Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial. This includes the use of an impartial witness 
where required according to local requirements. 
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• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• Subjects must be informed that their participation is voluntary. 
• Subjects must be informed about their privacy rights.  
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines75, Declaration of Helsinki74 and the 
IRB/IEC or site. 
• The medical record must include a statement that written informed consent was obtained 
before any trial-related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial-related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
• Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
• A copy of the informed consent form(s) must be provided to the subject.  
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the subject may receive other written information during the 
trial.  
Different initiatives for subject retention will be implemented throughout this trial. Site retention 
activities may include cooking classes, group meetings and others. Materials and items will be 
supplied if locally acceptable. The retention items will be relevant for the subjects’ participation in 
the trial and/or their obesity and will not exceed local fair market value. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
The initiatives for subject retention must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
 Data protection 
• Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records 
or datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
• The subject and any biological material obtained from the subject will be identified by 
subject number, visit number and trial ID. Appropriate measures such as encryption or 
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leaving out certain identifiers will be enforced to protect the identity of subjects as required 
by local, regional and national requirements.  
• The subject must be informed about his/her privacy rights, including that his/her personal 
trial-related data will be used by Novo Nordisk in accordance with local data protection law. 
The disclosure of the data must also be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.6.2 
Trial safety group 
Not applicable for this trial. 
10.1.6.3 
Data monitoring committee 
Not applicable for this trial. 
10.1.6.4 
Event adjudication committee 
Not applicable for this trial. 
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)76, the Food and Drug Administration Amendment 
Act (FDAAA)77, European Commission Requirements1, 78, 79 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date is the last assessment of the primary endpoint, and is for this trial Last 
Subject First Treatment + 68 weeks corresponding to ‘end of treatment’ visit (V13). If the last 
subject is withdrawn early, the PCD is considered the date when the last subject would have 
completed ‘end of treatment’ visit. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to FDAAA. 
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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 trial including 
quality checking of the data. 
• All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• The following will be provided as paper CRFs:  
o Pregnancy forms (Maternal forms 1A, 1B and 2 and Paternal form) 
• The following will be provided as paper CRFs to be used when access to the CRF is revoked 
or the CRF is temporarily unavailable:  
o AE forms  
o Safety information forms  
o Technical complaint forms (also to be used to report complaints on trial product not 
yet allocated to a subject) 
• 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 trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents (original 
documents, data and records). Direct access includes permission to examine, analyse, verify 
and reproduce any record(s) and report(s) that are important to the evaluation of the trial. If 
the electronic medical record does not have a visible audit trail, the investigator must 
provide the monitor with signed and dated printouts. In addition, the relevant site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone).  
• Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
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• Monitors will review the subject’s medical records and other source data, e.g. PROs, to 
ensure consistency and/or identify omissions compared to the CRF.  
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 trial database.  
10.1.9 
Source documents. 
• All data entered in the eCRF must be verifiable in source documentation other than the CRF 
• For ePROs, data in the service providers’ database is considered source data. 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents, or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records. Also, current medical records 
must be available.  
• It must be possible to verify subject’s medical history in source documents, such as subject’s 
medical record  
• The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested, and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement at 
each site. There will only be one source document defined at any time for any data element. 
10.1.10 Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct 
of this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. This also applies for 
services outsourced to an external facility by the investigator. No records may be destroyed 
during the retention period without the written approval of Novo Nordisk. No records may 
be transferred to another location or party without written notification to Novo Nordisk.  
• The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF (eCRF) and other subject data will be 
provided in an electronic readable format to the investigator before access is revoked to the 
systems and/or electronic devices supplied by Novo Nordisk. Site-specific CRFs and other 
subject data (in an electronic readable format or as paper copies or prints) must be retained 
by the site. A copy of all data will be stored by Novo Nordisk. 
• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
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10.1.11 Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial 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 subjects by the investigator 
• discontinuation of further trial product development. 
10.1.12 Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
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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 trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible. Novo Nordisk may pay additional costs incurred in relation to assessments relevant for 
following the safety of the subject. Investigator must contact Novo Nordisk on a case by case basis 
for whether the costs will be covered. 
Novo Nordisk accepts liability in accordance with: Please refer to Appendix 7 (Section 10.7). 
10.1.14 Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One (or two) investigators will be appointed by Novo Nordisk to review and sign the CTR 
(signatory investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
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right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.80 
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 trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data and will be provided with the 
randomisation code after results are available. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10-1 will be performed by the local laboratory  
• Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. If additional laboratory sampling is needed, 
e.g. to follow up on AEs, this must be done at a local laboratory. 
• The investigator must review all laboratory results for concomitant illnesses and AEs. 
Table 10-1 
Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism1 
• HbA1c  
Pregnancy Testing 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2 
Notes: 
1For screening purposes only 
2Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
HbA1c; glycated haemoglobin, IRB; institutional review board, IEC; independent ethics committee
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an 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 meeting the AE definition 
• 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  
• Obesity-related surgical procedures, total knee replacements and knee arthroscopy 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
• Conditions present prior to the time point from which AEs are collected and anticipated day-
to-day fluctuations of these conditions, including those identified during screening or other 
trial 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. · Exceptions include; obesity-related surgical procedures, total knee 
replacements and knee arthroscopy. In these cases both the surgical procedure and the 
condition that leads to the procedure should be reported as AEs.  
• Medical or surgical procedures not preceded by an AE or worsening of a known condition 
(exceptions are obesity-related surgical procedures, which for this trial should be reported as 
individual AE's). 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
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The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalisation are AEs. If a 
complication prolongs hospitalisation or fulfils any other 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, trial-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 trial inclusion, are not 
considered AEs or SAEs.  
d. 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), which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious and reported 
as SAEs using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
• Suspicion of transmission of infectious agents via the IMP  
• Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL where no alternative 
aetiology exists (Hy's law) 
 
10.3.3 
Description of AEs requiring additional data collection  
Description of AEs requiring additional data collection (on specific event form)  
Adverse events requiring additional data collection 
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AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product (see Table 8-1). The selection of these events is based 
on the non-clinical and clinical data with semaglutide, knowledge from the GLP-1 RA drug class 
as well as regulatory requirements.  
Acute pancreatitis  
Diagnosis of acute pancreatitis requires two of the following three features: 
1. abdominal pain consistent with acute pancreatitis (onset of a persistent, severe, epigastric 
pain often radiating to the back) 
2. serum lipase activity (and/or amylase activity) at least three times greater than the upper 
limit of normal 
3. characteristic findings of acute pancreatitis on imaging. 
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 subject, 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 higher dose than intended. The administered dose must deviate 
from the intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily occur. 
• missed doses or drug pauses are not to be reported as a medication error. 
Misuse and abuse  
• Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
• Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. hypoglycaemia or other), this must be reported on an additional AE 
form. 
 
10.3.4 
Recording and follow-up of AE and/or SAE 
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. 
• SAEs and AEs listed in Section 8.3 and AEs/SAEs in connection with pregnancies, must be 
recorded by the investigator 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.  
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• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
• There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
• For all non-serious AEs, the applicable forms should be signed when the event is resolved or 
at the end of the trial at the latest. For sign-off of SAE-related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
• Novo Nordisk products used as concomitant medication: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as concomitant medication in 
the trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to 
report this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
• The investigator is obligated to assess the relationship between IMP and the occurrence of 
each AE/SAE. 
• Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
• Probable - Good reason and sufficient documentation to assume a causal relationship. 
• Possible - A causal relationship is conceivable and cannot be dismissed. 
• Unlikely - The event is most likely related to aetiology other than the IMP. 
• Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
• The investigator will also consult the IB in his/her 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. 
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Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
• Recovering/resolving: The condition is improving, and the subject is expected to recover 
from the event. 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).  
• Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
• Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the subject has not improved, and the 
symptoms are unchanged, or the outcome is not known.  
Note: 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 subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology. 
New or updated information will be recorded in the CRF. 
 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
• Relevant forms (AE form, safety information form and specific event forms) must be 
completed in the CRF.  
• For reporting and sign-off timelines, see Figure 10-1 below. 
• If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, 
and if the CRF is unavailable for more than 5 calendar days, then the site will use the paper 
safety information form (see box below). 
• The site will enter the SAE data into the CRF as soon as it becomes available. 
• After the trial is completed, the trial 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 subject or receives updated data on a previously reported SAE 
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after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk 
in accordance with Section 10.1.5. 
• 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 form within the 
designated reporting timelines (as illustrated in the figure below): 
• 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. 
• The specific event form for AEs requiring additional data collection within 14 calendar days  
 
 
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 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
• Documented total hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
• A postmenopausal state is defined as amenorrhoea for 12 months without an alternative 
medical cause.  
• Females ≥ 50 years of age can be considered postmenopausal (irrespective of treatment with 
a hormonal contraception or hormone replacement therapy (HRT)) if they have both: 
o Amenorrhoea and 
o Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
postmenopausal range and one of these was observed ≥1 year prior to screening. 
• Females ≥ 60 years of age can be considered postmenopausal. 
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use one of the highly effective contraception methods.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table below: 
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Table 10-1 
Highly effective contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
• Highly effective methodsb,d that have low user dependency (Failure rate of <1% per 
year when used consistently and correctly): 
o Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
o Intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS)b 
o Bilateral tubal occlusion 
o 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.) 
 
• Highly effective methodsb,d that are user dependent (Failure rate of <1% per year when 
used consistently and correctly): 
o Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulationc 
▪ oral 
▪ intravaginal 
▪ transdermal 
▪ injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the trial 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the trial and the preferred and usual lifestyle of the subject. 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical trials. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) 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. 
d) Contraception should be utilised during the treatment period and for at least 49 days (corresponding to time 
needed to eliminate trial product) after the last dose of trial product. This period should be extended by 30 days in 
case of genotoxicity. 
 
Pregnancy testing 
• Additional pregnancy testing should be performed during the treatment period, if required 
locally (Appendix 7, Section 10.7). 
• WOCBP should only be included after a negative highly sensitive urine pregnancy test 
(refer to Appendix 2, Section 10.2). 
• A pregnancy test should be performed at the end of relevant systemic exposure (refer to 
Appendix 2, Section 10.2). 
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• Pregnancy testing should be performed whenever a menstruation is missed or when 
pregnancy is otherwise suspected. 
Collection of pregnancy information  
Female subjects who become pregnant  
• Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this trial. 
• Information will be recorded on the appropriate form and submitted to Novo Nordisk within 
14 calendar days of learning of a subject's pregnancy (see Figure 10-2). 
• Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo 
Nordisk 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 SAE. If relevant, consider adding ‘gestational’, ‘pregnancy-related’ 
or a similar term when reporting the AE/SAE. 
• Pregnancy outcome should be documented in the subject's medical record. Abnormal 
pregnancy outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies 
and ectopic pregnancy) is considered an SAE. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the IMP by the investigator will be reported to Novo Nordisk as 
described in Section 10.3. While the investigator is not obligated to actively seek this 
information in former subjects, he or she may learn of an SAE through spontaneous 
reporting.  
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines for 
pregnancy  
Any female subject who becomes pregnant while participating in the trial will discontinue IMP.  
 
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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 
Technical complaint definition  
• A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does 
not concern the AE itself. 
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination) 
• Problems with packaging material including labelling 
• Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at 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 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must be 
completed. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
• 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 trial product that is not yet 
allocated to subject, 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 that were 
packed in the same DUN 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 product.  
 
10.5.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk. 
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10.6 
Appendix 6: Mitigations to ensure subject safety and data integrity during COVID-19  
In case local restrictions due to a COVID-19 outbreak 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. 
• Table 10-2 indicates the minimum requirements for assessments that should be performed 
during a lock-down, but sites should always try to follow the assessments outlined in 
Section 1.2 (original flowchart) 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. 
10.6.1 
Visits 
• Screening (visit 1) and randomisation (visit 2) should always be performed as physical on-
site visits. If a site is unable to perform these visits on-site, screening and randomisation of 
new subjects at that site should be on hold until on-site visits are possible. 
• Visits 4, 7, 9, 11, 13, and 14 should be performed as physical on-site visits, if in any way 
possible. 
• On-site visits (visits 3, 5, 6, 8, 10, and 12) can be converted to remote visits (video, phone or 
similar) or home visits. 
• At each visit the investigator must indicate in the eCRF how the visit was performed and 
specify the reason for the preferred assessment method. 
10.6.2 
Assessments 
• Assessments used for safety and the confirmatory endpoints should be prioritised. The 
preferred order for the method of assessment is: on-site, video, phone, home visit. Findings 
meeting the definition for an AE (refer to Appendix 3 [Section 10.3]) should be reported in 
the eCRF. 
• If the assessments indicated in Table 10-2 cannot be performed as on-site visits or remote 
visits, they should be performed at the first possible timepoint following the originally 
scheduled visit in agreement with Novo Nordisk. 
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10.6.3 
Minimum assessments following randomisation to be performed during lockdown 
Table 10-2 
Minimum assessments following randomisation to be performed during lockdown 
 
Dose escalation period 
Treatment period 
End of 
treatment 
End of trial 
Visit (V) 
P3 
V4 
P5 
P6 
V7 
P8 
V9 
P10 
V11 
P12 
V13 
V14 
Timing of Visit (Weeks) 
4 
8 
12 
16 
20 
28 
36 
44 
52 
60 
68 
75 
Visit Window (Days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
SUBJECT RELATED INFORMATION AND 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testc (8.3.5) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
Body Measurements (8.1.2) 
 
 
 
 
 
 
 
 
 
 
 
 
     Body Weight 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Clinical Outcome Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
    Western Ontario and McMaster Universities   
Osteoarthritis Index (WOMAC) (8.1.1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
    Patient Global Impression of Status (PGI-S) Pain 
 
 
 
 
X 
 
 
 
X 
 
X 
 
    Patient Global Impression of Change (PGI-C) Pain 
 
 
 
 
X 
 
 
 
X 
 
X 
 
    Short Form 36 V2.0 acute (SF-36) (8.1.4) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
    PGI-S Physical Function 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
    PGI-C Physical Function 
 
 
 
 
X 
 
 
 
X 
 
X 
 
SAFETY 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (8.3) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Dose escalation period 
Treatment period 
End of 
treatment 
End of trial 
Visit (V) 
P3 
V4 
P5 
P6 
V7 
P8 
V9 
P10 
V11 
P12 
V13 
V14 
Timing of Visit (Weeks) 
4 
8 
12 
16 
20 
28 
36 
44 
52 
60 
68 
75 
Visit Window (Days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +5 
Technical Complaint (8.3.9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (8.2.3) 
 
 
 
 
 
 
 
 
 
 
 
 
     Systolic Blood Pressure 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
     Diastolic Blood Pressure 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
     Pulse 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Physical Examination (8.2.2) 
 
 
 
 
 
 
 
 
 
 
X 
 
TRIAL MATERIAL 
 
 
 
 
 
 
 
 
 
 
 
 
     IWRS Session 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of Trial Product (6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
     Dispensing Visit 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
     Drug Accountability 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
REMINDERS 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria for discontinuation (7.1)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Diet and physical activity counselling (6.1.2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of the pain and pain medication diaryd (8.1.3) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Training in trial product, pen-handling 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Hand out dose reminder card (6.1) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
a Demography consists of date of birth, sex, ethnicity, and race (according to local regulation). 
b Smoking is defined as smoking at least one cigarette or equivalent daily. 
c For all female subjects of child-bearing potential. 
d The pain and pain medication diary should be filled in on a daily basis by the subject 
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10.7 
Appendix 7: Country-specific requirements  
 
For Denmark:  
Section 5.3 Exclusion criteria no. 27  
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable)  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner  
• sexual abstinence  
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are not considered highly effective birth control.  
For Canada: 
Appendix 1 Section 10.1.10 Retention of clinical trial documentation 
Part C, Division 5 of the Food and Drug Regulations [C.05.012] requires a 25 years retention period 
For France: 
1. Section 1.2 Flowchart 
Ethnic origin and race: Collection not allowed in France.  
Year of birth: Only year is collected for the date of birth.  
 
Appendix 1   Section 10.1.13 Indemnity statement 
The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 art. 88 I, IX, 
Journal Officiel of 11 August 2004. "The sponsor is responsible for identification of the harmful 
consequences of the biomedical the research for the person lending himself thereto and for 
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indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is 
not attributable to his fault of the fault of any intervening party, without the sponsor's being entitled 
to call on acts by a third party or the voluntary withdrawal of the person who had initially consented 
to cooperating in the research" 
Section 5.3 Exclusion criteria no. 27  
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable)  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner  
• sexual abstinence  
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are not considered highly effective birth control.  
For Norway:  
Section 5.3 Exclusion criteria no. 27  
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable)  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner  
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• sexual abstinence  
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are not considered highly effective birth control.  
For Sweden:  
Section 5.3 Exclusion criteria no. 27  
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable)  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner  
• sexual abstinence  
• A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are not considered highly effective birth control.  
 
 
For Spain: 
Appendix 1 Section 10.1.10 Retention of clinical trial documentation 
25 years according to the new Spanish Royal Decree 1090/2015 
Section 5.3 Exclusion criteria no. 27  
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable)  
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• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner  
• sexual abstinence  
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are not considered highly effective birth control.  
 
For US: 
Appendix 1 Section 10.1.5 Data protection 
In the United States, 21 CFR 312.62(c) and 21 CFR 812.140(d) require 2 years following the date a 
marketing application is approved for the drug for the indication for which it is being investigated; 
or, if no application is to be filed or if the application is not approved for such indication, until 2 
years after the investigation is discontinued and FDA is notified’.   
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10.8 
Appendix 8: Abbreviations  
6MWT 
six-minute walking test 
ACR 
American College of Rheumatology 
AE 
adverse event 
BMI 
body mass index 
CRF 
case report form 
CTR 
clinical trial report 
DFU 
directions for use 
DUN 
dispensing unit number 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
GCP 
Good Clinical Practice 
GLP-1 
glucose like peptide-1 
HbA1c 
glycated haemoglobin 
ICH 
International Council for Harmonisation 
IB 
Investigator’s Brochure 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
KL 
Kellgren Lawrence 
MEN2  
multiple endocrine neoplasia type 2 
MMRM 
mixed model for repeated measures  
MTC 
medullary thyroid cancer 
NRS 
Numerical Rating Scale  
OA 
osteoarthritis  
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of status 
PRO 
patient reported outcome 
RA 
receptor agonist  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 
Short Form (36) Health Survey 
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SUSAR 
suspected unexpected serious adverse reaction 
T2D 
Type 2 Diabetes Mellitus  
TMM 
trial materials manual 
WOCBP 
woman of child bearing potential 
WOMAC 
Western Ontario McMasters Osteoarthritis Index 
 
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10.9 
Appendix 9: Protocol amendment history 
Protocol version 2.0 (23 September 2020) 
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 Union1 for the 
countries participating in the NN9536-4578 trial.  
Overall rationale for preparing protocol, version 2.0: 
The rational for preparing protocol version 2.0 is to specify that anti-obesity treatment (e.g. 
medication) which is not part of the trial procedures is not allowed. This is to ensure alignment with 
the other clinical trials in the development of semaglutide for weight management and to ensure 
interpretability of treatment effect.  
 
Section # and name 
Description of change 
Brief rational  
Section 6.5 
Concomitant 
medication 
The following sentence was added to the 
protocol “During the trial subjects 
should not initiate any anti-obesity 
treatment (e.g. medication) which is not 
part of the trial procedures. If such 
treatment is initiated, the subject should 
be instructed to stop the anti-obesity 
treatment.” 
To not allow for other anti-obesity therapies 
(medication or bariatric surgery) is crucial to 
control the number of subjects actually on or 
starting other anti-obesity therapies at start or 
during the trial. By including wording of 
preventing other anti-obesity therapies in the 
trial protocol, it can be expected that only a 
small fraction of subjects will initiate other 
anti-obesity therapies (as seen in the phase 3a 
semaglutide trials NN9536-4373, -4374, -
4375 and -4376), which is considered to be 
sufficiently small to not affect the conclusion 
of semaglutide being superior to placebo in 
subjects with obesity and knee OA. 
 
Section 5.2 Exclusion 
criteria 
The following exclusion criterion was 
added “Treatment with any medication 
for the indication of obesity within the 
past 90 days before screening”  
Obesity medication taken within 90 days of 
the screening may influence metabolism and 
thus potentially affect the trial results.  
 
Section 5.2 Exclusion 
criteria 
Exclusion criteria 5 has been updated 
from “Use of pain patches, medical 
marijuana or opioids” to “Use of 
medical marijuana or opioids” 
Pain patches containing NSAIDs are allowed 
in the trial, deleting “pain patches” avoids 
confusion.  
 
Section 8.2 Safety 
assessment  
The following concomitant 
illness/medical history was changed to 
the below  
History of breast neoplasm 
History of gallbladder disease and 
procedure 
History of gastrointestinal disorder and 
neoplasm 
History of musculoskeletal system 
disorder 
History of pancreatic disease 
History of psychiatric disorder 
History of skin cancer and skin disorder 
History of weight disorder 
Revision and clarification of the specific 
topics of medical history and concomitant 
illness that will be recorded in the eCRF. 
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Other relevant concomitant 
illness/medical history (this also includes 
malignant neoplasm) 
Throughout the 
protocol 
Re-introduction of the specification of 
‘pancreatitis’ as ‘acute pancreatitis’  
Due to error the ‘acute’ was missing from the 
risk acute pancreatitis. Re-introduction of the 
specification of ‘pancreatitis’ as ‘acute 
pancreatitis’ was done to ensure alignment 
with the naming of the Novo Nordisk safety 
committee endorsed risk for semaglutide.  
Section 8 Trial 
assessments and 
procedures  
The following sentence was added 
Subject’s weight history must be 
recorded in the subject’s medical record. 
To specify that subject’s weight history is 
recorded. 
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Version: 
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Status: 
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Signature Page for VV-TMF-4175464 v2.0
Signature Page for VV-TMF-4175464 v2.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 27-Apr-2021 07:23:59
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9.1.1
Protocol Attachment
Protocol Attachment I is located in the Trial Master File.
If applicable, Protocol Attachment II is also located in the Trial Master File.
Content: Global key staff and Country key staff.
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Study ID: NN9536-4578
Clinical Study Report
Appendix 9.1.1
24 November 2023
1.0
Final
CONFIDENTIAL