Effects of Semaglutide on Functional Capacity in Patients With Type 2 Diabetes and Peripheral Arterial Disease
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2, Peripheral Arterial Disease
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04560998 
Sponsor trial ID: 
NN9535-4533 
Official title of study: 
Effect of semaglutide on functional capacity in patients with 
type 2 diabetes and peripheral artery disease 
Document date*: 
18 April 2023 
*Document date refers to the date on which the document was most recently updated.

Protocol 
CONFIDENTIAL 
Date: 
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Trial ID: NN9535-4533 
Version: 
7.0 
Status: 
Final 
Page: 
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Protocol
Trial ID: NN9535-4533 
Effects of semaglutide on functional capacity in patients with 
type 2 diabetes and peripheral arterial disease
Substance: Semaglutide s.c 
Universal Trial Number: U1111-1238-7071 
EudraCT Number: 2019-003399-38 
IND Number: 143.478 
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 No unpublished information contained herein may be 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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Protocol 
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Date: 
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Trial ID: NN9535-4533 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s) 
7.0 
18 April 2023 
All 
6.0 
06 June 2022 
Austria, Canada, Czech Republic, 
Denmark, Greece, India, Malaysia, 
Sweden, Thailand and United States 
5.0 
15 October 2021 
All 
4.0 
01 June 2021 
All 
3.0 
18 November 2020 
All except China 
2.0 
28 September 2020 
Czech Republic and Hungary 
1.0 
26 May 2020 
All 
Protocol version 7.0 (18 April 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.1 
Overall rationale for preparing protocol, version 7.0 
The overall rationale for the changes implemented in the amended protocol is to strengthen our 
approach of submitting a single trial to have the PAD information accepted into the label. This is 
achieved by elevating the supportive endpoint “Follow-up change in maximum walking distance on 
a constant load treadmill test” to confirmatory secondary endpoint with the purpose of ensuring that 
the follow-up period results are taken into consideration by regulators. 
Additionally, this amendment includes the inversion of confirmatory endpoints “Change in pain-
free walking distance on a constant load treadmill test” and “Change in Vascular Quality of Life 
Questionnaire-6 (VascuQoL-6) score”, as well as a small change in the wording of the secondary 
objective related to VascuQoL-6 questionnaire, to clarify the measured concepts. This will 
strengthen our position to submit a label containing the VascuQoL-6 results. 
New text is written as italic. 
 Section # and name 
Description of change 
Rationale 
Section 1.1 Synopsis 
Description of objectives and endpoints 
updated as specified below. 
To align synopsis with protocol 
updates 
Section 1.2 Flowchart 
Footnote added for V9A 
a) EOT follow-up visit (V9A) to be
performed 5 weeks after V8A.
Subsequent footnote numbering updated 
accordingly. 
For clarification 
Section 1.2 Flowchart 
PK sampling Semaglutide plasma 
concentration 
Renamed to clarify that this refers 
to PK sampling.  
Section 1.2 Flowchart 
Severe Hypoglycaemic episodes have 
been added to the high-level flowchart 
For completeness 
Section 1.2 Flowchart 
Footnote added for Treadmill 
assessments f 
To increase flexibility for the sites 
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 Section # and name 
Description of change 
Rationale 
 
f) The treadmill assessments at visits 6, 8 
and 9 can be performed at a later day 
than the other assessments and 
procedures at the given visit, provided 
that all assessments are completed 
within the visit window (visit windows 
are calculated from the randomisation 
date).  
 
Subsequent footnote numbering updated 
accordingly.  
Section 1.2 Flowchart 
Footnote added for eye examination  
 
k) Fundus photography/dilated 
fundoscopy should be performed: 
 within 90 days prior to screening or 
within the period between screening 
and randomisation, see details in 
Section 8.2.2 
 at V8 and V8A or within +/- 2 weeks 
of those visits  
 
Subsequent footnote numbering updated 
accordingly. 
To increase flexibility for the sites 
Section 3.1.1 Primary objective 
and estimands 
The primary estimand will be the 
treatment ratio of the median treatment 
ratio to baseline at week 52 in maximum 
walking distance (…) 
 
TwoA secondary estimands for the 
primary objective will be the treatment 
ratio of the median treatment ratio to 
baseline (i) at week 57 in maximum 
walking distance and (ii) at week 52 in 
pain free walking distance (…) 
 
The rationale for this pain-free walking 
estimand (…) 
See rationale above the table 
Section 3.1.1 Primary objective 
and estimands 
Table 3-1 updated to include two 
additional secondary estimands for the 
primary objective.  
The supportive secondary endpoint 
“Follow-up change in maximum 
walking distance on a constant load 
treadmill test” has been elevated to 
a confirmatory secondary endpoint  
Section 3.1.2 Secondary 
objectives and estimands 
PAD-specific health-related quality of 
life Patient reported symptoms and 
impacts of intermittent claudication 
(VascuQoL-6) 
To specify. The questionnaire is 
assessing the proximal concept of 
symptoms and impacts of 
intermittent claudication, that can 
be more directly associated with 
PAD defining concepts. At the 
same time, “quality of life” is a 
distal concept that could be 
influenced by multiple contextual 
factors that the questionnaire does 
not assess (whether environmental 
or personal, e.g. psychosocial 
factors, ethnicity, etc.) 
 
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 Section # and name 
Description of change 
Rationale 
The FDA is not likely to accept 
data related to quality of life, which 
they consider a broad and 
subjective term 
Section 3.2.2 Secondary 
endpoints 
Elevation of supportive endpoint to 
confirmatory and inversion of the other 
confirmatory endpoints 
 
Confirmatory secondary endpoints: 
 Follow-up change in maximum 
walking distance on a constant load 
treadmill test  
 Change in pain-free walking distance 
on a constant load treadmill test  
 Change in Vascular Quality of Life 
Questionnaire-6 (VascuQoL-6) score 
 Change in pain-free walking distance 
on a constant load treadmill test  
Supportive secondary endpoints: 
 Follow-up change in maximum 
walking distance on a constant load 
treadmill test  
See rationale above the table 
Section 3.2.3 Exploratory 
endpoint 
Footnote updated:  aThe activity tracker 
is only applied in a subset of patients 
(n=242125).  
To accommodate recruitment 
difficulties and prioritise 
recruitment activities for the main 
study 
Section 5 Trial population 
Expected number of patients to complete 
the activity tracker evaluation: 222 115 
(242 125 planned for randomisation, 
withdrawal rate of 8 % is anticipated). 
To accommodate recruitment 
difficulties and prioritise 
recruitment activities for the main 
study 
Section 7.1 Discontinuation of 
trial treatment 
If a patient has discontinued treatment 
with trial product prematurely, the site 
should perform a premature EOT visit 
(V8A) and Premature EOT follow up 
visit (V9A) as soon as possible after the 
decision to permanently discontinue 
treatment is taken, followed by an EOT 
follow-up visit (V9A) 5 weeks after V8A. 
See the flowchart, Section 1.2 for data to 
be collected at the time of treatment 
discontinuation (Premature EOT visit 
(V8A)) and Premature EOT follow-up 
visit (V9A) and for any further 
evaluations that need to be completed. 
Patients should continue with the 
originally scheduled site visits 
(including V8 and V9) after completing 
the Premature EOT follow-up visit 
(V9A). 
 
Efforts must be made to have patients 
who prematurely discontinue trial 
product treatment to attend and    
complete all scheduled visit procedures 
after completing the premature EOT 
visits. 
For clarification 
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 Section # and name 
Description of change 
Rationale 
 
However, as a minimum, these patients 
must be asked to attend visit 8 and 9 
(…) 
Section 7.2 Patient 
discontinuation/withdrawal from 
the trial 
If a patient withdraws consent, the 
investigator must ask the patient if 
he/she is willing, as soon as possible, to 
have assessment performed according to 
visit 8A and visit 9A, followed by an 
EOT follow-up visit (V9A) 5 weeks after 
V8A.  
For clarification 
Section 8.1.1 Treadmill 
assessments 
Minor editorial changes: 
 
The patient should be instructed before 
performing the treadmill test to ensure 
that in the course of the treadmill test, 
ensuring that (…).  
 
Patients should be encouraged to 
continue for as long as possible (…).  
 
The baseline treadmill test is to be 
performed in the beginning of the 
baseline visit and in the end of the 
baseline visit in order to evaluate  
For clarification 
Section 8.1.1 Treadmill 
assessments 
The treadmill assessments at visits 6, 8 
and 9 can be performed at a later day 
than the other assessments and 
procedures at the given visit, provided 
that all assessments are completed 
within the visit window (visit windows 
are calculated from the randomisation 
date) (Section 1.2).  
To increase flexibility for the sites 
Section 8.1.3 Physical activity 
tracker, patient training, 
dispensing and collection 
To evaluate the ambulatory walking 
ability in the daily life of the patient, an 
activity tracker is applied in a subset of 
242 125 patients (121 patients in each 
group) 
Sample size for sub-study updated 
to accommodate recruitment 
difficulties and prioritise 
recruitment activities for the main 
study 
Section 8.1.5.1 Pulse and blood 
pressure 
Systolic blood pressure is to be recorded 
as the mean of the last 2 systolic blood 
pressure readings, and diastolic blood 
pressure as the mean of the last 2 
diastolic blood pressure readings. The 
last 2 systolic and last 2 diastolic blood 
pressure measurements should be 
recorded in the eCRF. The eCRF will 
calculate the mean of the last 2 
measurements. 
For clarification 
Section 9.1 Statistical 
hypotheses 
The hypothesis for the confirmatory 
endpoint, ratio to baseline in maximum 
walking distance at week 57 and pain-
free walking distance at week 52 is the 
same as for the primary endpoint.  
To align with the changes in testing 
hierarchy of the endpoints 
Section 9.1 Statistical 
hypotheses 
Multiplicity adjustment: 
The following hierarchical testing 
strategy will be applied to control the 
type-I error at an overall alpha level 
(two-sided) of 0.05 across the 
confirmatory endpoints: 
To align with the changes in testing 
hierarchy of the endpoints. 
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 Section # and name 
Description of change 
Rationale 
1. Superiority of semaglutide 1 mg vs. 
placebo on ratio to baseline (week 0) 
at week 52 in maximum walking 
distance 
2. Superiority of semaglutide 1 mg vs. 
placebo on ratio to baseline (week 0) 
at week 57 in maximum walking 
distance 
3. Superiority of semaglutide 1 mg vs. 
placebo on change from baseline 
(week 0) to week 52 in VascuQoL-6 
score.  
4. Superiority of semaglutide 1 mg vs. 
placebo on ratio to baseline (week 0) 
at week 52 in pain-free walking 
distance 
5. Superiority of semaglutide 1 mg vs. 
placebo on change from baseline 
(week 0) to week 52 in VascuQoL-6 
score.  
Section 9.2 Sample size 
determination 
The confirmatory secondary endpoints 
are ratio to baseline (week 0) at week 57 
in maximum walking distance, change 
from baseline (week 0) to week 52 in 
VascuQoL-6 score and ratio to baseline 
(week 0) at week 52 in pain-free walking 
distance and change from baseline (week 
0) to week 52 in VascuQoL-6 score. 
Superiority will be tested for all three 
four endpoints.  
To align with the changes in testing 
hierarchy of the endpoints 
Section 9.2 Sample size 
determination 
Secondary confirmatory endpoints 
The same assumptions as for the primary 
endpoint apply for the ratio to baseline 
(week 0) at week 57 in maximum 
walking distance and ratio to baseline 
(week 0) at week 52 in pain-free walking 
distance. 
To align with the changes in testing 
hierarchy of the endpoints 
Section 9.2 Sample size 
determination 
Table 9-1 updated to reflect changes in 
testing hierarchy. 
To align with the changes in testing 
hierarchy of the endpoints 
Section 9.4.3.1 Confirmatory 
secondary endpoints 
The confirmatory secondary endpoints 
are: 
 Ratio to baseline (week 0) at week 57 
52 in pain-free maximum walking 
distance, and will be analysed 
similarly to the primary endpoint with 
regards to the estimands 
 Change from baseline (week 0) to 
week 52 in VascuQoL-6 score and 
will be analysed similarly to the 
primary endpoint with regards to 
estimands but will not be log-
transformed. 
 Ratio to baseline (week 0) at week 52 
in pain-free walking distance, and 
will be analysed similarly to the 
primary endpoint with regards to the 
estimands 
To align with the changes in testing 
hierarchy of the endpoints 
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 Section # and name 
Description of change 
Rationale 
Section 9.4.3.2 Supportive 
secondary endpoints 
The ratio to baseline in maximum 
walking distance and pain free walking 
distance at follow-up will be analysed 
similarly to the primary endpoint. 
To align with the changes in testing 
hierarchy of the endpoints 
Appendix 8 (Section 10.8) 
Country/region-specific 
requirements 
Country-specific requirement regarding 
optional biobanking included for 
Taiwan. 
No patients from Taiwan will 
participate in the optional biobank 
part of the trial 
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Table of contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of contents ............................................................................................................................................... 8 
1 Protocol summary ..................................................................................................................................... 11 
1.1 
Synopsis ............................................................................................................................................ 11 
1.2 
Flowchart .......................................................................................................................................... 14 
2 Introduction ............................................................................................................................................... 17 
2.1 
Trial rationale .................................................................................................................................... 17 
2.2 
Background ....................................................................................................................................... 17 
2.3 
Benefit-risk assessment ..................................................................................................................... 18 
2.3.1 
Risk assessment ................................................................................................................. 19 
2.3.2 
Benefit assessment ............................................................................................................. 21 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 22 
3 Objectives and endpoints .......................................................................................................................... 23 
3.1 
Primary, secondary and exploratory objectives and estimands......................................................... 23 
3.1.1 
Primary objective and estimands ....................................................................................... 23 
3.1.2 
Secondary objectives and estimands ................................................................................. 25 
3.1.3 
Exploratory objective ........................................................................................................ 26 
3.2 
Primary, secondary and exploratory endpoint .................................................................................. 27 
3.2.1 
Primary endpoint ............................................................................................................... 27 
3.2.2 
Secondary endpoints .......................................................................................................... 27 
3.2.2.1 
Confirmatory secondary endpoint .................................................................. 27 
3.2.2.2 
Supportive secondary endpoints .................................................................... 27 
3.2.3 
Exploratory endpoint ......................................................................................................... 28 
4 Trial design ................................................................................................................................................ 29 
4.1 
Overall design ................................................................................................................................... 29 
4.2 
Scientific rationale for trial design .................................................................................................... 29 
4.2.1 
Patient input into design .................................................................................................... 30 
4.3 
Justification for dose ......................................................................................................................... 30 
4.4 
Treatment of patients ........................................................................................................................ 30 
4.4.1 
Standard-of-care ................................................................................................................ 30 
4.5 
End of trial definition ........................................................................................................................ 31 
5 Trial population ......................................................................................................................................... 32 
5.1 
Inclusion criteria ............................................................................................................................... 32 
5.2 
Exclusion criteria .............................................................................................................................. 33 
5.3 
Lifestyle considerations .................................................................................................................... 34 
5.3.1 
Physical activity ................................................................................................................. 34 
5.4 
Screen failures ................................................................................................................................... 34 
5.5 
Run-in criteria and/or randomisation criteria and/or dosing day criteria .......................................... 35 
6 Treatments ................................................................................................................................................. 36 
6.1 
Preparation/handling/storage/accountability ..................................................................................... 36 
6.2 
Treatments administered ................................................................................................................... 36 
6.2.1 
Medical devices ................................................................................................................. 38 
6.2.1.1 
Non-investigational medical devices ............................................................. 38 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 38 
6.4 
Treatment compliance ....................................................................................................................... 39 
6.5 
Concomitant medication ................................................................................................................... 39 
6.5.1 
Rescue therapy ................................................................................................................... 40 
6.6 
Dose modification ............................................................................................................................. 40 
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6.7 
Treatment after end of trial ............................................................................................................... 40 
7 Discontinuation of trial treatment and patient discontinuation/withdrawal ....................................... 41 
7.1 
Discontinuation of trial treatment ..................................................................................................... 41 
7.1.1 
Temporary discontinuation of trial treatment .................................................................... 42 
7.2 
Patient discontinuation/withdrawal from the trial ............................................................................. 43 
7.2.1 
Replacement of patients..................................................................................................... 43 
7.3 
Lost to follow-up............................................................................................................................... 43 
8 Trial assessments and procedures............................................................................................................ 45 
8.1 
Efficacy assessments ......................................................................................................................... 45 
8.1.1 
Treadmill assessments ....................................................................................................... 46 
8.1.1.1 
Pain-free walking distance-inclined treadmill................................................ 46 
8.1.1.2 
Maximum walking distance-inclined treadmill.............................................. 46 
8.1.1.3 
Pain-free walking distance-flat treadmill ....................................................... 47 
8.1.2 
Patient Reported Outcome (PRO) questionnaires ............................................................. 47 
8.1.3 
Physical activity tracker, patient training, dispensing and collection ................................ 48 
8.1.4 
Clinical efficacy laboratory assessments ........................................................................... 48 
8.1.5 
Vital signs .......................................................................................................................... 48 
8.1.5.1 
Pulse and blood pressure ................................................................................ 48 
8.1.5.2 
Toe-brachial index (TBI) and Ankle-brachial index (ABI) ........................... 49 
8.1.6 
HbA1C ................................................................................................................................ 50 
8.1.7 
Body measurements ........................................................................................................... 51 
8.2 
Safety assessments ............................................................................................................................ 51 
8.2.1 
Physical examinations ....................................................................................................... 51 
8.2.2 
Eye examination ................................................................................................................ 51 
8.2.3 
Clinical safety laboratory assessments .............................................................................. 52 
8.3 
Adverse events and serious adverse events ....................................................................................... 52 
8.3.1 
Time period and frequency for collecting AE and SAE information ................................ 54 
8.3.2 
Method of detecting AEs and SAEs .................................................................................. 55 
8.3.3 
Follow-up of AEs and SAEs ............................................................................................. 55 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 55 
8.3.5 
Pregnancy .......................................................................................................................... 55 
8.3.6 
Cardiovascular and death events ....................................................................................... 55 
8.3.7 
Technical complaints ......................................................................................................... 56 
8.4 
Treatment of overdose ...................................................................................................................... 56 
8.5 
Pharmacokinetics .............................................................................................................................. 56 
8.6 
Pharmacodynamics ........................................................................................................................... 57 
8.7 
Genetics ............................................................................................................................................ 57 
8.8 
Biomarkers ........................................................................................................................................ 57 
8.9 
Immunogenicity assessments ............................................................................................................ 57 
9 Statistical considerations .......................................................................................................................... 58 
9.1 
Statistical hypotheses ........................................................................................................................ 58 
9.2 
Sample size determination ................................................................................................................ 58 
9.3 
Populations for analyses ................................................................................................................... 60 
9.4 
Statistical analyses ............................................................................................................................ 61 
9.4.1 
General considerations ...................................................................................................... 62 
9.4.2 
Primary endpoint ............................................................................................................... 62 
9.4.3 
Secondary endpoints .......................................................................................................... 64 
9.4.3.1 
Confirmatory secondary endpoints ................................................................ 64 
9.4.3.2 
Supportive secondary endpoints .................................................................... 64 
9.4.4 
Exploratory endpoints........................................................................................................ 65 
9.4.5 
Other safety analyses ......................................................................................................... 65 
9.4.6 
Other analyses ................................................................................................................... 65 
9.5 
Pharmacokinetic modelling .............................................................................................................. 65 
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9.6 
Interim analysis ................................................................................................................................. 65 
9.7 
Data monitoring committee .............................................................................................................. 65 
9.8 
Reporting of the main part of the trial ............................................................................................... 65 
10 Supporting documentation and operational considerations.................................................................. 66 
10.1 Appendix 1: Regulatory, ethical, and trial oversight considerations ................................................ 66 
10.1.1 
Regulatory and ethical considerations ............................................................................... 66 
10.1.2 
Financial disclosure ........................................................................................................... 66 
10.1.3 
Informed consent process .................................................................................................. 67 
10.1.4 
Information to patients during trial .................................................................................... 67 
10.1.5 
Data protection .................................................................................................................. 67 
10.1.6 
Committees structure ......................................................................................................... 68 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 68 
10.1.6.2 
Event adjudication committee ........................................................................ 68 
10.1.7 
Dissemination of clinical trial data .................................................................................... 68 
10.1.8 
Data quality assurance ....................................................................................................... 69 
10.1.8.1 
Case report forms ........................................................................................... 69 
10.1.8.2 
Monitoring ..................................................................................................... 69 
10.1.8.3 
Protocol compliance ....................................................................................... 70 
10.1.9 
Source documents .............................................................................................................. 70 
10.1.10 Retention of clinical trial documentation .......................................................................... 70 
10.1.11 Trial and site closure.......................................................................................................... 71 
10.1.12 Responsibilities .................................................................................................................. 71 
10.1.13 Indemnity statement .......................................................................................................... 72 
10.1.14 Publication policy .............................................................................................................. 72 
10.1.14.1 
Communication of results .............................................................................. 73 
10.1.14.2 
Authorship ...................................................................................................... 73 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 73 
10.1.14.4 
Investigator access to data and review of results ........................................... 73 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 74 
10.3 Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-up, 
and reporting ..................................................................................................................................... 76 
10.3.1 
Definition of AE ................................................................................................................ 76 
10.3.2 
Definition of an SAE ......................................................................................................... 76 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection ....... 77 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 79 
10.3.5 
Reporting of SAEs ............................................................................................................. 81 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 83 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 87 
10.5.1 
Definition of technical complaint ...................................................................................... 87 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 87 
10.5.3 
Reporting of technical complaints ..................................................................................... 88 
10.6 Appendix 6: Retention of human biosamples ................................................................................... 89 
10.7 Appendix 7: Severe hypoglycaemic episodes ................................................................................... 90 
10.8 Appendix 8: Country/region-specific requirements .......................................................................... 91 
10.8.1 
Optional pre-screening ...................................................................................................... 95 
10.9 Appendix 9: Abbreviations ............................................................................................................... 96 
10.10 Appendix 10: Protocol amendment history ...................................................................................... 98 
11 References ................................................................................................................................................ 108 
 
Attachment I Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale 
Lower extremity peripheral artery disease (PAD) is an atherosclerotic disease and is a major cause 
of disability in older men and women affecting more than 200 million people worldwide.3, 4 
Approximately 1/3 of all PAD patients have type 2 diabetes (T2D). The purpose of this trial is to 
demonstrate that semaglutide 1 mg once-weekly improves clinical outcomes including walking 
distance compared to placebo in patients with T2D and intermittent claudication due to PAD.  
Objectives and endpoints 
The primary objective is to demonstrate the effect of s.c. semaglutide 1 mg once-weekly on walking 
ability compared with placebo, both added to standard-of-care, in patients with T2D and PAD with 
intermittent claudication. 
The primary estimand will be the median treatment ratio to baseline at week 52 in maximum 
walking distance for semaglutide 1 mg versus placebo, both as add-on to standard-of-care, in all 
randomised patients, regardless of change in background medication, rescue treatment (e.g. 
revascularisation or starting cilostazol/pentoxifylline), and adherence to randomised treatment.  
Two secondary estimands for the primary objective will be the median treatment ratio to baseline (i) 
at week 57 in maximum walking distance and (ii) at week 52 in pain-free walking distance for 
semaglutide 1 mg versus placebo, both as add-on to standard-of-care, in all randomised patients, 
regardless of change in background medication and adherence to randomised treatment. The 
rationale for pain-free walking estimand is that the pain-free walking distance is of particular 
importance to the patient, who is reminded of their disease in the moment pain is experienced. 
The key secondary objectives are to compare the effect of s.c. semaglutide 1 mg once-weekly 
versus placebo, both added to standard-of-care in patients with T2D and PAD with intermittent 
claudication with regards to Patient-reported symptoms and impacts of intermittent claudication 
(VascuQoL-65). 
Overall design 
This is a 52-week, randomised, double-blind, placebo-controlled trial comparing s.c. semaglutide 
1 mg versus placebo both added to standard-of-care and administered once-weekly in patients with 
T2D and PAD with intermittent claudication. Screening period is approximately 2 weeks before 
randomisation, and patients will be randomised in a 1:1 ratio to receive either s.c. semaglutide 1 mg 
or placebo as add-on to standard-of-care. The treatment duration is 52 weeks including an eight 
weeks dose escalation period. The follow-up period is 5 weeks. 
Key inclusion criteria: 
 Male or female, age above or equal to 18 years at the time of signing informed consent. For 
Japan and Taiwan: Male or female, age above or equal to 20 years at the time of signing 
informed consent, Appendix 8, Section 10.8. 
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 Diagnosed with type 2 diabetes mellitus ≥ 180 days prior to the day of screening. 
 Symptomatic PAD with intermittent claudication corresponding to Fontaine stage IIa 
(Rutherford classification grade I, category 1 and 2) meeting all of the following: 
a. Stable symptoms of PAD with intermittent claudication in Fontaine stage IIa (able to walk 
without stopping > 200 m/656 feet/2 blocks) for ≥ 90 days prior to the day of screening 
based on patient interview. 
b. Screening flat treadmill test (3.2 km/h (2 mph)): Pain-free walking distance of 
≥ 200 meters/656 feet. 
c. Screening constant load treadmill test with fixed inclination of 12% and a fixed speed of 
3.2 km/h (2 mph): Walking distance ≤ 600 meters/1968 feet. 
d. Ankle-brachial-index (ABI) ≤ 0.90 or toe-brachial index (TBI) ≤ 0.70 (the leg with lowest 
index is chosen in case of bilateral disease). 
Key exclusion criteria: 
 Current or previous treatment with any GLP-1 receptor agonist (GLP-1-RA within 90 days 
prior to the day of screening. 
 Walking ability limited by conditions other than PAD (e.g. aortic aneurism, dysregulated 
arrhythmia or hypertension, angina pectoris, heart failure, chronic obstructive or restrictive 
pulmonary disease, Parkinson’s disease, severe peripheral neuropathy, amputations, wheel 
chair or walker dependency, osteoarthritis, morbid obesity, severe varicose veins, etc.). 
 Planned orthopaedic surgery in the legs, or other major surgery known on the day of 
screening (surgery affecting walking ability). 
 Vascular revascularisation procedure of any kind 180 days prior to the day of screening. 
 Planned arterial revascularisation known on the day of screening. 
 Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient 
ischemic attack within 180 days prior to the day of screening. 
 Heart failure presently classified as being in New York Heart Association (NYHA) class 
III−IV. 
Number of patients 
Approximately 1,143 patients will be screened to achieve 800 patients randomly assigned to trial 
product. Expected number of patients to complete the trial on or off trial product is 736. 
Treatment groups and duration 
The total duration of trial participation for each patient is approximately 59 weeks, including a 
screening period of approximately 2 weeks, a treatment period of 52 weeks and a follow-up period 
of 5 weeks. 
The investigational medicinal products (trial products) provided by Novo Nordisk are semaglutide, 
1.34 mg/mL (investigational medicinal product (IMP), test product) and semaglutide placebo (IMP, 
reference therapy). The dosage form is a solution for subcutaneous injection packed in a 1.5 mL 
pre-filled PDS290 pen-injector. 
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When discontinuing trial product at the end of the treatment period, the patient should be transferred 
to a suitable marketed product at the discretion of the investigator. GLP-1 RAs are not allowed to be 
prescribed during the 5-week follow-up period. 
Data monitoring committee  
Not applicable.
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1.2 
Flowchart 
Screening 
Baseline 
Treatment 
End of 
treatment 
Follow-
up 
Premature 
EOT 
Premature 
EOT 
follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
P7 
V8 
V9 
V8A 
V9Aa 
Timing of visit (weeks) 
-2b  
0  
4  
8  
12  
26 
49  
52  
57 
- 
- 
Visit window (days) 
-7; +13b 
±0 
±4 
±4 
±4 
±7 
±7 
±7 
+7 
±0 
±0 
PATIENT-RELATED INFORMATION 
AND ASSESSMENTS 
Informed consent and demographyc 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Information on regular exercised 
X 
 
 
 
 
 
 
 
 
 
Medical history/Concomitant illness 
X 
 
 
 
 
 
 
 
 
 
Diabetes history 
X 
 
 
 
 
 
 
 
 
 
 
Tobacco and nicotine products usee 
X 
 
 
 
X 
 
X 
X 
Childbearing potential 
X 
 
 
 
 
 
 
 
 
 
EFFICACY 
Treadmill assessmentsf 
   Pain-free walk distance-flat treadmill 
X 
 
 
 
 
 
 
 
 
 
 
   Pain-free walking distance-inclined treadmill 
 
Xg 
 
 
 
X 
 
X 
X 
X 
X 
   Max. walking distance-inclined treadmill 
X 
Xg 
 
 
 
X 
 
X 
X 
X 
X 
Lipids 
X 
 
 
X 
 
X 
 
X 
 
Toe-brachial index (TBI) 
X 
 
 
 
X 
 
X 
X 
X 
X 
Ankle-brachial index (ABI) 
X 
 
 
 
X 
 
X 
X 
X 
X 
PK sampling  
 
 
 
 
 
X 
 
X 
 
 
 
HbA1c 
Xh 
X 
 
X 
X 
 
X 
X 
Body weight 
X 
 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Patient-reported outcome (PRO)  
  Patient global impression of severity (PGI-S)i 
 
X 
 
 
 
X 
 
X 
 
X 
 
  Patient global impression of change (PGI-C)i 
 
 
 
 
 
X 
 
X 
 
X 
 
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Screening 
Baseline 
Treatment 
End of 
treatment 
Follow-
up 
Premature 
EOT 
Premature 
EOT 
follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
P7 
V8 
V9 
V8A 
V9Aa 
Timing of visit (weeks) 
-2b  
0  
4  
8  
12  
26 
49  
52  
57 
- 
- 
Visit window (days) 
-7; +13b 
±0 
±4 
±4 
±4 
±7 
±7 
±7 
+7 
±0 
±0 
  VascuQoL-6 questionnaire (VascuQoL-6) 
 
X 
 
 
 
X 
 
X 
 
X 
 
  Walking impairment questionnaire (WIQ) 
 
X 
 
 
 
X 
 
X 
 
X 
 
  Short Form 36 (SF-36) 
 
X 
 
 
 
X 
 
X 
 
X 
 
SAFETY 
Pregnancy testj 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Adverse event (AE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe hypoglycaemic episodes 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
  Biochemistry 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
  Haematology 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
 
X 
X 
Eye examinationk  
X 
 
 
 
 
 
X 
 
X 
 
Vital signs 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
OTHER ASSESSMENTS 
Biosamples for future analysis 
X 
 
 
X 
 
 
X 
 
X 
 
TRIAL MATERIALS 
 IWRS session 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hand out Directions for Use 
 
X 
 
 
 
 
 
 
 
 
 
Dispensing visit 
X 
X 
X 
X 
X 
 
 
 
Training in trial product, pen-handling 
 
X 
 
 
 
 
 
 
 
 
 
Drug accountability 
X 
X 
X 
X 
X 
 
X 
 
X 
 
REMINDERS  
Activity trackerl 
  Phone reminder to use activity tracker 
 
 
 
 
 
X 
 
 
 
 
  Dispense activity tracker 
X 
 
 
 
X 
 
 
 
 
 
Hand out ID card 
X 
 
 
 
 
 
 
 
 
 
 
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Notes:  
a)  EOT follow-up visit (V9A) to be performed 5 weeks after V8A. 
b) Visit 1 should be at least 2 weeks prior to visit 2 in the subset of patients included in the activity tracker sub-study. 
c) Demography: date of birth (month and year), sex, ethnicity, and race (according to local regulations).  
d) Information from patient.  
e) Tobacco use/smoking is defined as smoking at least one cigarette or equivalent daily. 
f) The treadmill assessments at visits 6, 8 and 9 can be performed at a later day than the other assessments and procedures at the given visit, provided that all assessments are completed 
within the visit window (visit windows are calculated from the randomisation date).  
g) Inclined treadmill assessment must be done twice at V2, see details in Section 8.1.1. 
h) Sample can be omitted if HbA1c criterion is based on historical data obtained within 90 days prior to screening. 
i) Related to both walking ability and quality of life. 
j) Only applicable for women of childbearing potential; For Czech Republic a pregnancy test is also performed at weeks 4, 8 and 12. Please see Section 10.8 (Appendix 8) for country 
specific requirements. 
k) Fundus photography/dilated fundoscopy should be performed: 
 within 90 days prior to screening or within the period between screening and randomisation, see details in Section 8.2.2 
 at V8 and V8A or within +/- 2 weeks of those visits  
l) Activity tracker used for measuring step count during Weeks -2 and -1 as well as Weeks 51 and 52. Only selected sites participate in this substudy. 
Abbreviations: EOT: End-of-Treatment; Hb: haemoglobin; HbA1c: glycosylated haemoglobin; IWRS: interactive web response system; Max: maximum; w: week. 
 
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2 
Introduction 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.  
2.1 
Trial rationale 
Semaglutide (trade name Ozempic) is a GLP-1 receptor agonist (GLP-1-RA) indicated to improve 
glycaemic control in patients with type 2 diabetes (T2D) as an adjunct to diet and exercise.6 In the 
large clinical development programme for subcutaneous (s.c.) semaglutide for once weekly (OW) 
administration in T2D, semaglutide was superior in terms of glycaemic control and weight loss vs. 
all comparators (placebo or other approved T2D treatments).6 In addition, the cardiovascular effects 
of semaglutide were assessed in a phase 3a cardiovascular outcomes trial (NN9535-3744, 
SUSTAIN 6). In this trial, treatment with semaglutide demonstrated a statistically significant 26% 
reduction in major adverse cardiovascular events (MACE) comprising death from cardiovascular 
causes, non-fatal myocardial infarction, and non-fatal stroke when compared to placebo in patients 
with T2D at high risk of cardiovascular events.7  
The mode of action for the reduction of cardiovascular events is believed mainly to be due to an 
anti-atherosclerotic effect of semaglutide. This hypothesis is supported by animal studies, where 
semaglutide attenuated the development of atherosclerosis by preventing aortic plaque progression 
and reducing plaque inflammation.8 Furthermore, a post-hoc analysis of data from the LEADER 
trial (EX2211-3748), investigating the effect of liraglutide (first generation GLP-1 receptor agonist) 
in patients with T2D and high risk of cardiovascular events, suggested a reduction in amputations in 
connection with foot ulcers when treated with liraglutide compared to placebo.9  
Lower extremity peripheral artery disease (PAD) is an atherosclerotic manifestation and is a major 
cause of disability in older men and women affecting more than 200 million people worldwide.3, 4 
T2D is together with smoking the two leading causes of PAD, and both critical limb ischemia and 
amputations are more common in PAD patients with T2D compared to PAD patients without T2D. 
Approximately 1/3 of all PAD patients have T2D. Major risk factors are obesity, older age, 
smoking, and diabetes. PAD is diagnosed based on symptoms, ankle-brachial index (ABI) < 0.90 
and often supplemented by relevant imaging. People with PAD have increased risk of 
cardiovascular mortality and morbidity, faster rates of functional decline and mobility loss due to 
amputations, which represent a significant socioeconomic burden.10, 11 
The purpose of this trial is to demonstrate that semaglutide 1 mg once-weekly improves clinical 
outcomes including walking distance compared to placebo in patients with T2D and intermittent 
claudication due to PAD.  
2.2 
Background 
To prevent the complications associated with T2D, the goal of the therapy is to mitigate the 
multiple heterogeneous metabolic defects associated with the disease and to reduce the occurrence 
of complications and comorbidities, e.g. atherosclerotic disease.12 
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Semaglutide is a next-generation glucagon-like peptide-1 (GLP-1) receptor analogue with a high 
degree of homology to human GLP-113 and is approved in several countries under the trade name 
Ozempic® by Novo Nordisk. 
Lower extremity arterial disease is the third leading cause of atherosclerotic cardiovascular 
morbidity, following coronary artery disease and stroke.2 Manifestations of PAD include 
intermittent claudication (30-40 % of PAD patients) limiting functional capacity, fatigue, rest pain, 
impairment in quality-of-life, and ultimately, with progression of the disease, necrosis and 
amputations3, 4, often below the knee.5, 6 PAD is prevalent in up to 30% of patients with diabetes, 
and for each 1% increase in glycosylated haemoglobin (HbA1c), the incidence of PAD increases 
28%.3, 7 Furthermore, higher rates of microvascular complications and major amputations are seen 
with increasing HbA1c.3, 7 
Intermittent claudication is the classical complaint in symptomatic PAD of the lower extremities 
and is associated with limited functional capacity reflected in impaired walking ability and health-
related quality of life. 
The combined findings in trials and known mechanisms of semaglutide suggest that the compound 
may be effective in the treatment of PAD with intermittent claudication in patients with T2D. 
Semaglutide might have both indirect (weight loss) and direct (vascular) effects in PAD with 
intermittent claudication. The potential weight loss induced by semaglutide 1 mg is expected to 
have a positive impact on functional capacity and health-related quality of life in itself. Other 
potential more direct mechanisms of semaglutide may include increased microvascular recruitment 
and improved blood flow by increasing nitrogenmonoxid formation, and decreasing vascular 
smooth cell proliferation, thereby also increasing functional capacity, and limiting calf pain.12 
The trial will include patients with T2D and stable PAD with intermittent claudication, Fontaine 
stage IIa. This population is appropriate for a functional outcome intervention and will ensure that 
the primary objective of the trial can be met within a reasonable timeframe and sample size and 
without a substantial number of patients progressing to amputation or revascularisation during the 
course of the trial. 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in below Sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of semaglutide may 
be found in the investigator’s brochure14 or summary of product characteristics/prescribing 
information6, 15 and any updates thereof.  
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2.3.1 
Risk assessment 
Table 2-1 
Potential risks of clinical significance 
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Trial treatment (semaglutide) 
Gastrointestinal disorders (GI) 
Consistent with other GLP-1 RAs, 
the most frequent adverse events 
(AEs) with semaglutide are 
gastrointestinal (GI) (nausea, 
vomiting and diarrhoea). In general, 
these reactions are mild or moderate 
in severity, of short duration, and 
dose dependent.   
In patients treated with GLP-1 RAs, 
nausea, vomiting and diarrhoea may 
lead to significant dehydration. This 
should be considered when treating 
patients with impaired renal function 
as it may cause a deterioration of 
renal function.  
Clinical trials have shown that a low 
starting dose and gradual dose 
escalation mitigates the risk of 
developing gastrointestinal 
symptoms.  
Patients with GI symptoms are 
recommended to drink plenty of 
fluids to avoid volume depletion. 
Episodes of hypoglycaemia 
There is a low risk of hypoglycaemic 
episodes when semaglutide is used 
as monotherapy. Patients treated 
with semaglutide in combination 
with sulfonylurea or insulin may 
have an increased risk of 
hypoglycaemia.  
The risk of hypoglycaemia can be 
lowered by reducing the dose of 
sulfonylurea or insulin when 
initiating treatment with 
semaglutide. 
Diabetic retinopathy complications  
In a 2-year clinical trial with s.c. 
semaglutide (NN9535-3744, 
SUSTAIN 6) involving 3,297 
patients with T2D, high 
cardiovascular (CV) risk, long 
duration of diabetes and poorly 
controlled blood glucose, event 
adjudication committee (EAC)-
confirmed events of diabetic 
retinopathy complications occurred 
in more patients treated with s.c. 
semaglutide (3.0%) compared to 
placebo (1.8%). The absolute risk 
increase for diabetic retinopathy 
complications was larger among 
patients with a history of diabetic 
retinopathy at baseline. In the 
patients who did not have a 
documented history of diabetic 
retinopathy the number of events 
were similar for s.c. semaglutide and 
placebo. In the other clinical trials up 
to 1 year involving 4,807 patients 
with T2D, AEs related to diabetic 
retinopathy were reported in similar 
proportions of patients treated with 
Rapid improvement in glucose 
control has been associated with a 
temporary worsening of diabetic 
retinopathy, but other mechanisms 
cannot be excluded. Long-term 
glycaemic control decreases the risk 
of diabetic retinopathy. These 
patients should be monitored closely 
and treated according to clinical 
guidelines.  
 
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
s.c. semaglutide (1.7%) and 
comparators (2.0%). 
Allergic reactions 
As with all protein-based 
pharmaceuticals, treatment with 
semaglutide may evoke allergic 
reactions, including serious allergic 
reactions such as anaphylactic 
reactions and angioedema.  
As a precaution, patients with known 
or suspected hypersensitivity to 
semaglutide or related products will 
not be enrolled in this trial. In 
addition, patients 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. 
Acute pancreatitis 
Acute pancreatitis has been observed 
with the use of GLP-1 RAs. In the 
completed phase 3 trials with 
semaglutide s.c. and oral 
semaglutide, both the event rate and 
the proportion of patients 
experiencing confirmed pancreatitis 
were similar with semaglutide and 
comparator. Few events were 
confirmed; the events occurred 
throughout the trial periods and the 
overall rates were similar to the rates 
reported in background populations. 
Patients should be informed of the 
characteristic symptoms of acute 
pancreatitis and if pancreatitis is 
suspected, semaglutide should be 
discontinued. If confirmed, 
semaglutide should not be restarted. 
Pancreatic cancer 
Patients with T2D have an increased 
risk of certain types of cancer such 
as pancreatic cancer. There is 
currently no support from non-
clinical studies, clinical trials or 
post-marketing data that GLP-1 
based therapies increase the risk of 
pancreatic cancer. However, 
pancreatic cancer has been classified 
as a potential class risk for all 
marketed GLP-1 RAs by regulatory 
agencies. There is no indication of 
an increased relative risk in the 
semaglutide treatment groups vs. 
comparator, including placebo. The 
rates of EAC-confirmed events of 
pancreatic cancer were consistently 
low across trials. 
Patients with presence or history of 
malignant neoplasm within 5 years 
prior to the day of screening will not 
be enrolled in this trial. 
Medullary thyroid cancer 
Thyroid C-cell tumours were seen in 
mouse and rat carcinogenicity 
studies after daily exposure to 
semaglutide for 2 years. The rodent 
C-cell tumours are caused by a non-
genotoxic, specific GLP-1 receptor 
mediated mechanism to which 
rodents are particularly sensitive. No 
C-cell tumours were observed in 
monkeys after 52 weeks exposure up 
To mitigate this risk, patients with a 
family or personal history of 
medullary thyroid carcinoma or 
multiple endocrine neoplasia type 2 
(MEN2) are excluded from clinical 
trials with semaglutide. 
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
to 52-fold above the clinical plasma 
exposure at 14 mg/day. The GLP-1 
receptor is not expressed in the 
normal human thyroid, and therefore 
the clinical relevance of the findings 
is considered to be low. 
Trial procedures 
Risk of COVID-19 infection in 
relation to trial participation  
Subjects 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 measure will 
be taken: 
 
Cautious subject 
recruitment planning to 
ensure controlled subject 
enrollment in countries 
where the COVID-19 
pandemic is evaluated to be 
sufficiently under control 
Other 
Pregnancy and fertility 
Studies in animals have shown 
reproductive toxicity. There are 
limited data from the use of 
semaglutide in pregnant women. 
Semaglutide should not be used 
during pregnancy. Women of 
childbearing potential are required to 
use highly effective contraceptive 
methods when participating in this 
trial Table 10-3.  If a patient wishes 
to become pregnant, or pregnancy 
occurs, semaglutide should be 
discontinued (please refer to protocol 
Section 8.3.5 for further guidance). 
The effect of semaglutide on fertility 
in humans is unknown.  
 
2.3.2 
Benefit assessment 
In clinical trials semaglutide has provided superior long-term glycaemic control in T2D and 
clinically relevant reductions in body weight as compared to commonly used marketed products and 
placebo. A statistically and clinically significant reduction in cardio vascular (CV) events has been 
demonstrated for semaglutide s.c. (SUSTAIN 6).7 
During the present trial it is expected that all patients, including those randomised to placebo will 
benefit from participation through frequent contact with the trial site, where diabetes, PAD and CV 
diseases are monitored and treated following careful medical examinations. To ensure all patients, 
including those receiving placebo, have an adequate glycaemic control and CV risk factor 
management, investigators are encouraged to optimise treatment with anti-diabetic medications as 
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well as medications affecting CV risk factors throughout the trial. All patients in this trial will 
receive trial product and auxiliary supplies free of charge. 
2.3.3 
Overall benefit-risk conclusion 
Data from the clinical development programme for semaglutide has not revealed any safety issues 
that would outweigh the benefits. The trial population will consist of T2D patients with established 
PAD and therefore an elevated risk of CV events. Assessment of diabetes and CV risk factors and 
appropriate attention to the standard of care treatment will be ensured throughout the trial. It is 
therefore concluded that the potential benefits from the trial will outweigh the potential risks for the 
semaglutide as well as the placebo treated patients. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of semaglutide may be found in the Investigator’s Brochure and any 
updates thereof.14 
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3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objectives and estimands 
3.1.1 
Primary objective and estimands 
The primary objective is to demonstrate the effect of s.c. semaglutide 1 mg once-weekly on walking 
ability compared with placebo, both added to standard-of-care, in patients with T2D and PAD with 
intermittent claudication. 
The primary estimand will be the median treatment ratio to baseline at week 52 in maximum 
walking distance for semaglutide 1 mg versus placebo, both as add-on to standard-of-care, in all 
randomised patients, regardless of change in background medication, rescue treatment (e.g., 
revascularisation or starting cilostazol/pentoxifylline), and adherence to randomised treatment. A 
composite strategy is used to handle intercurrent events of death and physical inability to perform 
the treadmill test, these intercurrent events are incorporated into the outcome by ascribing them an 
extreme unfavourable rank. 
Two secondary estimands for the primary objective will be the median treatment ratio to baseline (i) 
at week 57 in maximum walking distance and (ii) at week 52 in pain free walking distance for 
semaglutide 1 mg versus placebo, both as add-on to standard-of-care, in all randomised patients, 
regardless of change in background medication and adherence to randomised treatment. The 
rationale for pain-free walking estimand is that the pain-free walking distance is of particular 
importance to the patient, who is reminded of their disease in the moment pain is experienced. 
The primary and secondary estimands for the primary objective are listed in Table 3-1 below. 
Table 3-1 
Primary and secondary estimands for the primary objective 
Objective 
Estimand 
category 
Estimand 
Primary 
objective: 
To demonstrate 
the effect of s.c. 
semaglutide 1 
mg once-weekly 
on walking 
ability 
compared with 
placebo, both 
added to 
standard-of-
care, in patients 
with T2D and 
PAD with 
intermittent 
claudication 
  
Primary 
Treatment condition: 
Semaglutide 1 mg or placebo, regardless of adherence to randomised 
treatment and initiation of rescue treatment 
Variable/Endpoint: 
Ratio to baseline in maximum walking distance at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
Events of death or physical inability to perform the treadmill test are 
incorporated into the outcome by ascribing them an extreme unfavourable 
rank (composite) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “regardless of initiation of rescue treatment” (treatment policy) 
Population-level summary measure 
Median ratio of semaglutide 1 mg vs placebo 
Secondary 1a 
Treatment condition: 
Semaglutide 1 mg or placebo, had all patients adhered to randomised 
treatment and not received rescue treatment 
Variable/Endpoint: 
Ratio to baseline in maximum walking distance at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
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Objective 
Estimand 
category 
Estimand 
Discontinuation of trial product: “had the patient not discontinued treatment” 
(hypothetical) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “had rescue treatment not been available” (hypothetical) 
Events of death or physical inability to perform the treadmill test: “had the 
patient not died or been unable to perform the test” (hypothetical) 
Population-level summary measure 
Geometric mean ratio of semaglutide 1 mg vs placebo 
 
Secondary 2 
Treatment condition: 
Semaglutide 1 mg or placebo, regardless of adherence to randomised 
treatment and initiation of rescue treatment 
Variable/Endpoint: 
Ratio to baseline in maximum walking distance at week 57 
Population of interest 
All randomised 
Intercurrent event strategy 
Events of death or physical inability to perform the treadmill test are 
incorporated into the outcome by ascribing them an extreme unfavourable 
rank (composite) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “regardless of initiation of rescue treatment” (treatment policy) 
Population-level summary measure 
Median ratio of semaglutide 1 mg vs placebo 
 
Secondary 3 
Treatment condition: 
Semaglutide 1 mg or placebo, had all patients adhered to randomised 
treatment and not received rescue treatment 
Variable/Endpoint: 
Ratio to baseline in maximum walking distance at week 57 
Population of interest 
All randomised 
Intercurrent event strategy 
Discontinuation of trial product: “had the patient not discontinued treatment” 
(hypothetical) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “had rescue treatment not been available” (hypothetical) 
Events of death or physical inability to perform the treadmill test: “had the 
patient not died or been unable to perform the test” (hypothetical) 
Population-level summary measure 
Geometric mean ratio of semaglutide 1 mg vs placebo 
 
Secondary 4 
Treatment condition: 
Semaglutide 1 mg or placebo, regardless of adherence to randomised 
treatment and initiation of rescue treatment 
Variable/Endpoint: 
Ratio to baseline in pain free walking distance at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
Events of death or physical inability to perform the treadmill test are 
incorporated int/o the outcome by ascribing them an extreme unfavourable 
rank (composite) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “regardless of initiation of rescue treatment” (treatment policy) 
Population-level summary measure 
Median ratio of semaglutide 1 mg vs placebo 
 
Secondary 5a 
Treatment condition: 
Semaglutide 1 mg or placebo, had all patients adhered to randomised 
treatment and not received rescue treatment 
Variable/Endpoint: 
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Objective 
Estimand 
category 
Estimand 
Ratio to baseline in pain free walking distance at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
Discontinuation of trial product: “had the patient not discontinued treatment” 
(hypothetical) 
Interventions and medication related to worsening of PAD (rescue treatment): 
“had rescue treatment not been available” (hypothetical) 
Events of death or physical inability to perform the treadmill test: “had the 
patient not died or been unable to perform the test” (hypothetical) 
Population-level summary measure 
Geometric mean ratio of semaglutide 1 mg vs placebo 
Notes: a Not related to the confirmatory hypotheses. 
3.1.2 
Secondary objectives and estimands 
The secondary objectives are to compare the effect of s.c. semaglutide 1 mg once-weekly versus 
placebo, both added to standard-of-care in patients with T2D and PAD with intermittent 
claudication with regards to: 
 Patient-reported symptoms and impacts of intermittent claudication (VascuQoL-65) 
 Body weight 
 HbA1c 
 Lipids 
 Blood pressure 
 Non-invasive blood pressure indices (ankle-brachial index (ABI), toe-brachial index (TBI)) 
 Safety 
 Patient-reported walking ability (WIQ16) 
 Patient-reported health-related quality of life (SF-3617) 
The estimands related to the confirmatory secondary endpoint are described in Table 3-2. 
Table 3-2 
Estimands for the confirmatory secondary endpoint 
Objective 
Estimand category 
Estimand 
Secondary 
objective: 
To compare the 
effect of s.c. 
semaglutide 1 mg 
once-weekly 
versus placebo, 
both added to 
standard-of-care in 
patients with T2D 
and PAD with 
intermittent 
claudication with 
regards to disease 
specific patient 
reported outcome 
Secondary 1 
Treatment condition: 
Semaglutide 1 mg or placebo, regardless of adherence to randomised 
treatment and initiation of rescue treatment 
Variable/Endpoint: 
Change from baseline in VascuQoL-6 at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
Events of death are incorporated into the outcome by ascribing them 
an extreme unfavourable rank (composite) 
Interventions and medications related to worsening of PAD (rescue 
treatment): “regardless of initiation of rescue treatment” (treatment 
policy) 
Population-level summary measure 
Median difference between semaglutide 1 mg vs placebo 
Secondary 2a 
Treatment condition: 
Semaglutide 1 mg or placebo, had all patients adhered to randomised 
treatment and not received rescue treatment 
Variable/Endpoint: 
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Objective 
Estimand category 
Estimand 
Change from baseline in VascuQoL-6 at week 52 
Population of interest 
All randomised 
Intercurrent event strategy 
Discontinuation of trial product: “had the patient not discontinued 
treatment” (hypothetical) 
Interventions and medication related to worsening of PAD (rescue 
treatment): “had rescue treatment not been available” (hypothetical) 
Events of death: “had the patient not died” (hypothetical) 
Population-level summary measure 
Mean difference between semaglutide 1 mg vs placebo 
a Not related to the confirmatory hypotheses 
3.1.3 
Exploratory objective 
The exploratory objective is to compare the effects of s.c. semaglutide 1 mg once-weekly versus 
placebo, both added to standard-of-care in patients with T2D and PAD with intermittent 
claudication with regards to 
 Daily activity levels (wrist worn activity tracker) 
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3.2 
Primary, secondary and exploratory endpoint 
3.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in maximum walking distance on a 
constant load treadmill test  
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoint 
Endpoint title 
Time frame 
Unit 
Follow-up change in maximum walking 
distance on a constant load treadmill test  
From baseline (week 0) to end of 
follow-up (week 57) 
Ratio to baseline (no unit) 
Change in Vascular Quality of Life 
Questionnaire-6 (VascuQoL-6) score 
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range: 6 to 24) 
Change in pain-free walking distance on a 
constant load treadmill test  
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Follow-up change in pain-free walking distance 
on a constant load treadmill test  
From baseline (week 0) to end of 
follow-up (week 57) 
Ratio to baseline (no unit) 
Change in HbA1c 
From baseline (week 0) to end of 
treatment (week 52) 
%-point 
Change in body weight 
From baseline (week 0) to end of 
treatment (week 52) 
Kilogram 
Change in systolic blood pressure 
From baseline (week 0) to end of 
treatment (week 52) 
mmHg 
Change in total cholesterol 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in Low-density lipoprotein (LDL)-
cholesterol 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in High density lipoprotein (HDL)-
cholesterol 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in triglycerides 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in ABI 
From screening (week -2) to end of 
treatment (week 52) 
Ratio (no unit) 
Change in TBI 
From screening (week -2) to end of 
treatment (week 52) 
Ratio (no unit) 
Change in Walking Impairment Questionnaire 
(WIQ) global score 
From baseline (week 0) to end of 
treatment (week 52) 
%-point 
Change in Short Form 36 (SF-36) physical 
functioning domain 
From baseline (week 0) to end of 
treatment (week 52) 
Score, no unit (range: 19.03 to 
57.60) 
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3.2.3 
Exploratory endpoint 
Endpoint title 
Time frame 
Unit 
Change in mean daily number of stepsa 
From baseline (week 0) to end of 
treatment (week 52) 
Steps 
Notes: aThe activity tracker is only applied in a subset of patients (n=125). For the step count measured by activity 
tracker, measurements will be made at baseline (weeks -2 to -1) and at end of treatment (weeks 51 to 52).  
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4 
Trial design 
4.1 
Overall design 
This is a 52-week, randomised, double-blind, placebo-controlled trial comparing s.c. semaglutide 
1 mg versus placebo both added to standard-of-care and administered once-weekly in patients with 
T2D and PAD with intermittent claudication. Screening period is approximately 2 weeks before 
randomisation, and patients will be randomised in a 1:1 ratio to receive either s.c. semaglutide 1 mg 
or placebo as add-on to standard-of-care. The treatment duration is 52 weeks including an eight 
weeks dose escalation period. The follow-up period is 5 weeks. A schematic illustration of the trial 
design is shown in Figure 4-1. 
In addition to the main study, an evaluation of daily activity level will be performed in a subset of 
patients using a wrist-worn activity tracker to quantify the level of activity in selected time periods 
of the study. 
An external event adjudication committee (EAC) will perform ongoing adjudication of predefined 
CV events and other selected AEs in an independent and blinded manner. 
Figure 4-1 
Schematic trial design with the estimated duration of the trial periods including 
screening and follow-up periods. Randomisation 1:1 
 
Notes: Arrows indicate site visits. Visit window for screening is -7; +13 days. Note that in the subset of patients 
included in the activity tracker sub-study, the screening (visit 1) should be at least 2 weeks prior to randomisation 
(visit 2). 
Abbreviations: OW = once-weekly; s.c. = subcutaneous.  
4.2 
Scientific rationale for trial design 
To minimise bias, the trial is randomised, double-blinded and placebo-controlled. Blinded treatment 
with semaglutide 1 mg or placebo offers a robust method for assessment of the effects of 
semaglutide 1 mg. A broad spectrum of concomitant anti-hyperglycaemic medication, as well as 
treatments for co-morbidities and CV risk factors can be introduced or adjusted throughout the trial 
based on individual requirements and at investigator’s discretion. This is in accordance with a 
pragmatic approach to compare two treatment regimens: one where semaglutide 1 mg is available 
and another where it is not. 
To support the patient during the dose escalation period site visits will occur more frequently during 
the first months of the trial. To maximise retention and compliance, and to optimise treatment, e.g. 
regarding glycaemic control, the patient is in contact with the investigator at regular visits 
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throughout the trial. A multinational design has been chosen to ensure a sufficient screening pool of 
patients and to reflect the anticipated patient population.  
At screening all patients must demonstrate a pain-free walking distance (initial claudication 
distance) of more than 200 meters on a flat treadmill with a fixed speed (3.2 km/h, 2 mph) to 
confirm their Fontaine IIa stage. To make the trial population more homogeneous, an upper limit in 
maximum walking distance of 600 meters on a constant-load treadmill test with fixed speed 
(3.2 km/h, 2 mph) and fixed inclination (12%) must be demonstrated at screening in accordance 
with guidelines.15-17 At baseline, a constant-load treadmill test with fixed speed (3.2 km/h, 2 mph) 
and fixed inclination (12%) and assessment of Patient Reported Outcomes (PROs) will be 
performed.  
A treatment duration of 52 weeks was chosen to allow sufficient time to observe a potential 
treatment effect in relation to walking ability considering the hypothesised mechanisms of actions 
of semaglutide-induced weight loss and anti-atherosclerotic effects.  
The trial will include a population of patients with T2D and PAD Fontaine stage IIa which is an 
appropriate risk target population for a functional improvement intervention and will ensure that the 
primary objective of the trial can be evaluated within a reasonable timeframe and sample size. 
4.2.1 
Patient input into design 
There have been no patient involvement or suggestions to this trial. 
4.3 
Justification for dose 
The target maintenance dose of 1 mg per week has been shown to have a positive benefit risk 
profile in T2D and is approved in a number of countries globally. Furthermore, a reduction in 
MACE has been observed with this dose in the SUSTAIN 6 trial.7 The maximum approved dose 
was chosen to optimise the potential for effects in relation to walking ability. 
4.4 
Treatment of patients 
4.4.1 
Standard-of-care 
The effect of s.c. semaglutide 1 mg will be assessed as an add-on to standard-of-care. This is in 
accordance with a pragmatic approach to compare two treatment regimens: one where semaglutide 
1 mg is available and another where it is not. 
To ensure that all patients, including those receiving placebo, have an adequate glycaemic control 
and management of their PAD, investigators are encouraged to optimise treatment throughout 
the trial in accordance with treatment guidelines including guidelines from the European Society of 
Cardiology (ESC)18 and the American Heart association (AHA).19 Anti-diabetic medications and 
medications affecting relevant cardiovascular risk factors are to be added and/or background 
treatment to be optimised. Initiating treatment with any other GLP-1 RAs is not permitted during 
the entire trial. 
Counselling of lifestyle modifications including recommendations on exercise and smoking 
cessation are to be provided as per guidelines. 
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Recommendations for standard-of-care will be provided in guidance documents. 
4.5 
End of trial definition 
A patient is considered to have completed the trial if he/she has completed all phases of the trial 
including the last follow-up visit (week 57). If a randomised patient has died during trial, `date of 
trial completion` is the date of death. 
The end of the trial is defined as the date of the last visit of the last patient 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. 
Number of patients to be investigated 
Planned number of patients to be screened meaning the number of patients providing informed 
consent: 1,143 (screening failure rate of 30 % is anticipated). 
Planned number of patients to be randomised: 800. 
Expected number of patients to complete the trial on or off trial product: 736 (withdrawal rate of 
8% is anticipated). 
Expected number of patients to complete the activity tracker evaluation: 115 (125 planned for 
randomisation, withdrawal rate of 8 % is anticipated). 
5.1 
Inclusion criteria 
Patients 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. 
For Japan and Taiwan: Male or female, age above or equal to 20 years at the time of signing 
informed consent, Appendix 8, Section 10.8. 
3. Diagnosed with type 2 diabetes mellitus ≥ 180 days prior to the day of screening. 
4. Symptomatic PAD with intermittent claudication corresponding to Fontaine stage IIa 
(Rutherford classification grade I, category 1 and 2) meeting all of the following: 
a) Stable symptoms of PAD with intermittent claudication in Fontaine stage IIa (able to walk 
without stopping > 200 m/656 feet/2 blocks) for ≥ 90 days prior to the day of screening 
based on patient interview.  
b) Screening flat treadmill test (3.2 km/h (2 mph)): Pain-free walking distance of 
≥ 200 meters/656 feet. 
c) Screening constant load treadmill test with fixed inclination of 12% and a fixed speed of 
3.2 km/h (2 mph): Walking distance ≤ 600 meters/1968 feet. 
d) Ankle-brachial-index (ABI) ≤ 0.90 or toe-brachial index (TBI) ≤ 0.70 (the leg with lowest 
index is chosen in case of bilateral disease). 
5. For patients receiving PAD standard of care non-drug (e.g. exercise) or drug therapy (e.g. statin, 
cilostazol or pentoxifylline), treatment must have been stable for at least 90 days prior to the day 
of screening, as judged by investigator.  
6. HbA1c ≤10% (≤86 mmol/mol) based on latest available measurements prior to randomisation 
(visit 2). Laboratory results for inclusion can be based on medical records (no more than 90 days 
old at screening) or central laboratory measurement obtained at the screening visit.a 
                                                 
a If based on central laboratory, both National Glycohemoglobin Standardization Program (NGSP) and International 
Federation of Clinical Chemistry and Laboratory Medicine (IFCC) need to be within limit.  
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5.2 
Exclusion criteria  
All exclusion criteria are based on the patient´s medical records, except for exclusion criterion #3, 
which is based on pregnancy test. Furthermore, exclusion criterion #12 (renal impairment) may be 
based on assessment of eGFR by the central laboratory.  
Patients are excluded from the trial, if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as randomisation. 
3. 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 (see Appendix 4, Section 10.4 for 
further guidance). For country specific requirements see Appendix 8, Section 10.8. 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening*. 
5. Current or previous treatment with any GLP-1 receptor agonist within 90 days prior to the day of 
screening. 
6. Walking ability limited by conditions other than PAD (e.g. aortic aneurism, dysregulated 
arrhythmia or hypertension, angina pectoris, heart failure, chronic obstructive or restrictive 
pulmonary disease, Parkinson’s disease, severe peripheral neuropathy, amputations, wheel chair 
or walker dependency, osteoarthritis, morbid obesity, severe varicose veins, etc.). 
India: For country-specific requirements, please refer to Appendix 8 (Section 10.8) 
7. Planned orthopaedic surgery in the legs, or other major surgery known on the day of screening 
(surgery affecting walking ability). 
8. Vascular revascularisation procedure of any kind 180 days prior to the day of screening. 
9. Planned arterial revascularisation known on the day of screening. 
10. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischemic 
attack (TIA) within 180 days prior to the day of screening. 
11. Heart failure presently classified as being in New York Heart Association (NYHA) class III−IV. 
India: For country-specific requirements, please refer to Appendix 8 (Section 10.8) 
12. Renal impairment based on latest available measurements/evaluation prior to randomisation 
(visit 2). Renal impairment can be diagnosed based on an estimated Glomerular Filtration Rate 
(eGFR) value of eGFR< 30ml/min/1.73 m2 (measured within last six months) as defined by 
KDIGO 20122 or chronic or intermittent haemodialysis or peritoneal dialysis.  
13. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and 
squamous cell skin cancer and any carcinoma in-situ are allowed. 
14. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
15. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy.b Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
16. Any disorder, which in the investigator’s opinion might jeopardise patient´s safety or compliance 
with the protocol. 
                                                 
b “Uncontrolled and potentially unstable” indicate retinopathy that has recently progressed to a level that requires 
intervention or is approaching intervention but has yet to be brought under control. In this case the patient is not eligible 
for participation in the trial.  
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17. For Hungary only: Presence or history of pancreatitis (acute or chronic). 
*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 
COVID-19 postinfectious conditions is allowed if the last dose of the investigational medicinal 
product has been received more than 30 days before screening. For Japan and China: Co-
participation in COVID-19 trials are not allowed, see country/region-specific requirements 
(Appendix 8, Section 10.8). 
Rationale for trial population 
The trial will include patients who are representative of the intended target population of patients 
with T2D and PAD with intermittent claudication. Thus, it is intended to enrol a population of adult 
patients with T2D and PAD in Fontaine stage IIa, corresponding to Rutherford classification grade 
1, categories 1 and 2, as these are considered an appropriate target population for a pharmacological 
treatment to improve walking distance. Since there is no upper limit in the maximum walking 
distance for a population with PAD and intermittent claudication in Fontaine stage IIa, a maximum 
walking distance less than 600 meters on a constant-load treadmill test with a fixed speed 
(3.2 km/h; 2 mph) and fixed inclination (12%), has been set in this trial to make the trial population 
more homogeneous20 and to ensure a certain degree of disease severity, making it likely that an 
improvement can be shown over a 52 week period of time. 
Requirements with regards to meeting either the ABI or TBI threshold are in place to ensure that 
walking distance is limited due to PAD instead of other conditions. ABI and TBI should be 
measured and documented for both legs throughout the trial. 
5.3 
Lifestyle considerations 
5.3.1 
Physical activity 
As exercise is part of standard of care in PAD, patients will be encouraged to exercise according to 
guidelines. No assistance with exercise nor restrictions are applied. 
5.4 
Screen failures 
Screen failures are defined as patients 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 patients to meet 
requirements from regulatory authorities.  
Minimal information includes informed consent date, demography, screen failure details, and 
eligibility criteria. 
A screen failure session must be made in the interactive web response system (IWRS). 
If patients withdraw their consent prior to randomisation or do not return for randomisation a screen 
failure session must be made in the interactive web response system (IWRS). The reason for failure 
will in all cases be captured in the electronic case report forms (eCRF).  
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Rescreening 
Due to the long recruitment period, rescreening is allowed once for the following eligibility criteria: 
 inclusion criteria #1-#6, except 4b), #4c) and #4d). 
 exclusion criteria #3, #4, #5, #8, #10, #15 and #16. 
Reasons for rescreening must be documented. Rescreening should only be performed if the 
investigator considers it likely the subject would be eligible based on the new screening. Previously 
randomised subjects cannot be rescreened. 
Note that in case of rescreening, screening results for inclusion criteria #4b) and #4c) (treadmill 
test) and criterion #4d) (ABI/TBI) and can be reused, if it is within 90 days from last screening. 
Hence, if rescreening is performed more than 90 days after initial screening visit, the screening 
treadmill tests are to be performed again and ABI/TBI to be re-assessed, even though the test 
fulfilled inclusion criteria #4 at the initial screening visit. 
Subjects who are rescreened are required to sign a new informed consent form and provided with a 
new subject ID. In case of rescreening, a new screening session must be made in the IWRS. 
In case of technical issues (e.g. haemolysed, lost samples or broken equipment), re-sampling/re-
assessment is allowed for the affected parameters/assessments and is not considered rescreening.  
5.5 
Run-in criteria and/or randomisation criteria and/or dosing day criteria 
Not applicable. 
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6 
Treatments 
6.1 
Preparation/handling/storage/accountability 
Only patients randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
Information on in-use conditions and in-use time will be available on the trial product label and in 
the trial materials manual (TMM). 
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to screening 
and randomisation. 
The following requirements must be followed: 
 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 patient before it 
has been evaluated and approved for further use by Novo Nordisk. Additional details 
regarding handling of temperature deviations can be found in the trial materials manual 
(TMM). 
 The investigator or designee is responsible for drug accountability and record maintenance 
(i.e. receipt, accountability and final disposition records). 
 The investigator or designee must instruct the patient in what to return at next visit. 
 Drug accountability should be performed in the IWRS by registering pen-injectors as 
returned either as used/partly used, unused or as lost.  
 Destruction of trial products can be performed on an ongoing basis and will be done 
according to local procedures after accountability is finalised by the site and reconciled by 
the monitor. 
 All returned, un-used, expired or damaged trial products (for technical complaint samples, 
see Appendix 5, Section 10.5) must be stored separately from non-allocated trial products. 
No temperature monitoring is required. 
 Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
6.2 
Treatments administered 
The investigational medicinal products (trial products) provided by Novo Nordisk are listed in 
Table 6-1. The trial products are packed blinded and are visually identical. For dose escalation, 
please refer to overall design, Section 4.1. 
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The investigator must document that directions for use are given to the patient verbally and in 
writing as a Direction for Use (DFU) document, at the first dispensing visit. 
Investigational medicinal products (IMP) 
Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Trial product name: 
Semaglutide, 1.34 mg/mL 
(IMP, test product) 
Semaglutide placebo 
(IMP, reference therapy) 
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous 
Subcutaneous 
Dosing instructions 
Once-weekly 
Once-weekly  
Packaging 
1.5 mL pre-filled PDS290 pen-
injector 
1.5 mL pre-filled PDS290 pen-
injector 
 
All baseline assessments must be done prior to administration of the first dose of trial product.  
Patients will be instructed to inject the trial product s.c. once-weekly at the same day of the week (to 
the extent possible) throughout the trial. Injections may be administered in the abdomen, thigh or 
upper arm, at any time of day irrespective of meals. 
Dose escalation intervals are applied to lower the risk of gastrointestinal adverse events (AEs). 
Dose escalation of semaglutide/placebo will take place during the first 8 weeks after randomisation 
(Section 4.2). Patients should remain on the 1 mg dose level throughout the maintenance period; 
however, to prevent permanent premature treatment discontinuation and ensure as much exposure 
as possible, dose reductions, extensions of dose escalation intervals and treatment pauses are 
allowed e.g., if treatment with the trial product is associated with unacceptable adverse events or 
due to other circumstances. Dose adjustments are at the discretion of the investigator (please refer to 
Section 6.6). If a dose is missed, the missed dose should be taken as soon as possible within 5 days 
after the missed dose. If more than 5 days have passed, the missed dose should be skipped, and the 
next dose should be administered on the regularly scheduled day.  
Auxiliary supplies provided by Novo Nordisk: 
 needles for the PDS290 pen-injector (maximum needle length 6 mm) 
 directions for use for the prefilled PDS290 pen-injector 
Only needles provided by Novo Nordisk must be used for administration of trial product. 
Shipment of trial product to patient’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 patient’s home by courier service. 
The process for sending trial product from the trial site or pharmacy to a patient’s home is described 
in the “Trial site/pharmacy instruction for shipment of trial product to patients’ homes” document. 
This document contains detailed instructions for preparing packaging and setting up the pick-up of 
trial product, handover of trial product from the trial site or pharmacy staff to the courier, required 
temperature monitoring of trial product, delivery to and receipt of trial product by the patient. The 
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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 patient’s home will be adequately trained in this process. 
6.2.1 
Medical devices 
Non-investigational medical device: PDS290 pen-injector and activity tracker. 
Training in the PDS290 pen-injector 
The patients must be trained according to the directions for use in handling the pen-injector when 
dispensed the first time and training must be repeated during the trial as needed. The investigator 
must document that directions for use are given verbally and in writing the first time trial product is 
dispensed and again during the trial as needed. Training is the responsibility of the investigator or 
delegate. 
Activity tracker 
Please refer to Section 8.1.3. 
6.2.1.1 
Non-investigational medical devices 
Non-investigational medical devices are listed in Section 6.1 as auxiliary supplies. 
6.3 
Measures to minimise bias: Randomisation and blinding 
This trial is double-blind. All patients 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/allocated at the trial visits summarised in the flowchart, Section 1.2. 
At screening, each patient will be assigned a unique 6-digit patient number, which will remain the 
same throughout the trial. Each site is assigned a 3-digit number and all patient numbers will start 
with the site number. 
The trial products containing active drug and placebo are visually identical and will be packed in a 
manner that maintains blinding. 
The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a patients’ treatment is warranted. Patient 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 patients’ treatment unless this could delay emergency treatment of the patient. If a 
patient’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 blind break, the IWRS helpdesk should be contacted. Contact details are listed in 
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Attachment I. If the blind has been broken by an investigator, the patient may continue treatment 
with trial product if judged as safe by the investigator. 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to encourage patient compliance. 
When patients self-administer trial product at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. If any suspicion of non-compliance arises, apart from occasionally one or 
more missed doses, the site must enter into a dialogue with the patient, re-emphasizing the 
importance of compliance and uncover barriers to compliance. This dialogue must be documented.  
Compliance will be assessed by cross checking the following sources and comparing these to the 
expected use: 
 Drug accountability information; counting returned trial product, visual inspection of pens 
 Questioning of patients 
Treatment start and stop dates will be recorded in the case report form (CRF). 
6.5 
Concomitant medication 
Only medication other than the trial product that the patient is receiving at the time of 
randomisation or receives during the trial for the following reasons must be recorded in the eCRF: 
 To treat diabetes or PAD 
 To treat or prevent CV diseases (for example anti-hypertensives, lipid-lowering agents, 
anticoagulants, aspirin and other antiplatelet agents) 
 In relation to an SAE, if relevant 
 Administered in relation to a clinical trial for COVID-19 prevention or treatment 
 Approved COVID-19 vaccine 
The information collected for each concomitant medication includes trade name or generic name, 
indication; start date and stop date or continuation, and related AE number when applicable.  
Initiating treatment with any other GLP-1 receptor agonists are not permitted during the entire trial. 
Other changes to background medications can take place during the trial. Risk of hypoglycaemic 
episodes is described in Section 2.3.1. 
Medication in the relevant groups mentioned above that the patient 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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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 therapy 
The following rescue medication or rescue therapy (revascularisation) may be applied and should 
be reported on the concomitant medication form or on a specific event form, respectively.  
 Medication: Starting on cilostazol or increasing dose of cilostazol with 20 % or more. 
Starting on pentoxifylline or increasing dose of pentoxifylline with 20 % or more.  
 Revascularisation: Peripheral procedures including both endovascular / percutaneous 
procedures and open surgical revascularisation including hybrid procedures (e.g. 
combination of endovascular and open surgical revascularisation). 
Patients that are started on rescue medication should continue to follow the protocol-specified visit 
schedule and stay on randomised treatment unless the investigator judges that it jeopardises safety. 
Rescue medications should be documented in medical records and reported in the case report form 
(CRF) as mentioned above.  
6.6 
Dose modification 
Patients should remain on the 1 mg dose level throughout the maintenance period; however, to 
prevent permanent premature treatment discontinuation and ensure as much exposure as possible, 
dose reductions, extensions of dose-escalation intervals and treatment pauses are allowed e.g., if 
treatment with the trial product is associated with unacceptable adverse events or due to other 
circumstances. Dose adjustments are at the discretion of the investigator and modifications should 
be reported in the eCRF. Patients will be followed for the complete duration of the trial and 
extensive efforts will be made to collect outcome data for all randomised patients. 
6.7 
Treatment after end of trial 
When discontinuing trial product at the end of the treatment period, the patient should be transferred 
to a suitable marketed product at the discretion of the investigator. GLP-1 RAs are not allowed to be 
prescribed during the 5-week follow-up period. 
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7 
Discontinuation of trial treatment and patient 
discontinuation/withdrawal 
Treatment of a patient 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 patients attend and complete all scheduled visit procedures, to collect 
the required data for the analysis of the primary (and confirmatory secondary) endpoint. Only 
patients who withdraw consent will be considered as withdrawn from the trial. Patients must be 
educated about the continued scientific importance of their data, even if they discontinue trial 
product. 
7.1 
Discontinuation of trial treatment 
Discontinuation of treatment can be decided by both the investigator and the patient. The patient 
may be discontinued from trial product at any time during the trial at the discretion of the 
investigator for safety, compliance or administrative reasons. Treatment with trial product can be 
resumed if later deemed safe.  
Temporary or permanent discontinuation of treatment with trial product will not lead to withdrawal 
from the trial.  
The trial product must be discontinued, if any of the following applies for the patient: 
1. Pregnancy 
2. Intention of becoming pregnant 
3. Simultaneous use of an approved or non-approved investigational medicinal product in 
another clinical trial* 
4. If acute pancreatitis is suspected, trial product should be discontinued; if confirmed, trial 
product should not be restarted 
5. Other safety concerns, at the discretion of the investigator 
*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 
COVID-19 postinfectious conditions is allowed at the investigator discretion without discontinuing 
trial product. Note: Co-participation in COVID-19 trials are not allowed in China and Japan, see 
country/region-specific requirements in Appendix 8 (Section 10.8). 
Ad 1 and 2: If a patient intends to become pregnant, trial product must be discontinued at least 5 
weeks before the contraceptive method is stopped. If a patient becomes pregnant unintentionally, 
trial product must be discontinued immediately during pregnancy, and during breast feeding. The 
patient will continue the other trial procedures or will be followed-up via phone contacts.  
Ad 3: With the exception of an approved or non-approved investigational product for prevention or 
treatment of COVID-19, patients should be advised not to participate in other clinical trials, while 
participating in this trial. If done, treatment with trial product should be discontinued. If 
participation in the other trial is stopped, treatment can be resumed if there are no safety concerns at 
the discretion of the investigator after discussing with a Novo Nordisk medical expert. 
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If a patient has discontinued treatment with trial product prematurely, the site should perform a 
premature EOT visit (V8A) as soon as possible after the decision to permanently discontinue 
treatment is taken, followed by an EOT follow-up visit (V9A) 5 weeks after V8A. See the 
flowchart, Section 1.2 for data to be collected at the time of treatment discontinuation (V8A and 
V9A) and for any further evaluations that need to be completed. Patients should continue with the 
originally scheduled site visits (including V8 and V9) after completing the Premature EOT follow-
up visit (V9A). 
Once dosing has been initiated, the investigator should evaluate the safety profile at an individual 
patient level on an ongoing basis, based on all available information. If a safety concern emerges, 
trial product discontinuation should be considered at the investigator´s discretion. 
Efforts must be made to have patients who prematurely discontinue trial product treatment to attend 
and complete all scheduled visit procedures after completing the premature EOT visits (including 
visits 8 and 9), to collect the required data for the analysis of the primary (and confirmatory 
secondary) endpoint. Only patients who withdraw consent will be considered as withdrawn from the 
trial. Patients must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. 
If a patient is unwilling to attend any of the scheduled clinic visits, efforts should be made to have 
the remaining visits converted to phone contacts. However, as a minimum, these patients must be 
asked to attend visit 8 and 9, and information about the attempts to follow-up with the patient must 
be documented in the medical records. 
To assess the potential disease modifying effect of semaglutide 1 mg, testing for key endpoints will 
be performed at the follow-up visit (week 57), 5 weeks after end-of-treatment. The 5-week follow 
up is chosen due to the half-life of semaglutide and is considered appropriate for end of systemic 
exposure. 
When initiating new anti-diabetic treatment after the discontinuation of trial product, the half-life of 
semaglutide of approximately one week should be kept in mind. 
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 
session must be made in the IWRS. 
7.1.1 
Temporary discontinuation of trial treatment 
Temporary treatment discontinuation is allowed at the discretion of the investigator and the reason 
for discontinuation must be recorded in the eCRF. Treatment with trial product should be resumed 
if the circumstances later allow (Section 6.2). Similarly, patients who discontinue trial product on 
their own initiative should be encouraged to resume the treatment (Section 6.2). At both instances 
dose escalation may be necessary (Section 6.2). Date and last trial product dose should be recorded 
in the eCRF. A treatment status session in the IWRS should be performed when a patient is on 
treatment pause or resumes treatment. 
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7.2 
Patient discontinuation/withdrawal from the trial 
A patient may withdraw consent at any time at his/her own request. 
If a patient withdraws consent, the investigator must ask the patient if he/she is willing, as soon as 
possible, to have assessment performed according to visit 8A, followed by an EOT follow-up visit 
(V9A) 5 weeks after V8A. See the flowchart (Section 1.2) for data to be collected. 
Final drug accountability must be performed even if the patient is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS. 
If the patient withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a patient 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 patient 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 patient's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF. 
For patients who are withdrawn, when the trial comes to an end, the investigator must scrutinise 
publicly available registries to determine vital status, unless prohibited by local regulations or 
specifically prohibited by the patient upon withdrawal of consent. Please also refer to Section 4.5 
for further details. 
7.2.1 
Replacement of patients 
Patients who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A patient 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 patient fails to return to the site for a required visit: 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
trial. 
 Before a patient is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, at least three telephone calls and, if 
necessary, a certified letter to the patient's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient's source document. 
 
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 Should the patient 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, Section 1.2. 
 Informed consent must be obtained before any trial related activity, Section 10.1.3. 
 All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all inclusion criteria and none of the exclusion criteria. 
 The investigator will maintain a screening log to record details of all patients screened and 
to confirm eligibility or record reason for screen failure, as applicable. 
 Procedures conducted as part of the patient's routine clinical management (e.g. eye 
examination), and obtained before signing of the informed consent, may be utilised for 
screening or baseline purposes, provided the procedures meet the protocol-specified criteria. 
 At screening, patients 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. 
 Each patient should be asked to provide contact information for persons (preferably at 
least 3), e.g. relative, primary care provider or other, whom the investigator can contact in 
case of issues when trying to contact the patient during the trial. The sites are encouraged to 
maintain as current details as possible throughout the course of the trial. For country-specific 
requirements see Appendix 8, Section 10.8. 
 The investigator should, if the patient agrees, inform the patient’s primary physician about 
the patient’s participation in the trial. 
 Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
 It is the responsibility of the investigator to schedule visits including laboratory assessments 
and contacts as per protocol, see flowchart, Section 1.2, and to ensure they take place. For 
drug treatment compliance see Section 6.4. 
 One phone contact is scheduled in the trial, see Section 1.2. During this, the investigator 
should remind the trial patient to use the activity tracker, if applicable.  
 Review of completed PRO questionnaires and laboratory reports etc. must be documented 
either on the documents or in the patient's source documents. If clarification of entries or 
discrepancies in the PRO questionnaires are needed, the patient must be questioned, and a 
conclusion made in the patient's source documents. Care must be taken not to bias the 
patient. 
 Investigator must ensure that data from the PRO questionnaires are transcribed to the eCRF. 
 Future biomarker testing is planned and will not be included in the clinical trial report 
(CTR). Please refer to Section 8.8. 
 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, Section 1.2. 
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8.1.1 
Treadmill assessments 
Treadmill assessments should be performed only on treadmills meant for medical use after correct 
calibration. Relevant medical personnel should be readily available to take care of the patients. A 
study manual will be made available for all sites describing the treadmill assessments in detail. 
The constant-load treadmill test is a standardised method for the functional assessment of patients 
with PAD. The constant-load test is performed at a single work rate of 2 mph (3.2 km/h) at an 
inclination of 12%.21, 22 The results of a constant-load test are expressed in units of distance walked. 
The test requires a treadmill capable of setting the speed and inclination at the required values 
(speed 3.2 km/h, inclination of 12%). The technician instructing and supervising the treadmill test 
should preferably be unaware of HbA1c, AEs, side effects, and laboratory parameters that could 
indicate the patient´s randomisation (semaglutide 1 mg or placebo). 
The patient should be instructed before performing the treadmill test to ensure that he/she 
understands that there will be two important time points during the same test (see the following 
Sections). Patients should be encouraged to continue for as long as possible disregarding the pain. 
Treadmill testing is to be discontinued on the patient´s request or in the absence of claudication 
after a total walking duration of 20 minutes. Firstly, the patient should indicate when pain starts in 
either leg (pain-free walking distance) but continue on the treadmill without stopping. Hereafter, the 
patient should continue despite the pain until it is impossible for him to walk more (max walking 
distance).  
The baseline treadmill test is to be performed in the beginning of the baseline visit and in the end of 
the baseline visit to evaluate the variability within a single patient. As a minimum the two 
assessments should be one hour apart. This duplicate assessment is only needed at baseline.  
 
The treadmill assessments at visits 6, 8 and 9 can be performed at a later day than the other 
assessments and procedures at the given visit, provided that all assessments are completed within 
the visit window (visit windows are calculated from the randomisation date) (Section 1.2).  
8.1.1.1 
Pain-free walking distance-inclined treadmill 
The patient is instructed to indicate (verbally or with a pre-defined sign) when pain starts in either 
leg and to continue on the treadmill without stopping at this stage. The distance walked is noted as 
the pain-free walking distance. It is important that the patient is carefully instructed that he/she 
should continue walking at this time point. The patient should also report if experiencing pain in 
non-index leg and the time should be noted. This measurement is performed at baseline, week 26, 
EOT visit and Follow-up visit, please refer to flowchart, Section 1.2. 
8.1.1.2 
Maximum walking distance-inclined treadmill 
The patient continues on the treadmill after indicating onset of pain and should continue as long as 
possible until pain limits further activity. This distance is noted as the maximum walking distance. 
This measurement is performed both at screening, baseline, week 26, EOT visit, and Follow-up 
visit, please refer to flowchart, Section 1.2. 
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8.1.1.3 
Pain-free walking distance-flat treadmill 
At the screening visit, proper classification of Fontaine IIa claudication has to be confirmed on a 
flat treadmill mimicking a normal walking situation. If the patient is able to walk at least 200 m 
(656 feet)on a flat treadmill with a fixed speed of 3.2 km/h (2 mph) before onset of pain in either 
leg, the patient is potentially eligible. This test is only performed at screening and not at any other 
timepoint in the trial, please refer to flowchart, Section 1.2. 
8.1.2 
Patient Reported Outcome (PRO) questionnaires 
PRO questionnaires will be assessed at baseline (V2), at 6 months visit (V6) and at end-of-treatment 
(Visit 8/8A). PRO questionnaires are to be performed prior to other visit-related activities. Patients 
should be given the opportunity to complete the questionnaires by themselves without interruption. 
Each of the questionnaires takes approximately 5-10 minutes to complete. 
In this functional outcome trial, two disease-specific PRO questionnaires have been chosen for 
evaluation of the patient´s experience of symptoms and function: 
 Vascular Quality of Life 6 items (VascuQoL-6) 
 Walking Impairment Questionnaire (WIQ) 
One generic PRO questionnaire has been selected to evaluate the patient´s health-related quality of 
life:  
 Short Form 36 (SF-36) 
Furthermore, the Patient Global Impression of Change /-Severity (PGI-C / PGI-S) will be correlated 
to the primary and secondary confirmatory endpoints to assess a clinical meaningful change. 
The daily level of activity is furthermore investigated using activity tracker in a sub-population. 
Questionnaires 
A more comprehensive overall PAD-related Quality of Life and functional measurement is 
performed using the VascuQoL-6 questionnaire,23 which with 6 questions covers social, emotional, 
functional as well as pain- and symptom-related aspects of the patient´s overall quality of life. This 
questionnaire was developed from the original 25 item questionnaire, which shows good evidence 
of construct validity and responsiveness and some evidence of content validity and internal 
consistency.24 
The patient-based ambulatory walking ability will be measured using the (WIQ) for PAD patients16 
which assesses the ability to walk at various speeds and distances and the ability to climb stairs. 
Evidence for internal consistency, test re-test reliability and responsiveness exist.25 
Overall health-related quality of life is evaluated using the Short Form 36 v2.0 acute (SF-36). SF-36 
is a generic measure of health status that yields 2 summary scores for physical health and mental 
health and 8 domain scores.17  
To establish what difference in walking distance that comprises a meaningful change for the patient, 
two questions have been developed in the Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) system. A change from one response category to the next (1-
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step change) in the PGI-S (4-point scale) comprises a threshold for clinically meaningful change 
and this will be used as anchor for evaluation of a meaningful within-patient change from baseline 
in walking distance. 
8.1.3 
Physical activity tracker, patient training, dispensing and collection 
To evaluate the ambulatory walking ability in the daily life of the patient, an activity tracker is 
applied in a subset of 125 patients. Through a wrist-worn activity tracker, the daily activity level 
will be measured in a 2-week period both in the beginning of the trial, and in the end. This is a 
supplement to the treadmill testing and questionnaires, reflecting the potential influence on the real-
life activity level of the patients. 
Physical activity data will be collected using a small wrist worn physical activity tracker designed 
for documenting physical activity. Data will be collected and transferred to Novo Nordisk from the 
physical activity tracker without site or patient interaction by a small data hub placed at the patient's 
home. Data can also be transferred manually at study site as a back-up solution in case of hub 
transfer failure. The patient and the study site will be blinded to the physical activity data which are 
collected. During the course of the study, the study site will have access to data on patients wearing 
compliance and it is recommended that the study site encourages the patient e.g., via phone and/or 
email to wear the physical activity tracker, if not done so. 
The site staff must instruct the patient according to following recommendations: 
 The physical activity tracker should be worn on the non-dominant arm  
 The physical activity tracker should be firmly attached to the wrist and the tracker should 
not be able to slide up and down when the arm moves 
 The patient should wear the physical activity tracker as much as possible, preferably 
24 hours per day during the two 2-week periods. 
 The measurements from the physical activity tracker are summarised into daily measures 
representing different aspects of physical activity. The study site will have access to data on 
the patient’s wearing compliance. 
The physical activity tracker should be returned to the site when the site has un-assigned the 
physical activity tracker, either at the next clinic visit or as agreed with the site. 
8.1.4 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments as defined in Appendix 2, Section 10.2 must be 
conducted in accordance with the flowchart (see Section 1.2). 
8.1.5 
Vital signs 
8.1.5.1 
Pulse and blood pressure 
Pulse rate as well as diastolic and systolic blood pressure will be assessed. When done in 
connection with a treadmill test, pulse and blood pressure should be assessed before the treadmill 
test. 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for the 
patient in a quiet setting without distractions (e.g., no use of television, cell phones). First time 
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blood pressure is assessed (V1) it should be performed at both arms. The arm with the highest blood 
measurement should be used for all future measurements. Blood pressure and pulse rate 
measurements will be assessed sitting with a completely automated device. Manual techniques must 
be used only if an automated device is not available. 
Blood pressure and pulse rate to be measured as listed in flowchart, Section 1.2. Blood pressure will 
consist of 2 systolic and 2 diastolic blood pressure measurements with intervals of at least 1-
2 minutes. An additional third blood pressure measurement must be performed if the first two 
readings on systolic or diastolic blood pressure differ by >10 mmHg. The last 2 systolic and last 2 
diastolic blood pressure measurements should be recorded in the eCRF. The eCRF will calculate the 
mean of the last 2 measurements. 
Pulse rate will be measured in connection to the blood pressure measurements. The pulse rate is to 
be recorded as the last 2 measurements. The eCRF will calculate the mean of the last 2 
measurements. 
8.1.5.2 
Toe-brachial index (TBI) and Ankle-brachial index (ABI) 
Measurements of the ankle-brachial index (ABI) and toe-brachial index (TBI) are the most common 
methods for assessing PAD. The measurements should be performed in the supine patient after at 
least 5 minutes of resting. The measurements can be performed by an automatic calibrated 
Sphygmomanometer or by Doppler method. If both methods are available, the Doppler method is 
preferred. The same method should be used throughout the trial for the individual patient. The 
brachial blood pressure is measured simultaneously with each toe or ankle pressure. Note that both 
ABI and TBI are calculated averages of two measurements in each location, hence, at each 
scheduled assessment two measurements must be performed at each location (i.e. both right and left 
ankle, arm and toe). 
The ABI is calculated as a ratio of the higher ankle systolic pressure to the higher systolic pressure 
measured in both arms. The ankle pressure is preferably measured using a Doppler probe to obtain 
systolic pressures in the following locations: posterior tibial and anterior tibial artery systolic 
pressures. The higher of the tibial pressure is chosen for the numerator for each leg, and the higher 
of the left and right brachial systolic pressure is chosen for the denominator.26 
The ankle pressure is measured using a blood pressure cuff chosen according to the limb size. The 
width of the cuff should contour at least 40% of the limb circumference. If a Doppler device is used, 
an 8-10 MHz Doppler probe should be used (standard vascular probe).  
The TBI is calculated as a ratio of the toe systolic pressure to the higher systolic pressure measured 
in both arms.27, 28 If toe pressure is measured by laser Doppler flowmetry (LDF) this should be with 
linear deflation pressure and a cuff that is at least 1.2 times wider than the toe (usually a 2.5 – 
3.0 cm cuff for the great toe). Equipment for measurement of toe pressure should be standard 
equipment in all vascular surgical departments for TBI measurement. The Doppler probe is applied 
to the plantar surface of the distal portion of cleaned great toe (or in absence of it on the second 
toe), and the occlusive cuff is placed around the proximal portion of the toe. 
The ABI and TBI should be measured and noted for both legs and toes throughout the trial. 
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8.1.6 
HbA1C 
HbA1c will be measured in a blood sample and be analysed at central lab according to the flowchart, 
Section 1.2. Note that the screening HbA1c sample can be omitted if HbA1c criterion is based on 
historical data obtained within 90 days prior to screening. 
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8.1.7 
Body measurements  
Height and weight will be measured and recorded as specified in the flowchart, Section 1.2. 
The patient can wear indoor, daytime clothing with no shoes.  
Body weight must be measured (with an empty bladder, without shoes and only wearing light 
clothing) on a calibrated digital scale and recorded in the eCRF in kilogram or pound [kg / lb], with 
one decimal. The body weight should be assessed on the same calibrated weighing scale equipment 
throughout the trial, if possible. The scale must be calibrated yearly as a minimum, unless the 
manufacturer certifies that calibration of the weighing scale is valid for the life-time of the scale. 
Height is measured without shoes in centimetres or inches [cm / in] and recorded in the eCRF with 
one decimal. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart, Section 1.2.  
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 patient experienced prior to the time point from which 
AEs are collected. Only relevant and significant medical history, including COVID-19, as judged 
by the investigator should be recorded in the eCRF at the screening visit (V1). Findings of specific 
medical history should be described in designated forms. 
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.  
8.2.1 
Physical examinations 
A physical examination will include assessments of the: 
 general appearance 
 respiratory system 
 cardiovascular system 
 gastrointestinal system 
 foot ulcers 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Eye examination 
Patients with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention but has yet to be brought under control.  
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Results of an eye examination performed by an ophthalmologist or another suitably qualified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a pre-corneal or corneal contact lens examination). Pharmacological pupil-
dilation is a requirement unless using a digital fundus photography camera specified for non-dilated 
examination. Optical coherence tomography and visual acuity testing are not acceptable for 
evaluating retinopathy or maculopathy.  
If the patient had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the patient has experienced worsening of visual function since 
the last examination. If the applicable eye examination was performed before the patient signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial. 
After randomisation an eye examination performed according to above must be performed as per 
protocol flowchart in Section 1.2. The investigator should indicate the outcome of each eye 
examination. Relevant findings prior to randomisation must be recorded as concomitant 
illness/medical history. While relevant findings occurring after randomisation should be reported as 
an AE, please refer to Section 8.3. 
8.2.3 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2, must be 
conducted in accordance with the laboratory manual and the protocol flowchart, Section 1.2. 
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 
 AEs leading to discontinuation of trial product 
 AEs of COVID-19, irrespective of seriousness 
 
Note: 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. 
 Pregnancies 
 Episodes of severe hypoglycaemia 
 Selected types of AEs (SAEs and non-SAEs) requiring additional data collection and events 
for adjudication (Table 8-1). 
 Technical complaints 
The definition of AEs and SAEs can be found in Appendix 3, Section 10.3, along with a description 
of events for adjudication and AEs requiring additional data collection. 
Japan: For AE reporting requirements please see Appendix 8, Section 10.8.  
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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, 
together with events for adjudication. 
Events for adjudication require data collection on an adjudication form. Event adjudication will be 
performed in randomised patients and will be evaluated by an independent external event 
adjudication committee (EAC) in a blinded manner, please refer to Appendix 1, Section 10.1.6.2 
The list of events for adjudication can be found in Table 8-1 and the reporting timelines in 
Figure 10-1. Refer to Appendix 3, Section 10.3 for further details on criteria for reporting of events 
for adjudication. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) and 
events for adjudication  
Event type  
AE requiring additional 
data collection 
Event for adjudication 
 
Medication error 
X 
 
Misuse and abuse 
X 
 
Death (all cause) 
 
X 
Acute coronary syndrome (ACS) 
X  
(specific event form only in 
case of coronary 
revascularisation) 
X 
Events leading to coronary artery revascularisation 
(non-ACS) 
Note: The underlying condition should be reported as 
the AE diagnosis  
X 
 
Stroke or transient ischemic attack (TIA)  
X 
(specific event form only in 
case of carotid 
revascularisation) 
X 
Events leading to carotid artery revascularisation 
(non-TIA/-stroke related) 
Note: The underlying condition should be reported as 
the AE diagnosis  
X 
 
Acute or chronic limb ischemia requiring 
hospitalisation 
X 
(specific event form only in 
case of limb 
revascularisation) 
X 
Events leading to peripheral artery revascularisation 
(not related to acute or chronic limb ischemia) 
Note: The underlying condition should be reported as 
the AE diagnosis  
X 
 
A detailed description of the events mentioned in the above table can be found in Appendix 3, 
Section 10.3.3. 
There are four ways to identify events relevant for adjudication as described below: 
1. Investigator-reported events for adjudication: investigator selects the appropriate AE 
category relevant for adjudication (see Appendix 3, Section 10.3.3). 
2. AEs reported with fatal outcome. 
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3. AE search (standardised screening): All AEs not reported with an AE category relevant for 
adjudication will undergo screening to identify potential events for adjudication. 
Investigators will be notified of these events in the electronic data capture (EDC) system. 
4. EAC-identified events: Unreported events relevant for adjudication identified by the EAC 
during review of source documents provided for another event for adjudication. Investigators 
will be notified of these events in the EDC system and has the option to report the EAC-
identified event. 
For each event relevant for adjudication an event type specific adjudication form should be 
completed in the EDC system within 14 days. 
Copies of source documents should be uploaded to the event adjudication system (EAS) as soon as 
possible and preferably within 4 weeks. In cases where the EAS is not accessible the investigator 
should ensure that the relevant source documents are collected and saved locally until the EAS is 
ready. If no, or insufficient source documents are provided to the adjudication supplier, the 
investigator can be asked to complete a clinical narrative to be uploaded to the EAS. 
If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS. 
An Event Adjudication Site Manual will be provided to each site detailing which source documents 
are relevant and how these should be provided to the adjudication supplier. The anonymization and 
labelling requirements are also described in the site manual. 
Episodes of severe hypoglycaemia 
Episodes of severe hypoglycaemia require additional data collection on a severe hypoglycaemic 
episode form regardless of seriousness. As opposed to AEs requiring additional data collection 
(Table 8-1), non-serious, severe hypoglycaemic episodes do not require an AE form to be filled in.  
If the severe hypoglycaemic episode fulfils the criteria for an SAE then, in addition to the severe 
hypoglycaemic episodes form, an AE form and a safety information form must be filled in, please 
refer to Appendix 3, Section 10.3.5. For more information on episodes of severe hypoglycaemia, 
please refer to Appendix 7, Section 10.7. 
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 randomisation visit and until 
the follow-up visit at the time points specified in the flowchart, Section 1.2. 
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 10.3.4. 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 patients. However, if 
the investigator learns of any SAE, including a death, at any time after a patient has been 
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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. 
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 10.3.5. 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the patient 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 patient at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
patient 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 10.3.4  
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 patients 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, institutional review board (IRB)/independent ethics committee (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 patients will be collected after first exposure to trial product and 
until pregnancy outcome. 
If a female patient 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. 
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8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5, Section 10.5. 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to the patient´s clinical signs and symptoms. 
Overdoses of up to 4 mg in a single dose have been reported in clinical trials. The most commonly 
adverse reaction was nausea. All patients recovered without complications. 
A prolonged period of observation and treatment for these symptoms may be necessary, taking into 
account the long half-life of semaglutide of approximately one week. 
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 patient for overdose-related 
AE/SAE. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the patient. 
For more information on overdose, also consult the current version of the semaglutide investigator's 
brochure.14  
8.5 
Pharmacokinetics 
 Single blood samples for measuring plasma concentration of semaglutide will be drawn on 
visits specified in the flowchart. 
 The dosing information should be transcribed into the CRF for the date of the last dose of 
trial product prior to the PK assessment, as outlined in the flowchart. 
 The exact timing of obtaining the PK sample must be recorded on the laboratory form. 
 The purpose of measuring plasma semaglutide levels is to conduct exposure-response, and 
to evaluate adherence to the treatment. 
 Blood samples for PK assessments must be collected, handled and shipped according to the 
description in the laboratory manual supplied by the central laboratory. The bioanalysis of 
semaglutide PK will be performed by a special laboratory. Semaglutide PK samples will be 
stored at the special laboratory responsible for PK until final CTR in case Novo Nordisk 
requests further analysis of the PK samples. Details of the bioanalysis will be outlined in a 
bioanalytical study plan issued by the special laboratory. 
 PK samples will not be taken in China. 
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8.6 
Pharmacodynamics 
Not applicable 
8.7 
Genetics 
Not applicable 
8.8 
Biomarkers  
Collection of samples for biomarker research is part of this trial. Participation in the biobank 
component is optional. Patients who do not wish to participate in the biobank component may still 
participate in the trial. For the biobank, samples will be collected according to the flow chart, 
Section 1.2 and stored for future use. 
Optional samples for biomarker research that should be collected from patients in the trial where 
possible are the following: 
 serum 
 plasma 
The samples are collected for the purpose of allowing future analyses of circulating biomarkers, at a 
later point in time when new knowledge or improved measurement techniques may have become 
available. The analyses may include biomarkers currently known or discovered in the future.  
In addition, samples will be stored, and analysis may be performed on biomarker variants thought to 
play a role in PAD including, but not limited to serum and plasma analytes, or tissue biomarkers, to 
evaluate their association with observed clinical responses to semaglutide 1 mg. 
These samples need to be frozen and should be sent to the central laboratory. The analyses are 
likely to be performed after the trial has come to an end, and results will therefore not be part of the 
clinical trial report. The biobank samples may be stored up to 15 years after end of trial at a central 
laboratory (see Appendix 6, Section 10.6).  
8.9 
Immunogenicity assessments 
Not applicable. 
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9 
Statistical considerations  
9.1 
Statistical hypotheses 
For the primary endpoint, ratio to baseline in maximum walking distance at week 52, the following 
confirmatory one-sided hypothesis is planned to be tested. Let the median ratio to baseline for 
semaglutide 1 mg and placebo be defined as Msema and Mplacebo, respectively. Superiority for the 
maximum walking distance at week 52 will then be tested as: 
H0: Msema ≤ Mplacebo against Ha: Msema > Mplac 
Operationally the hypotheses will be evaluated by two-sided tests. 
The hypothesis for the confirmatory endpoint, ratio to baseline in maximum walking distance at 
week 57 and pain-free walking distance at week 52 is the same as for the primary endpoint. 
Likewise, the hypothesis for the confirmatory endpoint, change from baseline in Vascu-Qol-6 score 
at week 52, is the same as for the primary endpoint, except that M denotes median change from 
baseline.  
Multiplicity adjustment 
The following hierarchical testing strategy will be applied to control the type-I error at an overall 
alpha level (two-sided) of 0.05 across the confirmatory endpoints: 
1. Superiority of semaglutide 1 mg vs. placebo on ratio to baseline (week 0) at week 52 in 
maximum walking distance 
2. Superiority of semaglutide 1 mg vs. placebo on ratio to baseline (week 0) at week 57 in 
maximum walking distance 
3. Superiority of semaglutide 1 mg vs. placebo on change from baseline (week 0) to week 52 in 
VascuQoL-6 score.  
4. Superiority of semaglutide 1 mg vs. placebo on ratio to baseline (week 0) at week 52 in pain-
free walking distance. 
9.2 
Sample size determination  
The primary endpoint is ratio to baseline (week 0) at week 52 in maximum walking distance on a 
constant-load treadmill test. The confirmatory secondary endpoints are ratio to baseline (week 0) at 
week 57 in maximum walking distance, change from baseline (week 0) to week 52 in VascuQoL-6 
score and ratio to baseline (week 0) at week 52 in pain-free walking distance. Superiority will be 
tested for all four endpoints. The type-I error rate will be controlled in the strong sense across the 
primary and the confirmatory secondary hypotheses at an overall alpha level (two-sided) of 0.05 as 
described above.  
The trial is designed to have 89% power to be able to detect a 20% improvement in maximum 
walking distance at week 52 compared to baseline for semaglutide 1 mg relative to placebo, hence 
confirm superiority for the primary endpoint. This effect size is expected to be clinically relevant 
(evaluated by the PGI-S) and is considered achievable due to the potential mode-of-action of 
semaglutide as described in the introduction (Section 2.2). 
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Primary endpoint 
The power has been calculated using stochastic simulation. First, a complete dataset has been 
simulated using a normal distribution for the log-transformed primary endpoint.  
Treatment ratio (semaglutide 1 mg versus placebo) is assumed to be 1.2, the coefficient of variation 
to be 0.8 and a 1:1 randomisation. There is some uncertainty over the coefficient of variation but 
based on results from the cilostazol trials (by dividing the standard deviation with the mean)29-31 an 
assumption of a coefficient of variation of 0.8 seems plausible.  
Missing observations due to death (2% in total corresponding to 8 deaths in each treatment group), 
inability to perform the treadmill test (3% in total corresponding to 12 cases in each treatment 
group), and due to other reasons (3% in total corresponding to 12 cases in each treatment group), 
have been introduced in the complete dataset assuming equal distribution between treatment groups.  
First, log-transformed endpoints that are missing due to other reasons than death or inability to 
perform the walking test are imputed by sampling from a normal distribution corresponding to the 
theoretical distribution in the placebo group. Second, the resulting imputed dataset is analysed using 
Wilcoxon rank-sum-test, where ranks are assigned as follows: Patients with non-missing 
observations are assigned ranks according to the observed endpoint. Patients with missing 
observation due to death or physical inability to perform the treadmill test are assigned ranks as 
described in Section 9.4.2. Third, the imputed standardized Wilcoxon test statistics are combined 
using Rubin’s rule to obtain a p-value.  
Repeating the simulation 5,000 times, each with 50 imputations, 800 patients must be randomised 
to obtain 89% power for confirming superiority for the primary endpoint. 
Secondary confirmatory endpoints 
The same assumptions as for the primary endpoint apply for the ratio to baseline (week 0) at week 
57 in maximum walking distance and ratio to baseline (week 0) at week 52 in pain-free walking 
distance. This is also assumed achievable due to the mode of actions of semaglutide. Therefore, 
with 800 randomised patients there is a marginal power of 89% for confirming superiority for this 
secondary confirmatory endpoint. 
For change from baseline (week 0) to week 52 in VascuQoL-6 score, the power for confirming 
superiority is calculated similar to the power for the primary endpoint. Stochastic simulation based 
on an assumption of a treatment difference of 2 points and a standard deviation of 5 are assumed 
based on earlier trials.32 
Missing observations (8%) in total have been introduced in the simulated complete dataset in the 
same way as for the primary endpoint. The resulting imputed dataset is analysed using a Wilcoxon 
rank-sum-test with ranks assigned using the same algorithm for the primary endpoint and combined 
using Rubin’s rule to obtain a p-value. Repeating the simulation 5,000 times, each with 
50 imputations, with 800 randomised patients, the power is >99% for confirming superiority of 
VascuQoL-6 score.  
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Overall power 
The joint (effective) power is calculated under the assumption of independence of endpoints by 
multiplying the respective marginal powers successively. Since some of these endpoints/tests are 
positively correlated, the assumption of independence is viewed as conservative. 
With the above assumptions, 89% power for confirming superiority for the primary endpoint will 
require a total of 800 randomised patients (400 patients randomised in each treatment group), when 
comparing semaglutide 1 mg to placebo. Table 9-1 summarises the assumptions for the sample size 
calculation and provides an overview of the marginal and joint power for each hypothesis. 
Table 9-1 
Assumptions used in sample size calculation and power for meeting individual 
hypotheses as well as joint power 
Endpoint 
Hypothesis 
Assumptions 
Randomised 
patients 
Marginal 
power 
Joint 
power 
Maximum walking 
distance 
Superiority 
Treatment ratio = 1.2 
Coefficient of variation = 0.8 
800 
89% 
89% 
VascuQoL-6 score 
Superiority 
Treatment difference = 2-points 
Standard deviation = 5 
800 
> 99% 
~89% 
Pain-free walking 
distance 
Superiority 
Treatment ratio = 1.2 
Coefficient of variation = 0.8 
800 
89% 
~79% 
Abbreviations: VascuQoL-6: Vascular Quality of Life-6  
Each scenario assumes 2% (8 per treatment group) dead; 3% unable to perform walking test 
(walking test endpoints only, 12 per treatment group); 3% missing due to other reasons (12 per 
treatment group). 
The sample size calculations above are sensitive to the assumptions made for the true treatment 
ratio for the primary endpoint. Table 9-2 illustrates this with six alternative set of assumptions. 
Table 9-2 
Power with different assumptions for the treatment ratio for the primary 
endpoint 
Treatment ratio 
Coefficient of variation 
Power obtained with 800 randomised patients 
1.2 
0.8 
89% 
1.2 
1.0 
77% 
1.2 
1.5 
53% 
1.3 
0.8 
>99% 
1.3 
1.0 
98% 
1.3 
1.5 
85% 
 
Approximately 1,143 patients will be screened to achieve 800 patients (screening failure rate of 
30 % is anticipated) randomly assigned to trial product. 
9.3 
Populations for analyses 
Data selection for statistical analyses will be a two-step process, first selecting patients based on the 
analysis population and subsequently events/data for those patients based on the observation period, 
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see Table 9-3 and for definitions of analysis populations and observation periods, respectively. The 
following populations are defined: 
Table 9-3 
Analysis populations 
Population 
Description 
Randomised 
All patients randomised 
Full analysis set (FAS) 
All patients randomised. Patients will be analysed according to the randomised 
treatment 
Safety analysis set (SAS) 
All patients randomly assigned to trial treatment and who take at least 1 dose of 
trial product. Patients will be analysed according to the trial product received for 
the majority of the period they were on treatment 
 
Table 9-4 
Observation periods 
Observation period 
Description 
In-trial 
This observation period is defined as the period from the date of randomisation 
to the first of the following dates, both inclusive: 
 
Date of the end-of-trial visit (V9) 
 
Date of death 
 
Date when patient withdrew informed consent 
 
Date of last contact for patients lost to follow-up 
On-treatment  
This observation period includes assessments and events for the time period 
where patients are exposed to the investigational medicinal products, regardless 
of whether the patients have received rescue treatment or not, as well as baseline 
assessments. The observation period starts at the date of first dose of trial 
product and ends at the follow-up visit for endpoints related to adverse events, 
and at last treatment day + 7 days for other endpoints.  
More details regarding the on-treatment end date can be found in the Statistical 
Analysis Plan (SAP). 
On-treament without rescue 
treatment 
This observation period includes assessments and events for the time period 
where patients were exposed to trial product and before rescue treatment. Thus, 
this observation period is a subset of the on-treatment period, excluding 
observations at and following rescue treatment 
 
In general patients should not be excluded from an analysis set and observations should not be 
excluded from an observation period, if they fulfil the criteria. If patients or observations are 
excluded, the reasons for their exclusion must be documented before database lock and described in 
the clinical trial report. Any decision to exclude either a patient or single observation from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be finalised prior to first patient first visit (FPFV), and it 
will include a more technical and detailed description of the statistical analyses described in this 
Section. This Section is a summary of the planned statistical analyses of the most important 
endpoints including primary and confirmatory secondary endpoints. 
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9.4.1 
General considerations 
Where applicable, the comparison presented from a statistical analysis will be semaglutide 1.0 mg 
versus placebo and results will be presented by the estimated treatment contrast with associated 
two-sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference. 
Unless otherwise mentioned, baseline assessment is defined as the latest available measurement 
from the randomisation visit (V2) or the screening visit (V1). Thus, if a V2 assessment is missing 
then the assessment from V1 will be used as the baseline assessment, if available. For the endpoint 
‘maximum walking distance’, the baseline assessment is defined as the mean of the two 
assessments from the randomisation visit (V2). If only one of the assessments is available, this will 
be used as the baseline assessment, and if no assessments are available at V2 then the assessment at 
V1 will be used. 
Data from all countries and sites will be analysed and reported together. 
9.4.2 
Primary endpoint 
The primary endpoint is ratio to baseline (week 0) at week 52 in maximum walking distance on a 
constant-load treadmill. 
According to the primary estimand (see Section 3.1.1), the primary analysis will be based on all 
randomised patients and the in-trial observation period and, as per the composite strategy for 
handling intercurrent events, patients with missing values at 52 weeks due to death or physical 
inability to perform the walking test, will be handled by ascribing them an extreme unfavourable 
rank.  
Specifically, ranks for the primary endpoint will be assigned as follows: 
1. Patients with missing values due to death are ordered by time of death (the earlier death, the 
worse rank) 
2. Patients with missing values due to being physically unable to perform the test are ranked more 
favourably than all deaths, and ordered by the walking distance at baseline (a higher baseline 
value corresponds to a greater deterioration and so is assigned a worse rank) 
3. Patients with observed values or missing values due to other reasons than death or inability to 
perform the walking test, are ranked more favourably than all deaths or patients unable to 
perform the walking test, and ordered according to their actual or imputed value, see below (the 
lower the walking distance relative to baseline, the worse rank) 
The maximum walking distance will be log-transformed and the analysis will be based on 
difference between the log transformed value at week 52 and baseline. 
Patients with missing values for the primary endpoint due to other reasons than death or inability to 
perform the walking test will have their values imputed using multiple imputation under a missing 
at random (MAR) assumption.  
Imputation will be performed separately within groups defined by randomised treatment and 
treatment status at week 52, for a total of four groups: 
9.4.2.1.1.1 
semaglutide/on-treatment;  
9.4.2.1.1.2 
semaglutide/off-treatment;  
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9.4.2.1.1.3 
 placebo/on-treatment;  
9.4.2.1.1.4 
 placebo/off-treatment.  
First, intermittent missing values are imputed Markov Chain Monte Carlo (MCMC) to obtain a 
monotone missing data pattern, generating 500 complete data sets. Second, sequential conditional 
linear regression will be used to impute monotone missing values, starting with the first visit after 
baseline and sequentially continuing to the last planned visit at week 52. The regression model used 
for imputation will include baseline and post-baseline values for the endpoint observed prior to the 
visit in question as covariates. 
Table 9-5 summarises the handling of missing values for the primary analysis. 
The 500 complete data sets will be analysed using a Wilcoxon rank-test.  Rubin’s rule will be used 
to combine the standardised Wilcoxon test statistics. The confirmatory statistical testing will be 
based on the p-value from the pooled standardised Wilcoxon test statistic.  
Superiority is considered confirmed if the p-value is strictly below 0.05.  
For estimation of effect in relation to the primary estimand, the Hodges-Lehmann estimator will be 
calculated on log-transformed data for each of the 500 complete data sets. Rubin’s rule will be used 
to obtain inferences. Results will be back transformed to original scale, thus showing the median 
treatment ratio of the ratio to baseline in maximum walking distance and 95% confidence intervals. 
Table 9-5 
Handling of missing and observed values for the primary estimand/analysis 
Assessment 
at week 52 
Patients on 
randomised 
treatment 
at week 52? 
Type description 
Handling  
Available 
Yes 
Available on randomised treatment 
Patients with a week 52 assessment and on randomised 
treatment  
Use observed value 
No 
Available but discontinued 
Patients who discontinued treatment prematurely but 
returned to have a week 52 assessment  
Use observed value 
Missing 
Yes 
Physically unable to perform walking test on 
randomised treatment 
Patients on randomised treatment but without a week 52 
assessment due to inability to perform walking test 
Incorporate into endpoint 
(composite strategy) 
Missing on randomised treatment 
Patients on randomised treatment but without a week 52 
assessment for other reasons than inability to perform 
walking test 
Impute in own treatment 
group based on 
‘Available on 
randomised treatment’ 
No 
Physically unable to perform walking test and 
discontinued 
Patients who discontinued randomised treatment 
prematurely, returned to have a week 52 assessment but 
were unable to perform walking test 
Incorporate into endpoint 
(composite strategy) 
Death 
Patients without a week 52 assessment due to death 
Incorporate into endpoint 
(composite strategy) 
Missing and discontinued 
Patients who discontinued randomised treatment 
prematurely and did not return to have an assessment at 
week 52. 
Impute in own treatment 
group based on 
‘Available but 
discontinued’ 
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The secondary estimand for the primary endpoint (see Section 3.1.1), will be based on all 
randomised patients and the on-treatment without rescue treatment observation period. The 
maximum walking distance will be log-transformed and the change from baseline to the 52 weeks 
will be analysed using a mixed model for repeated measurements (MMRM). The model will 
include measurements at both week 26 and 52 as dependent variables. The independent effects 
included in the model will be treatment and region as categorical fixed effects and baseline 
maximum walking distance (log-transformed) as a covariate, all nested within visit (week) as a 
factor. An unstructured covariance matrix for measurements within the same patient will be 
employed. From the MMRM model the treatment difference at week 52 will be estimated and the 
corresponding 95% confidence interval and p-value will be calculated. The estimated treatment 
difference and confidence intervals will be back transformed to original scale, and thus present the 
estimated treatment ratio with confidence interval. 
Sensitivity analyses 
As a sensitivity analysis for the primary estimand, a two-dimensional tipping point analysis will be 
performed. Missing data will be imputed according to the primary multiple imputation approach 
and fixed values 1 and 2 will be added to each imputed value in the semaglutide treatment group 
and placebo treatment group, respectively. The primary analysis will then be performed with these 
delta-adjusted imputations. This will be repeated for a grid of (1, 2)-values, including scenarios 
where patients with missing values in the semaglutide group have worse outcomes than those in the 
placebo group. This sensitivity analysis evaluates the robustness of the superiority conclusion to 
deviations from the MAR assumption for missing data. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Confirmatory secondary endpoints 
The confirmatory secondary endpoints are: 
 Ratio to baseline (week 0) at week 57 in maximum walking distance, and will be analysed 
similarly to the primary endpoint with regards to the estimands 
 Change from baseline (week 0) to week 52 in VascuQoL-6 score and will be analysed 
similarly to the primary endpoint with regards to estimands but will not be log-transformed. 
 Ratio to baseline (week 0) at week 52 in pain-free walking distance, and will be analysed 
similarly to the primary endpoint with regards to the estimands 
The confirmatory tests will be based on the primary estimand (the composite strategy and treatment 
policy estimand). 
9.4.3.2 
Supportive secondary endpoints 
The ratio to baseline in pain free walking distance at follow-up will be analysed similarly to the 
primary endpoint. 
All other supportive secondary endpoints will be analysed using a model similar to the MMRM 
model described as the secondary estimand for the primary endpoint. 
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For details on analyses of additional supportive secondary endpoints, please refer to the SAP. 
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set.  
The adverse events will be reported descriptively. 
9.4.6 
Other analyses  
The ‘Change of Patient Global Impression of Severity (PGI-S) category’ will be used for an anchor-
based analysis to determine the meaningful within-patient change in the maximum walking distance 
and VascuQoL-6. The within-patient standard deviation, estimated using the baseline maximum 
walking distance, will be used as a secondary and supportive measure of the meaningful within-
patient change in the maximum walking distance. 
For other analyses, please refer to the SAP.  
9.5 
Pharmacokinetic modelling 
Exposure-response analyses will be used as supportive evidence for the evaluation of efficacy and 
safety and further to support the investigated dose of semaglutide in subjects with PAD. Plasma 
semaglutide concentrations will be used to derive model-based estimates of steady-state average 
concentrations for each subject, utilizing a population pharmacokinetic modelling approach that 
leverages information from the SUSTAIN programme. Relevant efficacy and safety endpoints will 
be related to steady-state average concentrations and subjected to model-based exposure-response 
analysis. A modelling analysis plan will be prepared prior to database lock outlining details of the 
analyses. The results from the exposure-response analysis will be reported separately from the CTR. 
9.6 
Interim analysis 
Not applicable 
9.7 
Data monitoring committee 
Not applicable  
9.8 
Reporting of the main part of the trial 
A database lock is planned shortly after last patient last visit (LPLV) of the trial. The results from 
the trial will thereafter be reported. 
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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 Helsinki33 and applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guideline34 
 Applicable laws and regulations 
The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved by 
the IRB/IEC before the trial is initiated. See Section 10.8 for country-specific requirements in 
Latvia. 
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the 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 patients. 
Before a site is allowed to start screening patients, 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. 
For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
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10.1.3 
Informed consent process 
 The investigator or his/her representative will explain the nature of the trial to the patient 
and answer all questions regarding the trial. 
 The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial.  
 Patients must be informed that their participation is voluntary. 
 Patients must be informed about their privacy rights.  
 Patients will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines34, Declaration of Helsinki33 and the 
IRB/IEC or site. 
 The informed consent form will contain a separate form that addresses long-term storage of 
human samples and or the use of samples for optional exploratory research.  
 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. 
 Patients 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 patient.  
10.1.4 
Information to patients during trial 
The site will be offered a communication package for the patient 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 patients. The written information will be translated and 
adjusted to local requirements and distributed to the patient at the discretion of the investigator. The 
patient may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the patient may receive other written information during the 
trial.  
All written information to patients 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 
 Patients will be assigned a 6-digit unique identifier, a patient number. Any patient records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the patient are transferred to Novo Nordisk. 
 The patient and any biological material obtained from the patient will be identified by 
patient number, visit number and trial ID. Appropriate measures such as encryption or 
leaving out certain identifiers will be enforced to protect the identity of patients as required 
by local, regional and national requirements.  
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 The patient 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 patient.  
 The patient 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 
Event adjudication committee 
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and deaths (see Section 8.3).The purpose of the adjudication is to evaluate events in a 
consistent manner according to standardised criteria using independent external medical experts. 
The EAC will evaluate events sent for adjudication using pre-defined definitions and guidelines in 
accordance with the EAC charter. The evaluation is based on review of pre-defined clinical data 
collected by the sites. The EAC is composed of permanent members covering all required medical 
specialities. EAC members must disclose any potential conflicts of interest and must be independent 
of Novo Nordisk. The EAC will have no authority to impact trial conduct, trial protocol or 
amendments. The assessments made by both the event adjudication committee and the investigator 
will be evaluated and included in the CTR.  
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)35, the Food and Drug Administration Amendment 
Act (FDAAA)36, European Commission Requirements1, 37, 38 and other relevant recommendations or 
regulations. If a patient 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 patient. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint and is for this 
trial last patient first visit (LPFV) + 54 weeks, corresponding to visit 8 (end of treatment). If the last 
patient is withdrawn early, the PCD is considered the date when the last patient would have 
completed visit 8. 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 patient data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory and activity tracker data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The following will be provided as paper CRFs: 
 Pregnancy forms 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable:  
 AE forms  
 Safety information forms 
 Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a patient) 
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 patients 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. 
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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.  
Monitors will review the patient’s medical records and other source data, e.g. the 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 
 The original of the completed PROs must not be removed from the site, unless they form 
part of the CRF, and a copy is kept at the site. 
 For Activity tracker, data in the service providers’ database is considered source data. 
 Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
 Data reported on the paper CRF or 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 patient’s medical history in source documents, such as patient’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. 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 patient data will be provided in an 
electronic readable format to the investigator before access is revoked to the system supplied by 
Novo Nordisk. Site-specific CRFs and other patient data (in an electronic readable format or as 
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paper copies or prints) must be retained by the site. A copy of all data will be stored by Novo 
Nordisk. 
Patient’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
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 patients 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 patients 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 patients.  
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 patient 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 
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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 
patients to a specific qualified physician who will be readily available to patients during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical 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 accepts liability in accordance with country specific requirements, see Appendix 8, 
Section 10.8.  
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 investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators.  
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10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of 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 patient to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
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.39 
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 
patients, 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.
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10.2 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory. 
Information on central laboratory can be found in Attachment I. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, e.g. 
to follow up on AEs, this must be done at a local laboratory. 
The central lab will communicate to the investigator abnormal values of parameters not requested in 
the protocol but identified by the laboratory equipment and/or their processes according to their lab 
SOPs. These data will not be transferred to the trial database. The investigator should review such 
values for AEs and report these according to this protocol. 
The investigator must review all laboratory results for concomitant illnesses and AEs. 
Laboratory samples will be destroyed no later than at finalisation of the CTR, except for biomarker 
samples, which will be stored as described in Appendix 6, Section 10.6. 
For female patients of childbearing potential, local urine pregnancy tests must be performed at 
screening according to flowchart, Section 1.2. Serum testing is mandatory if required by local 
regulations or the IRB/IEC. 
For haematology samples (differential count) where the test result is not normal, then a part of the 
sample may be kept for up to two years or according to local regulations.  
Human biosamples for future research will be stored as described in Appendix 6, Section 10.6. 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
 
HbA1c 
Lipids 
 
Cholesterol 
 
High density lipoprotein (HDL) cholesterol 
 
Low density lipoprotein (LDL) cholesterol 
 
Triglycerides 
Pharmacokinetics 
 
Plasma semaglutide 
Notes: Laboratory results that could unblind the trial (e.g. PK data) will not be reported to the trial sites until the trial 
has been unblinded. 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology 
 
Erythrocytes 
 
Haematocrit 
 
Haemoglobin 
 
Leucocytes 
 
Thrombocytes 
Biochemistrya 
 
Albumin 
 
Creatinine 
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Laboratory 
 assessments 
Parameters 
 
Potassium 
 
Sodium 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Gamma glutamyltransferase (GGT) 
 
Total bilirubin 
Pregnancy Testing 
 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)b 
Notes:  
a Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Section 10.3 (Hy’s Law) and Section 7.1. 
b Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
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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 patient that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavorable 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 
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. 
 Medical or surgical procedures not preceded by an AE or worsening of a known 
condition. 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 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 
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 Hospitalisation signifies that the patient 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 
patient 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 events for adjudication and AEs requiring additional data collection  
Description of events for adjudication and AEs requiring additional data collection (on 
specific event form)  
Events for adjudication 
An event for adjudication is a selected AE or death evaluated by an independent external EAC in 
a blinded manner, please refer to Section 10.1.6.2 and Figure 10-1. 
 Death: 
All cause death 
 Acute coronary syndrome: 
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Conditions include all types of acute myocardial infarction and hospitalisation for unstable 
angina pectoris 
 Stroke or transient ischemic attack: 
Episode of focal or global neurological dysfunction that could be caused by brain, spinal cord, 
or retinal vascular injury as a result of haemorrhage or ischaemia, with or without infarction 
 Acute or chronic limb ischemia requiring hospitalisation: 
Acute limb ischemia is defined as a sudden decrease in limb perfusion threatening viability of 
the limb and leading to an urgent, unscheduled hospitalisation.  
Chronic limb ischemia is defined as a chronic condition with rest pain, non-healing ulcers or 
gangrene and leading to an urgent, unscheduled hospitalisation with need for intervention 
such as a revascularization procedure, amputation or pharmacological therapy. 
Adverse events requiring additional data collection 
 Events leading to coronary artery revascularisation (ACS and non-ACS): 
 
ACS and non-ACS (e.g. stable angina pectoris) leading to catheter-based 
(percutaneous coronary intervention (PCI)) or a surgical procedure (coronary artery bypass 
surgery) designed to improve myocardial blood flow.  
 Note: The underlying condition should be reported as an AE diagnosis. 
 Events leading to carotid artery revascularisation: 
 
Carotid artery stenosis leading to a surgical procedure (carotid artery 
endarterectomy incl. angioplasty and carotid artery stenting).  
 Note: The underlying condition should be reported as an AE diagnosis. 
 Events leading to peripheral artery revascularisation: 
 
Any type of limb ischemia leading to a catheter-based (incl. endovascular 
procedures) or a surgical procedure (surgical thrombectomy/thromboendarterectomy and/or 
peripheral bypass surgery or endovascular / surgical treatment of aortic aneurysm) designed 
to improve blood flow to the limb.  
 Note: The underlying condition should be reported as an AE diagnosis. 
 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 patient, such as:  
 Administration of wrong drug  
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error 
unless it results in administration of wrong drug  
 Wrong route of administration, such as intramuscular instead of subcutaneous  
 Accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
patient were likely to happen as judged by the investigator, although they did not 
necessarily occur. 
 Treatment pauses are allowed in the trial, this should not be reported as a medication 
error. 
 Misuse and abuse  
 Situations where the IMP is intentionally and inappropriately used not in accordance with 
the protocol (e.g. overdose to maximise effect) 
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 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 
 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.   
 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 patient identifiers, with the 
exception of the patient 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 patient, 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:  
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 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 should use the investigator’s brochure for the assessment. For each 
AE/SAE, the investigator must document in the medical records that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the 
investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data. 
 The investigator may change his/her opinion of causality, in light of follow-up 
information, and update the causality assessment in the CRF. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The patient 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 patient 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 patient has completed the follow-
up period and is expected to recover. 
 Recovered/resolved with sequelae: The patient 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 patient 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 patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient 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 patient 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. 
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If a patient 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 and safety information form) 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 
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 patient or receives updated data on a previously 
reported SAE after CRF decommission, then the site can report this information on a 
paper AE and safety information form (see box below) or to Novo Nordisk by telephone. 
 
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  
 
 
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Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file.
AE identified
AE form       hours
SIF     calendar days
Sign off     calendar days
Is the AE serious or 
non-serious?
Is the AE leading to 
discontinuation of trial 
product, related to COVID-19 
or listed in table 8-1?
Does the AE require 
additional data 
collection?
Non-serious
Serious
No
Specific event form
(For SAE: 
     calendar days)
Yes

Timelines are from the awareness of an AE.

Queries and follow-up requests to be resolved      calendar days.

In general data must be recorded in the CRF as soon as possible, preferably within 
5 working days (see Appendix 1)
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
AE Form
No additional 
action
No additional 
action
No
Is the event to be 
adjudicated?
Adjudication form
      calendar days
Source data      weeks
Yes
No additional 
action
No
Yes
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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: 
▪ Amenorrhoea and 
▪ 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 
(Table 10-3).  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of patient’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male patients  
No contraception measures are required for male patients as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in Table 10-3 below: 
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Table 10-3 
Highly effective contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
 
Highly effective methodsb,f that have low user dependency (Failure rate of <1% per year when used 
consistently and correctly): 
 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS)b 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the woman of childbearing potential, and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
 
Highly effective methodsb,f that are user dependent (Failure rate of <1% per year when used 
consistently and correctly): 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
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 patient. 
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, 
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 5 weeks 
(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. 
 
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with: 
1. known intolerance to the highly effective methods mentioned in Table 10-3 or where the use of 
any of the listed highly effective contraceptive measures are contraindicated in the individual 
patient, and/or 
2. if the risk of initiating treatment with a specific highly effective method outweighs the benefit 
for the female. 
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Justification for accepting double barrier method should be at the discretion of the investigator 
taking into consideration his/her knowledge about the female’s medical history, concomitant illness, 
concomitant medication and observed AEs. The justification must be stated in the medical records. 
For country specific requirements, please see Appendix 8 (Section 10.8). 
Pregnancy testing 
 WOCBP should only be included after a negative highly sensitive urine pregnancy test (refer to 
Appendix 2, Section 10.2). 
 Additional urine pregnancy testing should be performed at end of treatment (V8) or at 
premature end of treatment (V8A) according to the flowchart. 
 Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy 
is otherwise suspected. 
 Additional pregnancy testing should be performed during the treatment period, if required 
locally (Appendix 8, Section 10.8). 
Collection of pregnancy information  
Female patients who become pregnant  
 Investigator will collect pregnancy information on any female patient 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 patient's pregnancy (see Figure 10-2). 
 Patient will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on patient 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 patient'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 
Appendix 3 (Section 10.3). While the investigator is not obligated to actively seek this 
information in former patients, he or she may learn of an SAE through spontaneous reporting.  
 
 
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Figure 10-2 Decision tree for determining the forms to complete with associated timelines for 
pregnancy 
.
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
 
Any female patient 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: 
6. One technical complaint form must be completed for each affected DUN. 
7. 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 patient, 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: Retention of human biosamples 
As new biomarkers related to the disease and/or safety, efficacy or mechanism of action of 
semaglutide may evolve during the conduct of the trial, the analyses of the stored biosamples may 
also include biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial.  
In countries where allowed, the trial will involve collection of human biosamples to be stored in a 
central archive (perhaps in another country) for future use as noted in Section 8.8. 
The following samples will be stored: 
 plasma 
 serum 
The samples will be stored at a secure central bio-repository after end of trial and until the research 
project terminates, but no longer than 15 years from end of trial after which they will be destroyed. 
Only Novo Nordisk staff and biorepository personnel will have access to the stored samples. 
Patients may withdraw from the biobank component of the trial at any time, independent of 
participation in the trial. If a patient withdraws from the biobank component all stored biosamples 
obtained from their own body will be destroyed. 
Confidentiality and personal data protection will be ensured during storage after the end of trial. 
In the event that the collected biosamples will be used in the future, care will be taken to target 
analyses within the scope defined in Section 8.8. 
For country specific requirements see Appendix 8 (Section 10.8).  
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10.7 
Appendix 7: Severe hypoglycaemic episodes 
Severe hypoglycaemia 
Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may 
not be available during an event, but neurological recovery following the return of plasma glucose 
to normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.40, 41 
 
 
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10.8 
Appendix 8: Country/region-specific requirements  
Austria 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Recommendations related to contraception and pregnancy testing in clinical trials”, as listed 
in Table 10-3. This means that the use of double barrier methods is not applicable for 
Austria.  
Belgium 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Use of methods of birth 
control for Belgium: E.g. Highly effective methods of birth control are defined as those, 
alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly; such as implants, injectables, combined oral contraceptives, 
some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the 
entire period of risk associated with the trial treatments) or vasectomised partner. 
 Appendix 1 (Section 10.1), Regulatory and ethical considerations: Indemnity statement: 
Novo Nordisk accepts liability in accordance with: Law concerning experiments on the 
human person of 07 May 2004 – Article 29: §1. Even if without fault, the sponsor is liable 
for the damage which the patient and/or his rightful claimants sustain, and which shows 
either a direct or an indirect connection with the trial. 
 Section 8, Trial assessments and procedures no 7: Collection of contact information for 
persons other than the patient not relevant for Belgium. 
Canada 
 Appendix 1 (Section 10.1), Regulatory, ethical, and trial oversight considerations. Retention 
of clinical trial documentation: Part C, Division 5 of the Food and Drug Regulations 
[C.05.012] requires a 25-year retention period. 
China 
 Sections 5.1, Inclusion criteria and 5.2, Exclusion criteria: The criteria will be assessed at 
the investigator's discretion unless otherwise stated. 
 Section 5.2, Exclusion criterion #4: Co-participation in COVID-19 trials are not allowed. 
 Section 7.1, Discontinuation criterion #3: Co-participation in COVID-19 trials are not 
allowed. 
 Section 8.5, Pharmacokinetics: PK samples will not be taken in China. 
 Section 8.8, Biomarkers: No subjects from China will participate in the optional biobank 
part of the trial. 
 Appendix 2 (Section 10.2), Clinical laboratory tests: The samples which tested at sites will 
be destroyed as biological waste according to local regulation, if applicable. The samples 
which tested at central lab will be destroyed as biological waste according to local regulation 
and lab manual. The laboratory samples for Chinese subjects will be destroyed no later than 
the finalization of the clinical trial report, or according to local regulatory requirement. 
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 Appendix 1 (Section 10.1), Regulatory, ethical, and trial oversight considerations: Any trial 
procedure conducted in China mainland should comply with “Regulations on management 
of Human Genetic Resources of People’s Republic of China” and relative guideline. 
http://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm 
 Appendix 1 (Section 10.1.7), Dissemination of clinical trial data. Information of the trial 
will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and novonordisk-trials.com as 
China HA has requested to disclose trial information (phase 1-3) at chinadrugtrials.org.cn 
since 2013. 
 Appendix 1 (Section 10.1.10), Retention of clinical trial documentation: About site specific 
data storage, sites have the equal right with sponsor. Long term preservation of Chinese 
Patients’ Trial Data is Prohibited in any other entities. 
Czech Republic 
 Section 1.2: Pregnancy testing for women of childbearing potential will be done in line with 
the schedule below: 
Screening 
Baseline 
Treatment 
End of 
treatment 
Follow-up 
Premature 
EOT 
Premature 
EOT 
follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
P7 
V8 
V9 
V8A 
V9A 
Timing of 
visit (weeks) 
-2  
0  
4  
8  
12  
26 
49  
52  
57 
- 
- 
Visit 
window (days) 
-7; +13 
±0 
±4 
±4 
±4 
±7 
±7 
±7 
+7 
±0 
±0 
Safety 
Pregnancy test 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 Section 1.2: Date of Birth: Patient’s full Date of Birth is not allowed to be collected and 
must be shortened to Year of Birth. 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 Appendix 4 (Section 10.4): In addition to the pregnancy testing described in the Flowchart 
(Section 1.2) and Appendix 4 (Section 10.4, for female subject of childbearing potential 
from Czech Republic, additional pregnancy testing will be done at week 4 (V3), week 8 
(V4) and week 12 (V5). The additional pregnancy testing will not be reported in the CRF. In 
case of pregnancy, trial product will be discontinued, and the investigator should follow the 
procedures outlined in Appendix 4 (Section 10.4). 
Denmark 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
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Germany 
 Section 1.2, Date of Birth: Patient’s full Date of Birth is not allowed to be collected and 
must be shortened to Year of Birth. 
 Section 5.2, Exclusion criterion #3: Contraceptive requirements as per CTFG guideline: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
Hungary 
 Section 1.2, Date of Birth: Patient’s full Date of Birth is not allowed to be collected and 
must be shortened to Year of Birth. 
 Section 5.2, Exclusion criterion #17: Presence or history of pancreatitis (acute or chronic). 
India 
 Section 5.2, Exclusion criterion #6:  
o Digital x-ray of the foot should be performed according to local practice as part of 
the screening procedure in subjects who do not have recent imaging (within 90 days 
prior to the screening visit) to exclude foot deformities which can impact walking 
ability.  
o Conditions other than PAD which affects the walking ability includes anaemia or 
any other condition which in the investigator’s opinion impacts the subjects walking 
ability. 
 Section 5.2, Exclusion criterion #11: Echocardiography should be performed according to 
local practice as part of the screening procedure in subjects who do not have recent imaging 
(within 90 days prior to the screening visit).  
Japan 
 Section 5.1, Inclusion criterion #2: Male or female, age above or equal to 20 years at the 
time of signing informed consent. 
 Section 5.2, Exclusion criterion #4: Co-participation in COVID-19 trials are not allowed. 
 Section 6.2, Preparation/Handling/Storage/Accountability: The head of the trial site or the 
trial product storage manager assigned by the head of the trial site (a pharmacist in 
principle) is responsible for control and accountability of the trial products. 
 Section 7.1, Discontinuation criterion #3: Co-participation in COVID-19 trials are not 
allowed. 
 Section 8.3: For Japan, all AEs irrespective of seriousness should be collected from the day 
of randomisation and until the follow-up visit, at the time points specified in the flowchart. 
A non-severe non-serious hypoglycaemic episode should be reported as an AE. A severe 
non-serious hypoglycaemic episode should be reported as an AE and in addition a specific 
event form (severe hypoglycaemic episode) should be filled out.  
 Appendix 1 (Section 10.1): Regulatory and ethical considerations: A name or a seal is 
accepted as a signature. 
Latvia 
 Section 10.1.1: Protocol, protocol amendments, informed consent form and investigator’s 
brochure, must be also submitted, reviewed, and approved by the regulatory authorities 
before the trial is initiated. 
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Malaysia 
 Appendix 6 (Section 10.6): No patients from Malaysia will participate in the optional 
biobank part of the trial. 
Norway 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_ 
HMA_CTFG_Contraception.pdf 
Spain 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_ 
HMA_CTFG_Contraception.pdf 
 Appendix 1 (Section 10.1): Regulatory, ethical, and trial oversight considerations. Retention 
of clinical trial documentation: 25 years according to the new Spanish Royal Decree 
1090/2015. 
Sweden 
 Section 5.2, Exclusion criterion #3 and Appendix 4 (Section 10.4): Contraceptive 
requirements as per EU CTFG guideline: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_ 
HMA_CTFG_Contraception.pdf. Recommendations related to contraception and pregnancy 
testing in clinical trials”, as listed in Table 10-3. 
 Section 6, Treatments: Refer to CSC for labelling requirements. 
Taiwan 
 Section 5.1, Inclusion criterion #2: Legal age is 20 years per local law. Thus, age limitation 
for adult trials shall be above or equal to 20 years in the entry criteria. 
 Appendix 6 (Section 10.6): No patients from Taiwan will participate in the optional biobank 
part of the trial. 
United States 
 Section 5.2, Exclusion criterion #15: Funduscopy/fundus photography will be performed by 
the investigator or a local Ophthalmologist/Optometrist according to local practise. 
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10.8.1 
Optional pre-screening 
Applicable for Austria, Canada, Czech Republic, Denmark, Greece, India, Malaysia, Sweden, 
Thailand and United States.  
In the countries mentioned above, the investigator may, after obtaining separate informed consent, 
perform pre-screening activities to identify potential study participants based on ABI and/or TBI 
(inclusion criterion #4d). Pre-screening is optional and participants must sign a separate informed 
consent form to participate. It is not necessary to obtain informed consent for the full study before 
pre-screening. The requirements for the informed consent process are the same as those outlined in 
Section 10.1.3. 
Pre-screening assessments may include: 
 Measurement of ABI and/or TBI. 
 Review of medical history and concomitant medication, including the option to review medical 
records obtained from relevant sources such as primary care physicians and hospitals.  
 
Pre-screening assessments are not defined as study-related procedures. Results of pre-screening will 
not be collected in the study database. Concerns related to any pre-screening assessment should not 
be reported as an AE. 
It is encouraged that potential participants who are determined to be potentially eligible for the 
study should proceed to screening (visit 1) as soon as possible and preferably within 1 month of 
pre-screening. If the candidate is deemed potentially eligible for participation in the study, all 
assessments and information required for screening (visit 1) must be collected in accordance with 
the flowchart (Section 1.2). 
The investigator must maintain a pre-screening log to record details of all candidates who were 
pre-screened and to track the outcome of the pre-screening. 
Pre-screening assessments performed after signature of the separate informed consent for 
pre-screening can be reimbursed by Novo Nordisk A/S.  
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10.9 
Appendix 9: Abbreviations  
ABI 
Ankle-brachial index  
ACS 
Acute coronary syndrome 
AE 
adverse event 
AHA 
American Heart association 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus disease 2019 
CRF 
case report form 
CTFG 
Clinical Trial Facilitation Group  
CTR 
clinical trial report 
CV 
Cardiovascular 
DFU 
directions for use 
DPP-4 i 
DPP-4 inhibitor 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EAS 
event adjudication system 
EDC 
Electronic data capture 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
ESC 
European Society of Cardiology 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPFV 
first patient first visit 
FU 
follow-up 
GI 
Gastrointestinal 
GLP-1-RA 
GLP-1 receptor agonist 
GCP 
Good Clinical Practice 
HA 
Health Authority 
Hb 
Haemoglobin 
HbA1c 
glycated haemoglobin 
hCG 
human chorionic gonadotropin 
HDL 
High density lipoprotein  
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IFCC 
International Federation of Clinical Chemistry and Laboratory Medicine  
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
KDIGO 
Kidney Disease Improving Global Outcomes 
LDF 
laser Doppler flowmetry 
LDL 
Low-density lipoprotein 
LPLV 
last patient last visit 
MACE 
Major adverse cardiovascular event 
Max 
Maximum 
MCMC 
Markov Chain Monte Carlo  
MEN2 
multiple endocrine neoplasia type 2 
MMRM 
mixed model for repeated measurements 
NGSP 
National Glycohemoglobin Standardization Program 
NYHA 
New York Heart Association  
OW 
Once-weekly 
PAD 
peripheral artery disease 
PCD 
primary completion date 
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PGI-C 
Patient global impression of change 
PGI-S 
Patient global impression of severity  
PG 
plasma glucose 
PK 
Pharmacokinetic 
PRO 
patient reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
s.c. 
Subcutaneous 
SF-36 
Short Form 36 
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
type 2 diabetes 
TBI 
Toe-brachial index 
TIA 
transient ischemic attack 
TMM 
trial materials manual 
V 
Visit 
VascuQoL-6  
VascuQoL-6 questionnaire 
W 
Week 
WIQ 
Walking impairment questionnaire  
WOCBP 
woman of child bearing potential 
 
 
 
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10.10 Appendix 10: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 6.0 (06 June 2022) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 6.0 
The overall rationale for the changes implemented in the amended protocol is to offer optional 
pre-screening for potential study participants in selected countries, to determine eligibility for the 
study based on ankle-brachial-index (ABI) and/or toe-brachial index (TBI), either by measurement 
of ABI and/or TBI or by review of medical records.  
 Section # and name 
Description of change 
Rationale 
Section 10.8: 
Country/Region-specific 
requirements – Optional 
pre-screening 
Section 10.8.1 Optional 
pre-screening 
New subsection added with 
description of optional 
pre-screening to determine 
eligibility based on ABI and/or 
TBI in selected countries  
To ease the screening process 
for sites and participants  
 
Protocol version 5.0 (15 October 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 5.0 
The overall rationale for the changes implemented in the amended protocol is to clarify trial-related 
procedures and to address local requirements in India.  
 Section # and name 
Description of change 
Rationale 
Section 2.3 Benefit-risk 
assessment 
Text added: or any updates 
thereof 
For correctness 
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 Section # and name 
Description of change 
Rationale 
Section 2.3.1 
Risk assessment, Table 2-1 
Angioedema added under allergic 
reactions 
To align with the 
investigator’s brochure where 
the risk of angioedema has 
been included based on post-
marketing reports and to align 
with the labelling of other 
marketed GLP-1 RAs 
Section 5.1 
Inclusion criterion 6 
‘85.8 mmol/mol’ changed to 
‘86 mmol/mol’ 
 
 
 
 
Footnote added: 
If based on central laboratory, 
both National Glycohemoglobin 
Standardization Program (NGSP) 
and International Federation of 
Clinical Chemistry and 
Laboratory Medicine (IFCC) need 
to be within limit 
To align with industry 
standard for conversion 
between NGSP and IFCC 
To clarify process and prevent 
protocol deviations due to 
unclarity 
Section 5.2 
Exclusion criterion #6   
Updated to include a reference to 
country-specific requirements for 
India 
To accommodate local 
requirements in India 
Section 5.2 
Exclusion criterion #11  
Updated to include a reference to 
country-specific requirements for 
India 
To accommodate local 
requirements in India 
Section 5.4 Screen failures 
Text deleted: ‘, and any serious 
adverse event (SAE).’ 
To align with flowchart and 
clarify SAEs should not be 
reported for screen failures 
Section 8.1.1 Treadmill 
assessments 
Text changed from ‘specific 
protocol’ to ‘study manual’ 
To clarify the wording of the 
study manual describing the 
treadmill assessments 
Section 8.1.2 Patient 
Reported Outcome (PRO) 
questionnaires 
Text changed from ‘Post-baseline 
assessments’ to ‘PRO 
questionnaires’  
To ensure consistency in 
administering PROs prior to 
other visit-related activities 
Section 8.1.5.1 Pulse and 
blood pressure 
Text added: First time blood 
pressure is assessed (V1) it should 
be performed at both arms. The 
arm with the highest blood 
To clarify process for blood 
pressure measurement  
 
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 Section # and name 
Description of change 
Rationale 
measurement should be used for 
all future measurements.   
 
Text deleted: ‘the mean of’  
Text added: The eCRF will 
calculate the mean of the last 2 
measurements. 
 
 
To align with the eCRF  
where the mean pulse rate is 
calculated automatically after 
recording of the last 2 
measurements 
Section 10.8 (Appendix 8) 
Country/region-specific 
requirements 
Requirements for India updated to 
include imaging as part of the 
screening procedure. Accordingly, 
echocardiography and digital x-
ray of the foot should be 
performed according to local 
practice during screening.  
To accommodate local 
requirements in India 
Section 10.9 (Appendix 9) 
Abbreviations  
Abbreviations added for NGSP 
and IFCC 
For correctness 
 
Protocol version 4.0 (27 May 2021) 
This amendment is considered to be non-substantial for all countries based on the criteria set forth 
in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall rationale for preparing protocol, version 4.0 
To facilitate recruitment in the trial, selected inclusion and exclusion criteria have been amended 
and the potential of rescreening of subjects has been introduced. 
 Section # and name 
Description of change 
Rationale 
Section 1.1 Synopsis and Section 5.1, 
Inclusion criterion #2.  
Country-specific 
requirements for age 
added for Taiwan 
To align with 
Section 10.8 
Section 1.2 Flowchart 
Visit window between 
screening (visit 1) and 
baseline (visit 2) revised 
from ±7 days to -7; 
+13 days. 
Footnote added: Visit 1 
should be at least 2 
weeks prior to visit 2 in 
To clarify process and 
prevent protocol 
deviations due to 
unclarity. 
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 Section # and name 
Description of change 
Rationale 
the subset of patients 
included in the activity 
tracker substudy. 
Section 1.2 Flowchart 
Footnote added: Inclined 
treadmill assessment 
must be done twice at V2. 
To clarify process and 
prevent protocol 
deviations due to 
unclarity 
Section 1.2 Flowchart 
Footnote added: Sample 
can be omitted if HbA1c 
criterion is based on 
historical data obtained 
within 90 days prior to 
screening 
To clarify process and 
prevent protocol 
deviations due to 
unclarity 
Section 2.3.1, Risk assessment;  
Table 2-1, Potential risks of clinical 
significance. 
Risk of COVID-19 
infection in relation to 
treatment omitted from 
table. 
Any risks in relation to 
COVID-19 treatment 
will be presented in the 
IB for the investigators 
to follow. 
Section 5.1 Inclusion criterion #6 
Lower HbA1c limit 
removed from criterion. 
Furthermore, it has been 
specified that criterion 
can be based on values 
obtained at screening or 
within 90 days prior to 
screening. 
To facilitate 
recruitment. The 
primary objective of the 
trial is to assess the 
effect of semaglutide on 
PAD disease. Removing 
the lower limit of 
HbA1c, and thereby 
allowing a better 
controlled T2D diabetes 
population, is 
considered not to impact 
trial objective or results.  
Section 5.1 Inclusion criterion 4d) 
Alignment of number of 
decimals of ABI and TBI 
included in criterion. 
To align with 
worksheets and EDC 
where we are requesting 
rounding to two 
decimals 
Section 5.2 Exclusion criteria 
Text added: 
Furthermore, exclusion 
criterion #12 (renal 
impairment) may be 
based on assessment of 
To clarify that criterion 
can be based on 
laboratory samples 
taken at screening visit 
(V1). 
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 Section # and name 
Description of change 
Rationale 
eGFR by central 
laboratory.  
Section 5.2 Exclusion criterion #2 
Previous participation 
changed from ‘signed 
informed consent’ to 
‘randomisation’ 
To enable rescreening. 
Section 5.2, Exclusion criterion #4, 
Section 7.1, Treatment discontinuation 
criterion #3 and Appendix 8 
(Section 10.8), country/region-specific 
requirements 
Note added that co-
participation in COVID-
19 trials are not allowed 
in China and Japan 
To comply with 
country/region-specific 
requirement 
Section 5.2 Exclusion criterion 5 
DDP-4 inhibitors omitted 
from criterion. 
To facilitate 
recruitment. There are 
no data supporting a 
clear benefit of DPP-4i 
on CV risk. Given that 
the endpoints defined in 
this trial is related to 
atherosclerosis, the use 
of DPP-4i is assessed to 
have minimal effect on 
trial results. 
Section 5.2 Exclusion criterion #12 
Renal impairment 
measured as based on 
latest available 
measurements/evaluation 
prior to randomisation 
(visit 2). Renal 
impairment can be 
diagnosed based on an 
estimated Glomerular 
Filtration Rate (eGFR) 
value of eGFR< 30 mL/ 
min/1.73 m2 (measured 
within last six months) as 
defined by KDIGO 20122 
or chronic or intermittent 
haemodialysis or 
peritoneal dialysis.  
To clarify that criteria 
should be evaluated 
based on the latest 
available assessment, 
Section 5.4 Screen failure 
Criteria for rescreening 
of subjects added 
To facilitate recruitment 
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 Section # and name 
Description of change 
Rationale 
Section 6.5 Concomitant medication 
DPP-4 inhibitors omitted 
from disallowed 
medication 
To reflect SoC 
treatment 
Section 8.1.2 Patient Reported Outcomes 
(PRO) questionnaires  
Text added: PRO 
questionnaires will be 
assessed at baseline (V2), 
at 6 months visit (V6) and 
at end-of-treatment (Visit 
8/8A). Post-baseline 
assessments are to be 
performed prior to other 
visit-related activities.  
To clarify that post-
baseline assessments is 
to be performed prior to 
other visit-related 
activities. 
Section 8.1.5.2 ABI and TBI 
Note added that 
calculation should be 
based on 2 
measurements. 
To clarify process and 
prevent protocol 
deviations due to 
unclarity. 
Section 8.5 Pharmacokinetics 
Text added: PK samples 
will not be taken in 
China. 
To comply with 
protocol version 3. 
Section 10.1.1 Regulatory and ethical 
considerations, and Section 10.8 
(Appendix 8) Country/region-specific 
requirements 
Text added: Protocol, 
protocol amendments, 
informed consent form 
and investigator’s 
brochure, must be also 
submitted, reviewed, and 
approved by the 
regulatory authorities 
before the trial is 
initiated. 
To comply with 
requirements in Latvia. 
Section 10.6 (Appendix 6): Retention of 
human biosamples 
Reference to Section 10.7 
removed from paragraph 
regarding country-
specific requirements 
Reference added in 
error 
Section 10.8 (Appendix 8) 
Country/region-specific requirements 
Text added: 
PK samples will not be 
taken in China. 
Co-participation in 
COVID-19 trials are not 
allowed. 
To comply with 
requirements in China. 
Section 10.8 (Appendix 8), 
Country/region-specific requirements 
Text added: 
PK samples will not be 
taken in China. 
Co-participation in 
COVID-19 trials are not 
allowed. 
To comply with 
protocol version 3. 
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Protocol version 3.0 (18 November 2020) 
This amendment is considered to be substantial for all countries based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. This amendment is not applicable in China. 
Overall rationale for preparing protocol, version 3 
Due to the COVID-19 pandemic the exclusion and discontinuation criteria have been amended to 
allow for simultaneous 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 COVID-19 postinfectious conditions. 
Additional blood sampling will be included for PK assessment. Plasma semaglutide concentrations 
will be used to describe the exposure-response analysis. PK samples will not be taken in China. 
 Section # and name 
Description of change 
Rationale 
Section 1.1 Synopsis 
Addition of “severe 
varicose veins” to Key 
exclusion criterion #2; 
IMP name corrected in 
Treatment group and 
duration 
For clarification  
Section 1.2 Flowchart 
Correction of minor 
errors and addition of 
“Semaglutide plasma 
concentration” row 
For clarification and to 
account for inclusion of 
PK samples 
Section 5.2 Exclusion criteria 
Addition to exclusion 
criterion #4 
*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 COVID-19 
postinfectious 
conditions is allowed if 
the last dose of the 
investigational 
medicinal product has 
been received more 
To allow for co-
participation in COVID-
19 trials 
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 Section # and name 
Description of change 
Rationale 
than 30 days before 
screening.    
Section 5.2 Exclusion criteria 
Addition of “severe 
varicose veins” to 
exclusion criterion #6 
For clarification 
Section 6.1 
Preparation/handling/storage/accountability 
Minor text revision 
For clarification  
Section 6.2 Treatments administered, 
Table 6-1 
IMP name corrected 
For clarification  
Section 6.5 Concomitant medication 
Text included for 
collection of COVID-
19 concomitant 
medication 
To specify that 
medication(s) in relation 
to a clinical trial for 
COVID-19 prevention or 
treatment as well as 
approved COVID-19 
vaccine must be 
recorded 
Section 7.1 Discontinuation of trial 
treatment 
Text added to 
discontinuation 
criterion #3 and Ad 3 
*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 COVID-19 
postinfectious 
conditions is allowed at 
the investigator 
discretion without 
discontinuing trial 
product.   
To allow for co-
participation in a 
COVID-19 trial 
Section 8 Trial assessments and procedures 
Text added to criterion 
#7 regarding country 
specific requirements 
Collection of patient 
contact information not 
relevant for BE 
Section 8.2 Safety assessments 
Addition of COVID-19 
in-text  
To include COVID-19 to 
the concomitant 
illness/medical history 
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 Section # and name 
Description of change 
Rationale 
that should be reported 
in the eCRF 
Section 8.3 Adverse events and serious 
adverse events 
Text regarding 
COVID-19 AEs 
included 
To describe the 
procedure for collection 
of COVID-19 AEs 
Section 8.5 Pharmacokinetics 
Section added 
To describe the 
procedure for collection 
of blood samples for PK 
assessment 
Section 9.5 Pharmacokinetic modelling 
Section added 
To describe the 
exposure-response 
analysis, based on 
plasma semaglutide 
concentrations and the 
efficacy and safety 
results 
Section 10.1.7 Dissemination of clinical 
trial data 
Correction of trial 
duration (54 days 
corrected to 54 weeks) 
For clarification 
Section 10.2 Appendix 2, Table 10-1 
Addition of PK 
sampling to efficacy 
laboratory assessments 
To comply with 
additions to Sections 8.5 
and 9.5 
Section 10.3.5 Reporting of SAEs, 
Figure 10-1 
Figure updated to 
include COVID-19 
AEs 
To describe the 
procedure for collection 
of COVID-19 AEs 
Section 10.8 Appendix 8: Country/ region-
specific requirements 
Text added regarding 
country-specific 
requirements 
Collection of contact 
information for persons 
other than the patient not 
relevant for Belgium 
Section 10.9 Appendix 9: Abbreviations 
Addition of COVID-19 
and PK  
For clarification 
 
Protocol version 2.0 (28 September 2020) 
This amendment is considered to be substantial for Hungary and Czech Republic based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
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Overall rationale for preparing protocol, version 2 
The overall rationale for this local protocol amendment is to comply with requirements of the Czech 
health authorities to include more frequent pregnancy reporting for WOCBP, and to comply with 
requirements of the Hungarian health authorities to include presence or history of pancreatitis to the 
exclusion criteria.  
 Section # and name 
Description of change 
Rationale 
Section 1.2, Flowchart 
Footnote d) updated with 
reference to Appendix 8 for 
specific requirements for 
pregnancy testing for Czech 
Republic. 
To comply with request from 
Czech health authorities.  
Section 5.2, Exclusion criteria 
Updated with an additional 
exclusion criterion (#17, for 
Hungary only): Presence or 
history of pancreatitis (acute 
or chronic). 
To comply with request from 
Hungarian health authorities. 
Section 10.8 (Appendix 8), 
Country/region-specific 
requirements 
Requirement for additional 
pregnancy testing of WOCBP 
from Czech Republic at week 
4, 8 and 12 added. 
To comply with request from 
Czech health authorities.  
Section 10.8 (Appendix 8), 
Country/region-specific 
requirements 
Presence or history of 
pancreatitis has been added as 
an exclusion criterion, for 
Hungary only. 
To comply with request from 
Hungarian health authorities. 
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11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. Kidney Int Suppl. 2013;3(1):1-150. 
3. 
Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. 
Comparison of global estimates of prevalence and risk factors for peripheral artery disease 
in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329-40. 
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Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive 
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Regensteiner J, Steiner J, Panzer R, Hiatt W. Evaluation of walking impairment by 
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A515. Web. 
6. 
Novo Nordisk A/S. Ozempic® (semaglutide), EU Summary of Product Characteristics 
(SmPC). 2018. 
7. 
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 
2016;375(19):1834-44. 
8. 
Novo Nordisk A/S. Investigator's Brochure, Ozempic ®  semaglutide s.c., NN9535(T2D), 
(edition 14). 2018. 
9. 
Dhatariya K, Bain SC, Buse JB, Simpson R, Tarnow L, Kaltoft MS, et al. The Impact of 
Liraglutide on Diabetes-Related Foot Ulceration and Associated Complications in Patients 
With Type 2 Diabetes at High Risk for Cardiovascular Events: Results From the LEADER 
Trial. Diabetes Care. 2018;41(10):2229-35. 
10. 
Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, et al. Ankle brachial 
index combined with Framingham Risk Score to predict cardiovascular events and 
mortality: a meta-analysis. JAMA. 2008;300(2):197-208. 
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Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 
2015;116(9):1509-26. 
12. 
DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients 
with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36 Suppl 2:S127-38. 
13. 
Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A, et al. 
Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): 
a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-86. 
14. 
Novo Nordisk A/S. Investigator's Brochure, semaglutide s.c. (Ozempic ®), project NN9535, 
edition 15. 31 Jul 2019. 
15. 
Novo Nordisk A/S. Ozempic®  (semaglutide), US Prescribing Information (PI). Dec 2017. 
16. 
Nicolaï SP, Kruidenier LM, Rouwet EV, Graffius K, Prins MH, Teijink JA. The walking 
impairment questionnaire: an effective tool to assess the effect of treatment in patients with 
intermittent claudication. J Vasc Surg. 2009;50(1):89-94. 
17. 
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30(6):473-83. 
18. 
Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al. Editor's 
Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial 
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