Clinical trial NCT04788511
Conditions: Obesity
Sponsor: Novo Nordisk A/S
Start date: 2021-03-16; Completion date: 2023-04-18
Enrollment: 529 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at how the participants daily life is affected by their heart failure. The study will also look at the change in participants body weight from the start to the end of the study. This is to compare the effect on heart failure symptoms and on body weight in people taking semaglutide (a new medicine) to people taking "dummy" medicine.

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

During the study participants will have talks with the study staff about healthy lifestyle choices including healthy food and physical activity.

The study will last for approximately 59 weeks. Participants will have 11 clinic visits and 1 phone call with the study doctor. Women: Women cannot take part if they are pregnant, breast-feeding or plan to become pregnant during the study period.

Detailed description:

Arms: arm 1: All participants will receive either semaglutide 2.4 mg once weekly or placebo once weekly as add-on to standard of care. During the first 16 weeks, the dose of semaglutide or placebo will be gradually escalated from 0.25 mg once weekly until target dose. arm 2: All participants will receive either semaglutide 2.4 mg once weekly or placebo once weekly as add-on to standard of care. During the first 16 weeks, the dose of semaglutide or placebo will be gradually escalated from 0.25 mg once weekly until target dose.
Interventions: intervention 1: Semaglutide intervention 2: Placebo (semaglutide)
Intervention descriptions: intervention 1: Semaglutide will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial.

Dose gradually escalated from 0.25 mg until target dose. The study will last for approximately 59 weeks. intervention 2: Placebo will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial.

The study will last for approximately 59 weeks.

Protocol documents:
Prot_002.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04788511 
Sponsor trial ID: 
EX9536-4665 
Official title of study: 
Effect of semaglutide s.c. 2.4 mg once weekly on function and
symptoms in subjects with obesity-related heart failure with
preserved ejection fraction
Document date*: 
21 June 2023 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.


Link
Link
List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Study ID: EX9536-4665
Clinical Study Report
Appendix 9.1.1
21 June 2023
1.0
Final
9.1.1 Protocol and protocol amendments
CONFIDENTIAL


Protocol 
CONFIDENTIAL 
Date: 
09 September 2022 Novo Nordisk 
Trial ID: EX9536-4665 
Version: 
6.0 
     
Status: 
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Page: 
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Protocol 
Including Amendment 1, dated 05 January 2021 
Including Amendment 2, dated 07 January 2021 
Including Amendment 3, dated 21, January 2021 
Including Amendment 4, dated 12 February 2021 
Including Amendment 5, dated 09 September 2022 
 
 
STEP-HFpEF 
Protocol title: Effect of semaglutide 2.4 mg once weekly on function and symptoms in 
subjects with obesity-related heart failure with preserved ejection fraction 
Substance: semaglutide 
Universal Trial Number: U1111-1243-4358 
EudraCT Number: 2019-004452-11 
Trial phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol 
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Date: 
09 September 2022 Novo Nordisk 
Trial ID: EX9536-4665 
Version: 
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Status: 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
 
Document version 
Date 
Applicable in country(-ies) and/or site(s) 
Protocol version 6.0 (including 
amendment 5) 
09 Sep 2022 
All 
Protocol version 5.0 (including 
amendment 4) 
12 Feb 2021 
Germany 
Protocol version 4.0 (including 
amendment 3) 
21 Jan 2021 
All 
Protocol version 3.0 (including 
amendment 2) 
07 Jan 2021 
Germany 
Protocol version 2.0 (including 
amendment 1) 
05 Jan 2021 
United Kingdom 
Protocol version 1.0 
28 Sep 2020 
All 
 
Protocol version 6.0 (09 September 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.1 
 
Overall rationale for preparing protocol, version 6.0: 
The overall rationale for the changes implemented in the amended protocol is an increasing interest 
in reporting results in a manner that reflects the clinical relevance across different domains 
including patient-reported outcomes combined with objective measures and events. 
 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Win ratio composite endpoint added to 
confirmatory secondary endpoints 
See overall rationale 
Section 3.1 Primary, secondary and 
exploratory objectives and estimand 
Secondary objectives changes to address 
added confirmatory secondary endpoint 
See overall rationale 
Section 3.2.2.1 Confirmatory 
secondary endpoints 
Win ratio composite endpoint added to 
confirmatory secondary endpoints 
See overall rationale 
Section 3.2.2.2 Supportive 
secondary endpoints 
Endpoints related to weight loss, KCCQ-CSS 
and 6MWD added to supportive secondary 
endpoints 
Alignment with SAP 
Section 3.2.3 Exploratory endpoints 
KCCQ endpoints added to exploratory 
endpoints  
Alignment with SAP 
Section 6.1.1 Medical devices 
Follow label instructions for storage and in-
use time conditions descriptions on the labels.  
Clarification 
Section 8.1.2 Clinical outcome 
assessment 
Reference to user guide 
Clarification 
Section 9.1 Statistical hypotheses 
Statistical hypotheses updated to reflect 
changes to testing hierarchy 
See overall rationale 
Section 9.2 Sample size 
determination 
Power calculation on confirmatory secondary 
endpoints updated to reflect changes to the 
testing hierarchy 
See overall rationale 
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Section 9.4.3.1 Statistical analyses 
Confirmatory secondary endpoints 
Description of statistical analyses updated to 
reflect inclusion of Win Ratio composite 
endpoint in confirmatory secondary endpoints 
See overall rationale 
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Table of Contents   
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 4 
1 
Protocol summary ..................................................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................................... 7 
1.2 
Flowchart ....................................................................................................................................... 10 
2 
Introduction ............................................................................................................................................. 13 
2.1 
Trial rationale ................................................................................................................................. 13 
2.2 
Background .................................................................................................................................... 14 
2.3 
Benefit-risk assessment .................................................................................................................. 14 
2.3.1 
Risk assessment ............................................................................................................... 15 
2.3.2 
Benefit assessment ........................................................................................................... 16 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 16 
3 
Objectives and endpoints ........................................................................................................................ 17 
3.1 
Primary, secondary and exploratory objectives and estimand ....................................................... 17 
3.2 
Primary, secondary and exploratory endpoint(s) ........................................................................... 18 
3.2.1 
Multiple primary endpoints ............................................................................................. 18 
3.2.2 
Secondary endpoints ........................................................................................................ 18 
3.2.2.1 
Confirmatory secondary endpoints ................................................................. 18 
3.2.2.2 
Supportive secondary endpoints ..................................................................... 19 
3.2.3 
Exploratory endpoint(s) ................................................................................................... 20 
4 
Trial design .............................................................................................................................................. 21 
4.1 
Overall design ................................................................................................................................ 21 
4.2 
Scientific rationale for trial design ................................................................................................. 21 
4.3 
Justification for dose ...................................................................................................................... 22 
4.4 
End of trial definition ..................................................................................................................... 22 
5 
Trial population ....................................................................................................................................... 23 
5.1 
Inclusion criteria ............................................................................................................................ 23 
5.2 
Exclusion criteria ........................................................................................................................... 24 
5.3 
Lifestyle considerations ................................................................................................................. 25 
5.4 
Screen failures ................................................................................................................................ 25 
6 
Treatments ............................................................................................................................................... 26 
6.1 
Treatments administered ................................................................................................................ 26 
6.1.1 
Medical devices ............................................................................................................... 28 
6.2 
Preparation/handling/storage/accountability .................................................................................. 28 
6.2.1 
Shipment of trial product to subject’s home .................................................................... 29 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 30 
6.4 
Treatment compliance .................................................................................................................... 30 
6.5 
Concomitant medication ................................................................................................................ 30 
6.6 
Dose modification .......................................................................................................................... 31 
6.7 
Treatment after end of trial ............................................................................................................ 31 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 32 
7.1 
Discontinuation of trial treatment .................................................................................................. 32 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 33 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 33 
7.2.1 
Replacement of subjects .................................................................................................. 34 
7.3 
Lost to follow-up ........................................................................................................................... 34 
8 
Trial assessments and procedures ......................................................................................................... 35 
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8.1 
Efficacy assessments ...................................................................................................................... 35 
8.1.1 
Body measurements ......................................................................................................... 35 
8.1.2 
Clinical outcome assessments ......................................................................................... 35 
8.1.3 
Echocardiography ............................................................................................................ 37 
8.1.4 
Clinical laboratory assessments ....................................................................................... 37 
8.2 
Safety assessments ......................................................................................................................... 37 
8.2.1 
Physical examinations ..................................................................................................... 37 
8.2.2 
Vital signs ........................................................................................................................ 37 
8.2.3 
Electrocardiograms .......................................................................................................... 38 
8.2.4 
New York Heart Association (NYHA) classification ..................................................... 38 
8.2.5 
Clinical safety laboratory assessments ............................................................................ 38 
8.3 
Adverse events and serious adverse events .................................................................................... 38 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 40 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 40 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 40 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 40 
8.3.5 
Pregnancy ........................................................................................................................ 41 
8.3.6 
Cardiovascular and death events ..................................................................................... 41 
8.3.7 
Technical complaints ....................................................................................................... 41 
8.4 
Treatment of overdose ................................................................................................................... 41 
8.5 
Pharmacokinetics ........................................................................................................................... 41 
8.6 
Pharmacodynamics ........................................................................................................................ 42 
8.7 
Genetics ......................................................................................................................................... 42 
8.8 
Biomarkers ..................................................................................................................................... 42 
8.9 
Immunogenicity assessments ......................................................................................................... 43 
8.10 
Health economics ........................................................................................................................... 43 
9 
Statistical considerations ........................................................................................................................ 44 
9.1 
Statistical hypotheses ..................................................................................................................... 44 
9.2 
Sample size determination ............................................................................................................. 45 
9.3 
Populations for analyses ................................................................................................................ 47 
9.4 
Statistical analyses ......................................................................................................................... 47 
9.4.1 
General considerations .................................................................................................... 47 
9.4.2 
Primary endpoints ............................................................................................................ 47 
9.4.3 
Secondary endpoint(s) ..................................................................................................... 48 
9.4.3.1 
Confirmatory secondary endpoint ................................................................... 48 
9.4.3.2 
Supportive secondary endpoints ..................................................................... 49 
9.4.4 
Exploratory endpoints ..................................................................................................... 49 
9.4.4.1 
Pharmacokinetic and/or pharmacodynamic modelling ................................... 49 
9.5 
Interim analyses ............................................................................................................................. 49 
9.6 
Data monitoring committee ........................................................................................................... 49 
9.7 
Reporting of the main part of the trial............................................................................................ 49 
10 Supporting documentation and operational considerations ............................................................... 50 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 50 
10.1.1 
Regulatory and ethical considerations ............................................................................. 50 
10.1.2 
Financial disclosure ......................................................................................................... 50 
10.1.3 
Informed consent process ................................................................................................ 50 
10.1.4 
Information to subjects during trial ................................................................................. 51 
10.1.5 
Data protection ................................................................................................................ 51 
10.1.6 
Committees structure ....................................................................................................... 52 
10.1.6.1 Novo Nordisk safety committee...................................................................... 52 
10.1.6.2 Event adjudication committee ......................................................................... 52 
10.1.6.3 Steering committee ......................................................................................... 52 
10.1.7 
Dissemination of clinical trial data .................................................................................. 52 
10.1.8 
Data quality assurance ..................................................................................................... 52 
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10.1.8.1 Case report forms ............................................................................................ 52
10.1.8.2 Monitoring ...................................................................................................... 53
10.1.8.3 Protocol compliance ........................................................................................ 54
10.1.9 
Source documents ............................................................................................................ 54
10.1.10 Retention of clinical trial documentation ........................................................................ 54
10.1.11 Trial and site closure ....................................................................................................... 55
10.1.12 Responsibilities................................................................................................................ 55
10.1.13 Indemnity statement ........................................................................................................ 56
10.1.14 Publication policy ............................................................................................................ 56
10.1.14.1 Communication of results ............................................................................... 56
10.1.14.2 Authorship ....................................................................................................... 57
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 57
10.1.14.4 Investigator access to data and review of results ............................................ 57
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 58
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 59
10.3.1
Definition of AE .............................................................................................................. 59
10.3.2
Definition of an SAE ....................................................................................................... 59
10.3.3
Description of events for adjudication and AEs requiring additional data collection ..... 61
10.3.4
Recording and follow-up of AE and/or SAE ................................................................... 62
10.3.5
Reporting of SAEs ........................................................................................................... 63
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 65
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 68
10.5.1 
Definition of technical complaint .................................................................................... 68
10.5.2 
Recording and follow-up of technical complaints ........................................................... 68
10.6
Appendix 6: Retention of human biosamples and genetics ........................................................... 70
10.7
Appendix 7: Country-specific requirements .................................................................................. 71
10.8
Appendix 8: Mitigations to ensure patient safety and data integrity during an emergency 
situation .......................................................................................................................................... 73
10.9
Appendix 9: Abbreviations ............................................................................................................ 78
10.10 Appendix 10: Protocol amendment history ................................................................................... 80
11 References ................................................................................................................................................ 84
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments. 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
Heart failure with preserved ejection fraction (HFpEF) in patients with obesity is associated with 
decreased health-related quality of life, worse heart failure symptoms, greater systemic 
inflammation and lower exercise capacity compared to HFpEF patients without obesity. A study of 
subjects with HFpEF and obesity has indicated that a weight loss of 3-7 kg increases exercise 
tolerance and HF-specific health-related quality of life.  
Objectives and endpoints: 
Primary objective 
To investigate the effects of semaglutide subcutaneous (s.c.) 2.4 mg once-weekly on physical 
function, symptoms and body weight compared with placebo, both added to standard of care, in 
subjects with obesity-related HFpEF. 
Secondary objectives 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly in improving the overall clinical 
benefit compared with placebo, both added to standard of care, in subjects with obesity-related 
HFpEF. 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on walking distance, biomarker of 
inflammation, disease specific aspects, social limitation, change in body composition and health-
related quality of life compared with placebo, both added to standard of care, in subjects with 
obesity-related HFpEF. 
Primary estimand 
The estimand will quantify the average change from baseline in Kansas City Cardiomyopathy 
Questionnaire (KCCQ) clinical summary score and average change from baseline in body weight of 
semaglutide s.c. 2.4 mg once-weekly relative to placebo, both added to standard of care, after 
52 weeks, in all randomised subjects regardless of adherence to randomised treatment (“treatment 
policy” estimand). 
Multiple primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in KCCQ clinical summary 
score  
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range; 0-100) 
Change in body weight 
From baseline (week 0) to end of 
treatment (week 52) 
 % 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in 6-minute walking distance 
From baseline (week 0) to end of 
treatment (week 52) 
Metres  
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Hierarchical composite of: 
Time to all-cause death,  
number of heart failure events requiring 
hospitalisation or urgent heart failure 
visit,  
time to first heart failure event 
requiring hospitalisation or urgent heart 
failure visit,  
difference at least 15 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
difference at least 10 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
difference at least 5 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
difference at least 30 metres in six-
minute walking distance change from 
baseline to 52 weeks 
(assessed by the win ratio)  
From baseline (week 0) to end of 
study (week 57) 
Total wins for each treatment 
group 
Change in C-Reactive Protein 
From baseline (week -2) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Overall design: 
This is a 52-week, randomised, placebo-controlled, double blind, multi-centre clinical trial 
comparing semaglutide s.c. 2.4 mg with placebo in subjects with obesity-related HFpEF.  
Eligible subjects will be randomised in a 1:1 manner to receive either semaglutide s.c. 2.4 mg or 
placebo once weekly as add-on to standard of care. 
Key inclusion criteria 
 Male or female, age above or equal to 18 years at the time of signing informed consent. 
 Body mass index (BMI) ≥ 30.0 kg/m2 
 New York Heart Association (NYHA) Class II-IV 
 Left ventricular ejection fraction (LVEF) ≥ 45 % at screening 
Key exclusion criteria 
 A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records 
 Haemoglobin A1c (HbA1c) ≥ 6.5 % (48 mmol/mol) based on latest available value from medical 
records, no older than 3 months or if unavailable a local measurement at screening 
Number of subjects: 
516 subjects will be randomly assigned to trial product. 
Treatment groups and duration: 
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a screening period of approximately 2 weeks. Eligible subjects will at visit 2 be randomised in a 1:1 
manner to receive either semaglutide 2.4 mg once weekly or placebo once weekly as add-on to 
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standard of care. During the first 16 weeks, the dose of semaglutide or placebo will be gradually 
escalated from 0.25 mg once weekly until target dose. The treatment will continue until the ‘end of 
treatment’ visit followed by a 5 weeks follow-up period. 
The following trial products will be supplied by Novo Nordisk A/S: 
 Semaglutide D 0.5 mg/mL, solution for injection, DV3396 0.5mL pen-injector 
 Semaglutide D 1.0 mg/mL, solution for injection, DV3396 0.5 mL pen-injector 
 Semaglutide D 2.0 mg/mL, solution for injection, DV3396 0.5 mL pen-injector 
 Semaglutide D 2.27 mg/mL, solution for injection, DV3396 0.75 mL pen-injector 
 Semaglutide D 3.2 mg/mL, solution for injection, DV3396 0.75 mL pen-injector  
 Semaglutide placebo Ia, solution for injection, 0.5mL pen-injector 
 Semaglutide placebo Ib, solution for injection, 0.75 mL pen-injector 
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1.2 
Flowchart 
 
Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
Informed consent and demographya (10.1.3) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria (5.1, 5.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination (8.2.1) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Medical history/Concomitant illness (8.2.1), Tobacco useb  
 
X 
 
 
 
 
 
 
 
 
 
 
Childbearing potential (10.2, 10.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication (6.5) 
 
Xc 
X 
X 
X 
X 
Xc 
X 
Xc 
X 
Xc 
X 
Body weight (8.1.1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height / BMI (8.1.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
Waist circumference (8.1.1) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Status (PGI-S) for KCCQ (8.1.2) 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
Patient Global Impression of Change (PGI-C) for KCCQ (8.1.2) 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) (8.1.2) 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
European Quality of Life five Dimensions five Level (EQ-5D-5L) (8.1.2) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Status (PGI-S) for 6MWT (8.1.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Change (PGI-C) for 6MWT (8.1.2) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
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Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
Six-minute walk test (6MWT) (8.1.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
NYHA classification / Vital Signs (8.2.2, 8.2.4)  
X 
 
 
 
 
 
X 
 
 
 
X 
 
Electrocardiogram (ECG) (8.2.3) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Echocardiography (8.1.3) 
X 
Xd 
 
 
 
 
 
 
 
 
Xd 
 
Laboratory assessments (10.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Semaglutide plasma concentration (10.2) 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test (only for women of childbearing potential)e (10.2) 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Healthy lifestyle counselling (5.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event and Events for adjudication (8.3, 10.3) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication error, Misuse and Abuse (8.3, 10.3.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug dispensing (6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Training in trial product, pen-handling (6.1) 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
Hand Out Directions for Use (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
Hand Out Dose Reminder Card 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Hand Out ID Card  
X 
 
 
 
 
 
 
 
 
 
 
 
Drug Accountability (6.2) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
IWRS session 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a) Demography consists of date of birth, sex, race and ethnicity (according to local regulation – Germany: for country-specific requirements, please see Appendix 7 (Section 10.7)). 
b) Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
c) Dose to be collected for loop diuretics. 
d) Only relevant for subjects included in the echocardiographic sub-study. 
e) For women of childbearing potential only. In addition to the planned assessments, urine dipstick pregnancy test should be performed at any time during the trial if a menstrual period is 
missed, or if pregnancy is suspected. (according to local regulation – United Kingdom and Germany: for country-specific requirements, please see Appendix 7 (Section 10.7)). 
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2 
Introduction 
There are currently no trials showing disease modifying benefits of treatment or improvement of 
outcomes in patients suffering from HFpEF. This could partly be due to the heterogeneity of this 
group of patients, which may call for different interventions based on sub-phenotype.2 This trial will 
focus on a more specific phenotype of obesity-related HFpEF and study the effect of body weight 
reduction obtained by semaglutide treatment on various clinical aspects in patients with HFpEF. 
Semaglutide 
Semaglutide is the next generation glucagon-like peptide-1 (GLP-1) analogue currently under 
development by Novo Nordisk for the treatment of weight management (NN9536, including the 
phase 3a STEP programme). Semaglutide has been optimised resulting in a longer half-life of 
approximately 160 hours, making it suitable for once-weekly dosing.3  GLP-1 is a physiological 
regulator of appetite and GLP-1 receptors are present in several areas of the brain involved in 
appetite regulation4. 
Clinical5-27 and non-clinical28 data indicate that the body weight (BW) reducing effect of 
semaglutide is mainly mediated by reduced energy intake. 2.4 mg semaglutide once weekly 
appeared to have a safe and well-tolerated profile (STEP programme), as seen with previous trials.   
A comprehensive review of results from the non-clinical and clinical studies of semaglutide can be 
found in the current version of the investigator’s brochure (IB)29 or any updates hereof.  
In the following, unless otherwise stated, “semaglutide 2.4 mg” will refer to semaglutide s.c. 2.4 mg 
once weekly. 
2.1 
Trial rationale 
Obesity is rapidly increasing worldwide and is a major risk factor for the development of HFpEF.30 
Patients with obesity and HFpEF show a very specific pathophysiological profile with the main 
common pathway through systemic inflammation.2 HFpEF in patients with obesity is associated 
with decreased health-related quality of life, worse heart failure symptoms, greater systemic 
inflammation and lower exercise capacity compared to HFpEF patients without obesity.31 This 
supports that obesity-related HFpEF should be treated as a specific entity, and that development of 
treatments that can promote a weight loss in this patient population is warranted.  
Semaglutide 2.4 mg once weekly has demonstrated substantial lowering of body weight of up to 
14.9 % by week 68 in subjects with obesity or overweight (NN9536 STEP programme). 
To explore if a structural and functional cardiac effect can be seen, an exploratory 
echocardiographic substudy is planned only in a subset of subjects to limit subject burden. 
The aim of the present trial is to investigate the effects of semaglutide 2.4 mg on symptoms, 
physical function, health-related quality of life, and weight-loss in a population with obesity-related 
HFpEF. 
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2.2 
Background 
Heart Failure with Preserved Ejection Fraction 
Heart failure (HF) is a haemodynamic disorder where the heart fails to keep up with the circulatory 
demands of the body (HFrEF), or does so at the expense of raised left ventricular filling pressures 
(HFpEF).32 HFpEF is a clinical syndrome of heart failure symptoms combined with normal or near-
to-normal LVEF and increased left ventricular filling pressures. The increased pressure can be 
measured by cardiac catheterization or estimated by echocardiography. Other echocardiographic 
findings include both structural and functional changes as part of diagnosing HFpEF, and left 
ventricular diastolic dysfunction (abnormal relaxation) is a key defining feature of HFpEF.33 The 
increased pressure generally leads to elevation of NT-proBNP and BNP due to increased ventricular 
wall tension,33 but levels of NT-proBNP are inversely related to body weight in both the general 
population34 and in the HFpEF patient population.2  
The prevalence of HFpEF has increased during the last decades and is now more frequent than heart 
failure with reduced ejection fraction (HFrEF).35-37 HF, including HFpEF, remains to be a leading 
cause of morbidity and mortality.35, 36 
To date, no pharmacological interventions to address HFpEF have been approved, and the current 
HF therapies do not directly target the fundamental metabolic derangements, thus making it one of 
the greatest unmet needs in cardiology today.38  
Obesity-related HFpEF 
Obesity, a chronic disease39 resulting in decreased health-related quality of life and 5-10 years 
reduced life expectancy,23, 40, 41 has been identified as a major risk factor for the development of 
HFpEF. The impact of obesity on HFpEF is probably due to a combination of mechanical 
mechanisms, volume overload, endocrine-, metabolic- and cellular signalling together with an 
altered inflammatory status.30 The aggregate of these factors ultimately lead to cardiomyocyte 
dysfunction  and impaired diastolic function of the heart, while contractility is preserved. More than 
83% of patients with HFpEF are found to have either overweight or obesity.42  
Obesity is associated with systemic inflammation43 and with increased risk of a variety of 
comorbidities including T2D, hypertension, dyslipidaemia, cardiovascular diseases, and risk of 
early death.12-26 A study of elderly subjects with HFpEF and obesity has indicated that a weight loss 
of 3-7 kg increases exercise tolerance and improvement in HF-specific health-related quality of life 
as assessed by the KCCQ.44  
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss without pharmacotherapy.39, 
45-53 Consequently, semaglutide may serve as a valuable adjunct to lifestyle intervention for 
individuals with obesity-related HFpEF in order to achieve and sustain a clinically relevant weight 
loss, to improve complications and health-related quality of life.  
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
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known and expected benefits and risks and reasonably expected adverse events of semaglutide may 
be found in the IB29 or any update hereof. 
2.3.1 
Risk assessment 
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Trial treatment(s)  
Gastrointestinal 
adverse event (AE) 
Consistent with findings with other GLP-1 RAs, 
the most frequently reported AE in clinical trials 
with semaglutide were gastrointestinal AEs. 
A low starting dose and dose escalation 
steps will be implemented to mitigate 
the risk of gastrointestinal AEs. 
Cholelithiasis  
Events of cholelithiasis were the most 
frequently reported gallbladder events in the 
phase 2 weight management trial (NN9536-
4153) and were in a few instances co-reported 
with event adjudication committee confirmed 
acute pancreatitis.  
If cholelithiasis is suspected, 
appropriate clinical follow-up is to be 
initiated at the investigator’s discretion. 
Acute pancreatitis  
Acute pancreatitis has been observed with the 
use of GLP-1 RA drug class. 
Subjects with a history of chronic 
pancreatitis or recent acute pancreatitis 
will not be enrolled in the trial. In 
addition, trial product should be 
discontinued in case of suspicion of 
acute pancreatitis in accordance to 
Section 7.1. 
Medullary thyroid 
cancer (MTC) (based 
on non-clinical data) 
Proliferative thyroid C-cell changes were seen 
in the mouse and rat carcinogenicity studies 
after daily exposure to semaglutide for 2 years. 
No hyperplasia was observed in monkeys after 
52 weeks exposure up to 13-fold above the 
clinical plasma exposure at 2.4 mg/week. In 
clinical trials with semaglutide, there have been 
no clinically relevant changes in calcitonin 
levels. The C-cell changes in rodents are 
mediated by the GLP-1 receptor, which is not 
expressed in the normal human thyroid. 
Accordingly, the risk of GLP-1 receptor-
mediated C-cell changes in humans is low.  
Exclusion criteria related to medical 
history of multiple endocrine neoplasia 
type 2 (MEN2) or MTC have been 
implemented. 
Pancreatic cancer 
There is currently no support from non-clinical 
studies, clinical trials or post-marketing data 
that GLP-1 RA based therapies increase the risk 
of pancreatic cancer, but pancreatic cancer has 
been classified as a potential class risk of GLP-1 
RAs by European Medicines Agency (EMA). 
Subjects with a history of malignant 
neoplasms within the past 5 years prior 
to screening will be excluded from the 
trial.  
Allergic reactions 
As is the case with all protein-based 
pharmaceuticals, subjects treated with 
semaglutide are at risk of developing 
immunogenic and allergic reactions.  
Subjects with known or suspected 
hypersensitivity to semaglutide or 
related products will not be enrolled.  
Risk of COVID-19 
infection in relation to 
trial treatment 
Available data does not suggest an increased 
risk of infection or a more severe progression of 
infection when treated with s.c. semaglutide. 
Detailed information about the known 
risks for s.c. semaglutide can be found 
in the investigator’s brochure and 
summary of product characteristics. 
Trial procedures 
Cubital haematoma 
Venous laboratory samples drawn at screening 
and selected visits may be associated with slight 
discomfort and complicated by bruising in the 
region. 
The number of blood samples have 
been reduced to the extent possible. 
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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 enrolment 
in countries where the COVID-19 
pandemic is evaluated to be sufficiently 
under control 
Other 
Pregnancy and fertility 
(based on non-clinical 
data)  
Studies in animals have shown reproductive 
toxicity. There is limited data from the use of 
semaglutide in pregnant women.  
Semaglutide should not be used during 
pregnancy. Exclusion and 
discontinuation criteria related to 
pregnancy have been implemented. 
2.3.2 
Benefit assessment 
Subjects will be treated with a regimen anticipated to be better than or equal to the weight 
management they receive at the time of entry into the trial. Results from the phase 3a weight 
management programme (NN9536, STEP) demonstrated that s.c. 2.4 mg semaglutide once weekly, 
as an adjunct to a reduced calorie diet and increased physical activity, was effective for weight loss 
in subjects with obesity, while displaying a satisfactory tolerability profile. Weight loss was 
accompanied by a consistent improvement in weight-related comorbidities, indicated by 
cardiovascular risk factors, lipid profile and glycaemic factors, as well as improvements in clinical 
outcome assessments.   
Benefits on HF-related symptoms, physical function, and health-related quality of life are to be 
established by the present trial, but we have indications that semaglutide will improve these 
measures. The close contact will ensure constant ongoing optimisation of the treatment of any 
comorbidity.  
In addition, it is expected that subjects will benefit from participation through close contact with the 
trial site and counselling by a qualified healthcare professional, all of which will most likely result 
in intensified weight management. 
2.3.3 
Overall benefit-risk conclusion 
Necessary precautions have been implemented in the design and planned conduct of the trial in 
order to minimize the risks and inconveniences of participation in the trial. The safety profile for 
semaglutide generated from the clinical and non-clinical development programme has not revealed 
any safety issues that would prohibit administration of semaglutide 2.4 mg. The results of the phase 
3a weight management programme (NN9536, STEP) indicate that semaglutide provides a clinically 
meaningful weight loss that will provide benefit and is expected to relieve symptoms and improve 
physical function. The anticipated benefits from healthy lifestyle counselling will include all 
subjects participating in this trial. 
Considering the measures taken to minimise risk to subjects participating in this trial, the potential 
risks identified in association with semaglutide are justified by the anticipated benefits that may be 
afforded to subjects with obesity-related HFpEF. 
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3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objectives and estimand 
Primary objective 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on physical function, symptoms 
and body weight compared with placebo, both added to standard of care, in subjects with obesity-
related HFpEF. 
Secondary objectives 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly in improving the overall clinical 
benefit compared with placebo, both added to standard of care, in subjects with obesity-related 
HFpEF. 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on walking distance, biomarker of 
inflammation, body composition, disease specific aspects, social limitation, and health-related 
quality of life compared with placebo, both added to standard of care, in subjects with obesity-
related HFpEF. 
Exploratory objectives 
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly versus placebo, both added to 
standard of care, in subjects with obesity-related HFpEF regarding:  
 Heart failure outcomes 
 Change in medications 
 Change in biomarkers of myocardial strain 
 Echocardiographic parameters of heart failure (in a subset of subjects) 
Primary estimand 
The estimand will quantify the average change from baseline in KCCQ clinical summary score and 
body weight of semaglutide s.c. 2.4 mg once-weekly relative to placebo, both added to standard of 
care, after 52 weeks, in all randomised subjects regardless of adherence to randomised treatment 
(“treatment policy” estimand). 
The handling of intercurrent events with respect to data collection and analysis is specified in 
Table 3-1 for the primary endpoints. Apart from the listed examples of intercurrent events, missing 
data will occur due to non-CV deaths (KCCQ clinical summary score), all deaths (body weight), 
withdrawn consent, loss to follow-up, or continued follow-up without endpoint evaluation. 
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Table 3-1: Handling of intercurrent events for the primary endpoints 
Intercurrent event 
Data collection  
Data analysis 
Temporary discontinuation of trial 
treatment 
Subjects will be followed, and data 
collected after intercurrent events 
Primary estimand: Data 
collected after intercurrent events 
used in analysis in line with a 
treatment-policy strategy 
 
CV deaths will be incorporated 
into the KCCQ clinical summary 
score by ascribing the outcome an 
unfavorable value in line with the 
composite strategy 
Initiation of other weight 
management drugs or bariatric 
surgery  
CV deaths* for KCCQ clinical 
summary score  
N/A 
* as determined by the event adjudication committee  
 
The secondary confirmatory endpoints will use the similar estimand where the strategy for change 
in six-minute walking distance will follow the strategy for KCCQ clinical summary score. 
For the hierarchical composite endpoint, the intercurrent event of CV death will be handled as part 
of the endpoint. 
3.2 
Primary, secondary and exploratory endpoint(s) 
 
3.2.1 
Multiple primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in KCCQ clinical summary 
score (see Section 8.1) 
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range; 0-100) 
Change in body weight 
From baseline (week 0) to end of 
treatment (week 52) 
 % 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in six-minute walking distance 
From baseline (week 0) to end of 
treatment (week 52) 
Metres  
Hierarchical composite of: 
Time to all-cause death,  
number of heart failure events requiring 
hospitalisation or urgent heart failure 
visit,  
time to first heart failure event 
requiring hospitalisation or urgent heart 
failure visit,  
difference at least 15 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
difference at least 10 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
difference at least 5 in KCCQ clinical 
summary score change from baseline to 
52 weeks, 
From baseline (week 0) to end of 
study (week 57) 
Total wins for each treatment 
group 
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difference at least 30 metres in six-
minute walking distance change from 
baseline to 52 weeks 
(assessed by the win ratio)  
Change in C-Reactive Protein (CRP) 
From baseline (week -2) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Subject achieving 10 % weight loss or 
more (Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject achieving 15 % weight loss or 
more (Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject achieving 20 % weight loss or 
more (Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject improving 5 points or more in 
KCCQ clinical summary score 
(Yes/No) (see Section 8.1)  
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject improving 10 points or more in 
KCCQ clinical summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Change in KCCQ overall summary 
score (see Section 8.1) 
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range 0-100) 
Subject achieving threshold for 
clinically meaningful within-subject 
change in KCCQ-CSS 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject achieving threshold for 
clinically meaningful within-subject 
change in 6MWD 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Change in systolic blood pressure 
(SBP) 
From baseline (week -2) to end of 
treatment (week 52) 
mmHg 
Change in waist circumference 
From baseline (week 0) to end of 
treatment (visit 52) 
cm 
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3.2.3 
Exploratory endpoint(s) 
Endpoint title 
Time frame 
Unit 
Change in antihypertensive medication  
From baseline (week 0) to end of 
treatment (week 52) 
Category (no unit; decrease / 
no change / increase) 
Change in loop diuretic medication  
From baseline (week 0) to end of 
treatment (week 52) 
Category (no unit, decrease / 
no change / increase) 
Change in NT-proBNP 
From baseline (week -2) to end of 
treatment (week 52) 
pg/mL 
Change in EQ-5D-5L score   
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range per item; 
1-5)  
Subject worsening 5 points or more in 
KCCQ clinical summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject worsening 10 points or more in 
KCCQ clinical summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject improving 5 points or more in 
KCCQ overall summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject improving 10 points or more in 
KCCQ overall summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject worsening 5 points or more in 
KCCQ overall summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Subject worsening 10 points or more in 
KCCQ overall summary score 
(Yes/No) 
From baseline (week 0) to end of 
treatment (week 52) 
Count of subjects 
Change in subscales of KCCQ (total 
symptom score, physical limitations 
score, social limitations score, and 
health-related quality of life) 
From baseline (week 0) to end of 
treatment (week 52) 
Score (no unit, range 0-100) 
Subject experiencing deterioration in 
NYHA Class (Yes/No) 
From baseline (week -2) to end of 
treatment (week 52) 
Count of subjects 
Time to first heart failure event 
(hospitalisation or urgent visit) 
From baseline (week 0) to end of 
treatment (week 52) 
Days 
Imaging sub study 
Change in left atrial volume 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in left ventricular (LV) filling 
pressure (diastolic function) (E/e´) 
From baseline (week 0) to end of 
treatment (week 52) 
Ratio to baseline (no unit) 
Change in global longitudinal strain 
From baseline (week 0) to end of 
treatment (week 52) 
% 
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4 
Trial design 
4.1 
Overall design 
This is a 52-week, randomised, placebo-controlled, double blind, multi-centre clinical trial 
comparing semaglutide s.c. 2.4 mg with placebo in subjects with obesity-related heart failure with 
preserved ejection fraction.  
Eligible subjects will be randomised in a 1:1 manner to receive either semaglutide s.c. 2.4 mg or 
placebo once weekly as add-on to standard of care (Figure 4-1). 
The trial includes a screening visit to assess the subject’s eligibility followed by a randomisation 
visit. A period of 16 weeks of dose escalation is planned to minimise gastrointestinal adverse events 
with a dose increase every 4th week. Hereafter a visit will take place every 8th week until end of 
treatment (week 52). Follow-up period is 5 weeks after end of treatment. 
A subset of 240 randomised subjects will undergo echocardiography assessment at randomisation to 
ensure at least 180 subjects undergoing echocardiography at the end of treatment.   
Randomisation will be stratified by BMI into two subgroups (BMI <35.0 and BMI ≥35.0). 
Figure 4-1 A schematic diagram of the trial design  
4.2 
Scientific rationale for trial design 
The trial population will consist of subjects with obesity (≥ BMI 30.0 kg/m2) and HFpEF 
(symptoms of HF, signs of HF, LVEF ≥ 45 %, and relevant structural heart disease and/or diastolic 
dysfunction).54 The trial population is chosen to optimise the likelihood of clinical benefit of weight 
loss by including subjects where the mechanism behind their HF is likely to be obesity. 
Although T2D is prevalent in the HFpEF population, it has been decided to exclude this group of 
subjects from the trial in order to get a homogenous study population.  
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Trial duration of 52 weeks has been chosen based on the STEP programme for weight management, 
in order to ensure enough time to realise full treatment effect on weight loss potential of the 
intervention as well as downstream effects on symptoms and function related to HF. The treatment 
length will be 52 weeks consisting of 36 weeks at maintenance dose of semaglutide 2.4 mg after 
16 weeks of dose escalation. A follow-up period after end-of-treatment of 5 weeks is planned in 
order to collect safety data. The follow-up period of 5 weeks has been chosen to account for the 
long half-life of semaglutide. 
Efforts will be made to ensure that the technician administering the six-minute walk test (6MWT) is 
unaware of other assessments that could reveal treatment group.  
4.3 
Justification for dose 
Results from the phase 3a weight management  programme (NN9536, STEP) showed that a 
maintenance dose of semaglutide s.c. 2.4 mg once weekly clinically meaningfully reduces body 
weight while displaying an acceptable tolerability profile. Since weight loss is expected to be part of 
symptom relief and better physical function in HFpEF patients, a large weight loss is attractive also 
in patients with obesity-related HFpEF. The once weekly dosing is anticipated to ease the burden of 
drug administration in clinical practice. Subjects will initiate treatment with a once-weekly dose of 
0.25 mg and follow a fixed dose escalation regimen, with dose increase every 4 weeks (to doses of 
0.5, 1.0, 1.7 mg/week), until the 2.4 mg/week maintenance dose is reached after 16 weeks. 
It is well known that to mitigate gastrointestinal adverse events with GLP-1 RA treatment, slow 
dose escalation to the maintenance dose is required. 
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial globally. 
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5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
 Subjects are eligible to be included in the trial only if all the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male or female, age above or equal to 18 years at the time of signing informed consent. 
3. BMI ≥ 30.0 kg/m2. 
4. NYHA Class II-IV. 
5. LVEF ≥ 45 % at screening. 
6. No hospitalisations due to heart failure between screening (visit 1) and randomisation (visit 2). 
7. Able to perform the 6MWT at screening with a minimum distance of 100 metres. 
8. KCCQ clinical summary score < 90 at screening. 
9. At least one of the following: 
a. Mean pulmonary wedge pressure ≥ 15 mmHg or left ventricular end diastolic 
pressure (LVEDP) ≥ 15 mmHg documented during catheterisation at rest or 
pulmonary artery (PA) diastolic pressure measured by implantable monitor ≥ 15 
mmHg or pulmonary wedge pressure or LVEDP ≥ 25 mmHg documented during 
catheterisation at exercise.  
b. If BMI < 35.0: NT-proBNP ≥ 220 pg/mL (for patients with sinus rhythm) or NT-
proBNP ≥ 660 pg/mL (for patients with persistent/permanent atrial fibrillation); if 
BMI ≥ 35.0: NT-proBNP  ≥ 125 pg/mL (for patients in sinus rhythm) or NT-proBNP  
≥ 375 pg/mL (for patients with persistent/ permanent atrial fibrillation) at screening 
(NT-proBNP analysed by the central laboratory) in combination with at least one of 
the following (documented by echocardiography within 12 months prior to or at 
screening): 
i. Septal é < 7 cm/sec or lateral é < 10 cm/sec or average E/é ≥ 15 
ii. PA systolic pressure > 35 mmHg 
iii. Left atrial (LA) enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or 
LA area ≥ 20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 
mL/m2) 
iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm  
c. Hospitalisation with a primary diagnosis of decompensated heart failure which 
required intravenous (IV) loop diuretic treatment, within the previous 12 months in 
combination with at least two of the following (documented by echocardiography 
within 12 months prior to or at screening): 
i. Septal é < 7 cm/sec or lateral é < 10 cm/sec or average E/é ≥ 15 
ii. PA systolic pressure > 35 mmHg 
iii. LA enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 
20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m2) 
iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm 
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v. Ongoing use of diuretic therapy for at least 30 days prior to screening 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
Cardiovascular-related: 
1. Myocardial infarction, stroke, hospitalisation for heart failure, unstable angina pectoris or 
transient ischemic attack within 30 days prior to the day of screening. 
2. Systolic blood pressure > 160 mmHg at screening. 
3. Planned coronary, carotid or peripheral artery revascularization. 
4. Any other condition judged by the investigator to be the primary cause of dyspnoea (such as 
heart failure due to restrictive cardiomyopathy or infiltrative conditions (e.g. amyloidosis), 
hypertrophic obstructive cardiomyopathy, primary pulmonary arterial hypertension, chronic 
obstructive pulmonary disease, right heart failure due to pulmonary disease, complex congenital 
heart disease, anaemia, or more than moderate heart valve disease). 
Obesity-related: 
5. Bariatric surgery prior to screening or planned bariatric surgery within the trial time course. 
6. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
Glycemia-related: 
7. HbA1c ≥ 6.5 % (48 mmol/mol) based on latest available value from medical records, no older 
than 3 months or if unavailable at local measurement at screening.  
8. History of type 1 or type 2 diabetes (history of gestational diabetes is allowed). 
9. Treatment with any GLP-1 receptor agonist within 90 days prior to the day of screening.  
General health and safety: 
10. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
11. Presence of acute pancreatitis within the last 180 days prior to screening.  
12. History or presence of chronic pancreatitis. 
13. End-stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis. 
14. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal 
and squamous cell cancer and any carcinoma in-situ are allowed. 
15. Known or suspected hypersensitivity to trial product(s) or related products. 
16. Participation in any clinical trial of an approved or non-approved device for the treatment of 
heart failure or obesity within 30 days before screening. 
17. Receipt of any investigational medicinal product within 30 days before screening  
18. 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. 
19. Major surgery scheduled for the duration of the trial, affecting walking ability in the opinion of 
the investigator. 
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20. Any disorder, including severe psychiatric disorder, suicidal behaviour within 90 days before 
screening, and suspected drug abuse, which in the investigator´s opinion might jeopardise 
subject´s safety or compliance with the protocol.  
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
5.3 
Lifestyle considerations 
At every visit the subject should be offered individualised healthy lifestyle counselling (including 
diet and physical activity). 
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes demography, screen failure 
details and eligibility criteria. 
A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial are allowed to be rescreened 
once. If the subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria 
related to laboratory parameters, re-sampling is not allowed. However, in case of technical issues 
(e.g. haemolysed or lost), re-sampling is allowed for the affected parameters. 
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6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
Table 6-1 
Investigational medicinal products provided by Novo Nordisk AS 
Trial product name: 
 
Dose  
Dosage form  
Route of 
administration 
Dosing 
instructions 
Delivery device  
Semaglutide D 0.5 
mg/mL DV3396  
0.25 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 1.0 
mg/mL DV3396  
0.5 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 2.0 
mg/mL DV3396  
1.0 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide placebo 
Ia 
NA 
Solution for 
injection 
s.c 
Once-weekly 
0.5 mL DV3396 
pen-injector 
Semaglutide D 2.27 
mg/mL DV3396  
1.7 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL 
DV3396 pen-
injector 
Semaglutide D 3.2 
mg/mL DV3396  
2.4 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL 
DV3396 pen-
injector 
Semaglutide placebo 
Ib 
NA 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL 
DV3396 pen-
injector 
 The investigator must document that directions for use are given to the subject verbally and in 
writing as a direction for use (DFU) document, at the first dispensing visit (as specified in the 
flowchart). 
 It is recommended that the investigator consults Novo Nordisk in case of persistent deviations 
from the planned escalation regimen. 
 Dose escalation of semaglutide/placebo should take place during the first 16 weeks after 
randomisation as described in Table 6-2. All subjects should aim at reaching the 
recommended target dose of semaglutide 2.4 mg once-weekly or placebo but individual 
escalation and dosing are allowed (see later in this section).
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Table 6-2 
Dose escalation and maintenance of semaglutide/semaglutide placebo 
Trial product name 
Dose 
Delivery device 
Duration 
Dose escalation period 
Semaglutide D 0.5 mg/mL DV3396 or 
semaglutide placebo Ia 
0.25 mg 
0.5 mL DV3396 pen-injector 
4 weeks 
Semaglutide D 1.0 mg/mL DV3396 or 
semaglutide placebo Ia 
0.5 mg 
0.5 mL DV3396 pen-injector 
4 weeks 
Semaglutide D 2.0 mg/mL DV3396 or 
semaglutide placebo Ia 
1.0 mg 
0.5 mL DV3396 pen-injector 
4 weeks 
Semaglutide D 2.27 mg/mL DV3396 or 
semaglutide placebo Ib 
1.7 mg 
0.75 mL DV3396 pen-injector 
4 weeks 
Maintenance period 
Semaglutide D 3.2 mg/mL DV3396 or 
semaglutide placebo Ib 
2.4 mg 
0.75 mL DV3396 pen-injector 
36 weeks 
Subjects will be instructed to inject semaglutide/placebo once weekly at the same day of the week 
(to the extent possible) throughout the trial. 
Injections may be administered in the thigh, abdomen or upper arm, at any time of day irrespective 
of meals. 
If a single dose of trial product is missed, it should be administered as soon as noticed, provided the 
time to the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next 
scheduled dose is less than 2 days (48 hours) away, the subject should not administer a dose until 
the next scheduled dose. A missed dose should not affect the scheduled dosing day of the week. 
If ≥ 2 consecutive doses of trial product are missed, the subject should be encouraged to 
recommence the treatment if considered safe as per the investigator’s discretion and if the subject 
does not meet any of the discontinuation criteria (7). The trial product should be continued as early 
as the situation allows. The missed doses should not affect the scheduled dosing day of the week. 
The start dose for re-initiation of trial product is at the investigator’s discretion but the following 
guidance can be used:  
 If ≤3 consecutive doses are missed, once-weekly regimen can be resumed as prescribed without 
dose reduction 
 If 4-5 consecutive doses are missed, it is recommended to resume treatment at 1.0 mg for 4 
weeks, and then escalate to 2.4 mg, using 1.7 mg as the intermediate dose for 4 weeks 
 If ≥6 consecutive doses are missed, it is recommended to restart treatment at 0.25 mg 
semaglutide and escalate to 2.4 mg, using the standard dose escalation regimen  
In case of questions related to re-initiation of trial product, the investigator should consult Novo 
Nordisk. 
If a subject does not tolerate the recommended target dose of 2.4 mg once weekly, the subject may 
stay at a lower dose level. To prevent 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 AEs or due to 
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other circumstances. Dose adjustments are at the discretion of the investigator. It is recommended 
that the subject makes at least one attempt to re-escalate to the recommended target dose of 2.4 mg 
once weekly. 
Date and dose are to be reported in the electronic case report form (eCRF) when trial product dose 
is initiated or changed (reason for change should also be reported). 
Auxiliary supplies 
Auxiliary supplies will be provided in accordance with the trial materials manual (TMM) and 
Table 6-3. 
Table 6-3 
Auxiliary supplies provided by Novo Nordisk A/S 
Auxiliary supply 
Details 
Direction for use (DFU) 
DFU for DV3396 pen-injector  
Not included in the dispensing unit and to be handed out separately  
Needle 
The DV3396 pen-injector comes with an integrated and hidden needle of 6 mm in 
length (29G), therefore no needles are required to be used with this pen-injector 
6.1.1 
Medical devices 
Information about the DV3396 pen-injector may be found in the IB29 and any updates hereof. 
Information about the use of the drug-device combination products can be found in the DFU.  
Training in the DV3396 pen-injector  
Site staff will train subjects according to the flowchart (Section 1.2). Novo Nordisk will train the 
site staff and only trained site staff can be allocated the task to train and supervise subjects. All 
training must be documented. 
The following should be emphasised during training of subjects: 
 use of the pen-injector (according to instruction guidelines given in the DFU) 
 subjects should be informed to follow label instructions for storage and in-use time 
conditions descriptions on the labels and in the TMM. In-use time starts if removed from the 
refrigerator. 
The investigator must document that DFU are given to the subjects orally and in writing at the first 
dispensing visit and that subjects are trained. Training must be repeated as specified in the flowchart 
(1.2) and, if needed, during the trial at regular intervals in order to ensure correct use of the pen-
injector. Training is the responsibility of the investigator or delegate. 
The first dose of trial product must be taken on the day of randomisation (V2) at the clinical site by 
self-administration under supervision by trained site staff.  
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply or administer trial product. 
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 Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the TMM. 
 Each site will be supplied with enough trial products for the trial on an ongoing basis. Trial 
product will be distributed to the sites according to screening and randomisation. 
 The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are 
reported and resolved before use of the trial products. 
 All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and delegated site staff. 
 The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any subject before it 
has been evaluated and approved for further use by Novo Nordisk. Additional details 
regarding handling of temperature deviations can be found in the TMM. 
 The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
 The investigator or designee must instruct the subject in what to return at next visit. 
 Drug accountability should be performed on a pen level and must be documented in the IWRS.  
 The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator.  
 Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor. 
 All returned, expired or damaged trial products (for technical complaint samples, see Section 
10.510.5) must be stored separately from non-allocated trial products. No temperature 
monitoring is required. 
 Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
6.2.1 
Shipment of trial product to subject’s home 
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product and auxiliaries from the trial site or pharmacy to the subject’s home by courier service.  
The process for sending trial product from the trial site or pharmacy to a subject’s home is 
described in the “Trial site/pharmacy instruction for shipment of trial product to patients’ homes” 
document. The document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
subject. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document.  
Investigators, trial site/pharmacy staff and subjects who will be involved in shipment of trial 
product to the subject’s home will be adequately trained in this process. 
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6.3 
Measures to minimise bias: Randomisation and blinding 
All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial product will be dispensed/allocated 
at the trial visits summarised in the flowchart. 
To ensure sufficient statistical power for subgroup analyses according to BMI, randomisation will 
be stratified into two subgroups (BMI <35.0 and BMI ≥35.0) and a maximum of 50% of subjects 
will be enforced on the lower BMI subgroup. 
The active drug and placebo are visually identical for the following trial products: 
 Semaglutide D 0.5 mg/mL, Semaglutide D 1.0 mg/mL, Semaglutide D 2.0 mg/mL DV3396 and  
Semaglutide placebo Ia 
 Semaglutide D 2.27 mg/mL, Semaglutide D 3.2 mg/mL and Semaglutide placebo Ib 
The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a subjects’ treatment is warranted. Subject safety 
must always be the first consideration in making such a determination. If the investigator decides 
that unblinding is warranted, the investigator should make every effort to contact Novo Nordisk 
prior to unblinding a subjects’ treatment unless this could delay emergency treatment of the subject. 
If a subject’s treatment is unblinded, Novo Nordisk (Global Safety department) must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation. The person breaking the blind must print the "code break 
confirmation" notification generated by the IWRS, sign and date the document. If IWRS is not 
accessible at the time of blind break, the IWRS helpdesk should be contacted. Contact details are 
listed in Attachment I. 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. If any suspicion of non-compliance arises, the site must enter into a 
dialogue with the subject, re-emphasizing the importance of compliance and uncover barriers to 
compliance. This dialogue must be documented. Compliance can be assessed by cross checking the 
following sources and comparing these to the expected use: 
 Drug accountability information; visual inspection of pen-injectors  
 Questioning of subjects about missed doses and current treatment dose at every visit 
 
Information on treatment dose and periods >14 days without treatment will be recorded in the 
eCRF. Treatment start and stop dates must be recorded in the eCRF.  
6.5 
Concomitant medication 
Initiation of any GLP-1 RA should be avoided during the trial. The investigators are encouraged to 
ensure constant ongoing optimisation of the treatment of any comorbidity. 
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Other than the trial product, only medications that the subject is receiving at the time of screening or 
during the trial, for the following indications, must be recorded in the eCRF: 
 To treat or prevent HF or cardiovascular diseases (e.g. antihypertensives, diuretics, lipid-
lowering agents, anticoagulants, aspirin and other antiplatelet agents). 
 To treat overweight or obesity. 
 To treat a serious adverse event (SAE) or medication which may provide further information on 
the SAE i.e. alternative aetiology.  
 To treat diabetes and diabetes complications (for subjects who develop diabetes during the 
trial). 
 COVID-19 vaccine 
The information collected for each concomitant medication includes start date and stop date or 
continuation, dose (only to be collected for loop diuretics at selected visits as outlined in the 
flowchart) and related AE number when applicable. 
Changes in concomitant medication listed above must be recorded at each visit. If a change is due to 
an SAE, then this must be reported according to Section 8.3. 
During the trial, subjects should not initiate any weight management drugs or treatment which is not 
part of the trial procedures. If such treatment is initiated, the subjects should be instructed to stop 
the treatment. 
6.6 
Dose modification 
Please refer to Section 6.1 for description of missed doses. 
6.7 
Treatment after end of trial 
After the end of trial, the subject should be treated at the discretion of the investigator. 
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7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have subjects, who discontinue trial product, to continue in the trial. 
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial.  
Temporary or permanent discontinuation of treatment with trial product will not lead to withdrawal 
from the trial.  
7.1 
Discontinuation of trial treatment 
 Discontinuation of treatment can be decided by both the investigator and the subject. 
 Subjects who discontinue trial product should be encouraged to continue with the scheduled 
visits and assessments to ensure continued healthy lifestyle counselling and data collection.  
 If the subject does not wish to attend the scheduled clinic visits, efforts should be made to have 
the visits converted to phone contacts. However, all effort should be made to have the subject 
attend at least the ‘end-of-treatment visit’ (V11) containing the final data collection of 
primary and confirmatory secondary efficacy endpoints and participate in the ‘end-of-trial 
phone contact’ (P12).  
 The ‘end-of-trial’ phone contact is scheduled 5 weeks after the ‘end-of-treatment’ visit, to 
ensure the safety of the subject. If the subject has discontinued trial product >5 weeks prior to 
the ‘end-of-treatment’ visit, and the requirements for the follow-up period prior to the ‘end-
of-trial’ phone contact is fulfilled, then the ‘end-of-trial’ phone contact can be performed in 
combination with the ‘end-of-treatment’ visit. 
 If the subject is unwilling to attend the ‘end-of-treatment’ and/or ‘end-of-trial’ phone contact, 
information about the attempts to follow up with the subject must be documented in the 
subject’s medical record.  
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern as judged by the investigator 
2. Suspicion of acute pancreatitis 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical trial. However, simultaneous participation in a ‘COVID-19 vaccine trial’ is allowed 
without discontinuing Novo Nordisk trial product. 
If acute pancreatitis is suspected appropriate actions should be initiated, including local 
measurements of amylase and lipase (see 10.3.3 for reporting).  
Subjects meeting discontinuation of trial product criterion no. 2 can resume trial product if the 
Atlanta criteria55 are not fulfilled and thus, the suspicion of acute pancreatitis is not confirmed. Trial 
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product may be resumed for subjects with a gallstone-induced pancreatitis in case of 
cholecystectomy.  
Subjects meeting discontinuation of trial product criteria no. 1, 3 and 4 can resume trial product, if 
the criteria are no longer met (Section 7.1.1). 
The primary reason for permanent discontinuation of trial product must be specified in the end-of-
treatment-form in the eCRF, and final drug accountability must be performed.  
7.1.1 
Temporary discontinuation of trial treatment 
If a subject has discontinued trial product due to temporary safety concern not related to trial 
product and treatment with trial product is allowed to be resumed, the guide for missed doses 
should be followed (Section 6.1). Similarly, a subject who discontinues trial product on their own 
initiative should be encouraged to resume trial product (Section 6.1). 
If a ‘treatment status’ session previously has been made in IWRS to indicate discontinuation of 
treatment, a new “treatment status” session must be made to resume trial product. 
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted; however 
a ‘treatment status’ session to discontinue treatment should not be made in  IWRS before diagnosis 
of acute pancreatitis is confirmed. Appropriate actions should be initiated, including local 
measurement of amylase and lipase (see appendix 3 (Section 10.3) for AE reporting). 
If acute pancreatitis is confirmed, treatment with trial product should not be restarted, and a 
‘treatment status’ session should be made in IWRS to indicate discontinuation of trial product. If the 
Atlanta criteria54 are not fulfilled, and thus, the suspicion of acute pancreatitis is not confirmed, 
treatment with trial product can be resumed. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to the ‘end of treatment’ visit (V11). See the 
flowchart for data to be collected. 
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment status session must be made in the IWRS to indicate discontinuation of treatment. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
Publicly available data sources should also be searched for withdrawn subjects to establish vital 
status (unless prohibited by local regulation). 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
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Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the ‘end-of-trial’ 
form in the eCRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether the subject wishes to and/or should continue in the trial. 
 Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
 Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
 If establishing direct contact is not possible, vital status (dead or alive) should be obtained. 
Publicly available data sources should also be searched at end of trial (unless prohibited by 
local regulation). 
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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 and Appendix 2 (Section 10.2). 
 Informed consent must be obtained before any trial related activity, see Section 10.1.310.1.3. 
 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion criteria and none of the exclusion criteria. 
 The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
 At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
 Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
 Review of ECG, laboratory reports and echocardiography must be documented either on the 
documents or in the subject's medical records. 
 Results of pregnancy testing must be documented in the subject's medical records. 
 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.  
8.1.1 
Body measurements 
Body weight should be measured without shoes and only wearing light clothing. It should be 
measured on a digital scale and recorded in kg or lb (one decimal with a precision of 0.1 kg or lb) 
using preferable the same scale throughout the trial. The scale must be calibrated according to 
manufacturer’s recommendation. 
Height is measured without shoes in centimetres or inches (one decimal with a precision of 0.1 
centimetres or inches). At screening BMI will be calculated by the eCRF and must agree with 
inclusion criterion no. 3. 
Waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest. Measurement must be obtained in standing position with a non-
stretchable measuring tape and to the nearest cm or inch.  
The tape should touch the skin but not compress soft tissue and twists in the tape should be avoided. 
The subject should be asked to breathe normally. The same measuring tape should be used 
throughout the trial. The measuring tape will be provided by Novo Nordisk to ensure 
standardisation. 
8.1.2 
Clinical outcome assessments 
Subjects should be given the opportunity to complete the questionnaires by themselves without 
interruption. Subjects must transcribe directly into a site-pad/web-solution. Subjects are not allowed 
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to answer the questions on paper. Site staff should activate and verify completion of the 
questionnaires (as specified in the TrialMax Slate® and TrialManager® Site User Guide). 
The following electronic patient reported outcome (ePRO) questionnaires will be used: 
Patient Global Impression of Status (PGI-S) for KCCQ version 1.0. 
Patient Global Impression of Change (PGI-C) for KCCQ version 1.0. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) version 2.0. 
 The KCCQ is a disease-specific health status instrument composed of 23 items that quantify the 
domains of physical limitation, symptoms, self-efficacy, social limitation, and health-related 
quality of life limitation from heart failure. The overall summary score and all domains have 
been independently demonstrated to be valid, reliable, and responsive to clinical change. 
Scores range from 0 to 100.56 
EuroQoL five dimensions five level (EQ-5D-5L). 
 The EQ-5D-5L will be used to estimate the impact on patients’ health-related quality of life and 
provides a description of patient’s problems by dimensions (descriptive system), a score for 
overall self-rated health (visual analogue scale (VAS) as well as an index score (EQ-5D-5L 
index)). EQ-5D index score range: 0 to 1 and EQ-5D-VAS: range 0 to 100. A higher score 
indicates better self-reported health status. If clarification of the test is needed, care must be 
taken not to bias the subject  
Patient Global Impression of Status (PGI-S) for 6MWT version 1.0. 
Patient Global Impression of Change (PGI-C) for 6MWT version 1.0. 
The following PRO test will be performed: 
6-minute walk test (6MWT) 
 The 6MWT assesses the distance a subject can walk in six minutes. It is a direct and timed 
measure of walking ability, which is technically simple, reproducible, and when 
administrators are well trained, readily standardised. The goal is for the subject to walk as far 
as possible in six minutes without running. The subject can self-pace and rest as needed as 
they traverse back and forth along a marked walkway of 66 feet (20 m) (Figure 8-1). The 
primary outcome is the distance covered over six minutes.  
 The 6MWT must be performed in accordance with the manual provided by Novo Nordisk. 
 
Figure 8-1 
Walkway marking for the 6-minute walk test 
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Planned time points for all efficacy assessments are provided in the flowchart (1.2).  
In order to assess the subject’s perception of the allocated treatment a question regarding this will 
be posed at the ‘end-of-treatment’ visit. 
8.1.3 
Echocardiography 
Echocardiography must be performed in all subjects at the screening visit assessing only the LVEF 
to ensure agreement with inclusion criterion number 5. 
Only for subjects participating in the sub study: 
The echocardiography must be performed as outlined in the flowchart. The echocardiography must 
be performed in accordance with the manual from the supplier. 
8.1.4 
Clinical laboratory assessments   
All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2, must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product. 
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. 
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 signs of HF, the cardiovascular, respiratory, 
gastrointestinal and general appearance. 
 Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital signs 
The method for measuring pulse rate and systolic and diastolic blood pressure needs to follow the 
standard clinical practice at site, however as a minimum: 
 Vital sign assessment should be preceded by at least 5 minutes of rest for the subject in a quiet 
setting without distractions (e.g. no use of television, cell phones). 
 Blood pressure and pulse rate measurements will be assessed with a completely automated 
device. Manual techniques must be used only if an automated device is not available. 
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8.2.3 
Electrocardiograms 
 12-lead ECG will be obtained as outlined in the flowchart using an ECG machine that 
automatically calculates the heart rate and measures PR and QRS intervals.  
 The investigator must perform review of the ECG for clinically significant abnormal findings. 
8.2.4 
New York Heart Association (NYHA) classification  
The investigator must assess the functional status of the subject based on below: 
 Class I: No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnoea. 
 Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnoea. 
 Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnoea. 
 Class IV: Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
8.2.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2,  must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on all the 
events listed below:  
 SAEs 
 Following AEs irrespective of seriousness: 
o AEs leading to premature treatment discontinuation 
o AEs related to COVID-19 
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. 
o AEs requiring additional data collection (Table 8-1) 
▪ Acute pancreatitis 
▪ Medication errors  
▪ Misuse and abuse 
 AEs for adjudication (Table 8-1): 
o Heart failure hospitalisations or urgent heart failure visits 
o Death 
 Pregnancies 
 Obesity related surgical procedures - the procedure (e.g. bariatric surgery) must be reported as 
an AE 
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Events for adjudication require data collection on an adjudication form. Event adjudication will be 
performed in randomised subjects and will be evaluated by an independent external event 
adjudication committee (EAC) in a blinded manner, please refer to Section 10.1.6.2. 
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 
 
Acute pancreatitis 
X 
 
Medication error 
X 
 
Misuse and abuse 
X 
 
Heart failure hospitalisations or urgent heart 
failure visits 
 
X 
Death 
 
X 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3). 
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 
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 eCRF. 
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 eCRF 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 eCRF 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. 
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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 end-of-trial visit, at the time points specified in the flowchart. 
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3, section 10.3. All SAEs must be recorded and reported to Novo Nordisk 
or designee within 24 hours, and the investigator must submit any updated SAE data to Novo 
Nordisk or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3, Section 10.3. 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3, Section 10.3.4. 
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 subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review board/independent ethics committee (IRB/IEC), and 
investigators. This also includes suspected unexpected serious adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
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8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected after first exposure to trial product and 
until end-of-trial. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4, Section 10.4. 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
8.3.7 
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. 
For Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk might ask 
the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in clinical 
trials. The most commonly reported AE was nausea. All subjects recovered without complications.  
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to subject’s clinical signs and symptoms. 
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse or abuse, please refer to Section 8.3 and Appendix 3, Section 10.3.3 for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE. A prolonged period of observation and treatment may be necessary, considering the long 
half-life of semaglutide of approximately one week. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose, also consult the current version of the IB29 or any updates 
hereof. 
8.5 
Pharmacokinetics 
 Blood samples for measuring plasma concentration of semaglutide will be drawn at 
 visit 7 and visit 11 according to the flowchart (Section 1.2) 
 The dosing information should be transcribed into the CRF for the date and time of the last two 
doses (approx. -2 and -1 week) of trial product prior to the PK assessment.  
 The exact timing of obtaining the PK sample must be recorded on the laboratory form. 
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 The purpose of measuring plasma semaglutide levels is to evaluate exposure-response 
relationship. 
 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. 
8.6 
Pharmacodynamics 
Not applicable for this trial. 
8.7 
Genetics 
A blood sample for genetic analysis will be collected from patients who have consented to 
participate in the optional biobank component of the trial. Refer to Section 8.8 and Appendix 6, 
Section 10.6 for further details. 
8.8 
Biomarkers 
Collection of samples for biomarker research is part of this trial. The following samples are required 
and will be collected from all subjects in this trial: 
 N-terminal pro-brain natriuretic peptide (NT-proBNP) 
 C-reactive protein (CRP) 
Collection of biosamples for future analysis (stored in a biobank) is a component of this trial. 
Participation in the biobank component is optional. Subjects 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 Table 10-1 and stored for future use. 
The samples are collected for the purpose of allowing future analyses of biomarkers, both genetic 
and circulating, 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. 
Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome with the purpose of understanding and predicting response to semaglutide as well as to 
understand obesity, cardiovascular, metabolic, or related conditions. 
Analyses of circulating biomarkers will measure hormones, metabolites or other non-genetic serum 
entity with the purpose of understanding and predicting response to semaglutide as well as 
understanding obesity, cardiovascular, metabolic, or related conditions. 
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 at a central laboratory up 
to 15 years after the study has been reported. 
Refer to Appendix 6, Section 10.6. 
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8.9 
Immunogenicity assessments 
Not applicable for this trial. 
8.10 
Health economics  
Not applicable for this trial. 
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9 
Statistical considerations  
9.1 
Statistical hypotheses 
The tests of superiority of semaglutide s.c. 2.4 mg once weekly versus placebo for the primary and 
confirmatory secondary endpoints are performed using a graphical testing system (Figure 9-1) that 
preserves the overall study-wise type I error of 5%.  
 
KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire; CRP: C-Reactive Protein; 6MWD: six-minute walking 
distance. Hierarchical composite endpoint as defined in Section 3.2.2.1 
Figure 9-1 
Tests of superiority of semaglutide s.c. 2.4 mg once weekly versus placebo for 
the primary and confirmatory secondary endpoints 
First, the multiple primary endpoints are tested, where for these two endpoints the alpha is split in 
1% for weight change and 4 % for change in KCCQ-CSS. The tests for the multiple endpoint will 
follow the weighted Holm-Bonferroni procedure57 (with weights one) such that if one of the two 
endpoints is superior then the full alpha can be recycled for the other endpoint and hence the 
remaining primary endpoint will be tested at the 5% significance level (two-sided).  
If both hypotheses are rejected and superiority is confirmed for both primary endpoints, then the 
confirmatory secondary endpoint will be tested according to the flow and weights as specified in 
Figure 9-1. The 5% alpha will be 50/50 split between 6MWD and the hierarchical composite 
endpoint, so that the hierarchical composite endpoint will be tested at 2.5% significance level, and if 
superiority is confirmed, the 6MWD will be tested at 3.75% significance level. If superiority is not 
confirmed for the hierarchical composite endpoint, the 6MWD will be tested at 2.5% significance 
level. If superiority is confirmed for both 6MWD and the hierarchical composite endpoint, CRP will 
be tested at 5% significance level, but if only 6MWD is confirmed CRP will be tested at 2.5% 
significance level, or if only the hierarchical composite is confirmed, CRP will be tested at 1.25% 
significance level.  
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9.2 
Sample size determination  
516 subjects will be randomly assigned to trial product. 
The trial is designed with a marginal power of at least 90% to detect differences on each of the dual 
primary endpoints with a study-wise type I error rate of 5%. 
The calculations for the primary endpoints and confirmatory secondary endpoints 6MWD and CRP 
are based on a t test on the mean difference assuming equal variances in the arms. The calculations 
for the composite hierarchical secondary endpoint are based on the win ratio.  
In the NN9536-4373 trial (STEP-1) with 1961 randomised subjects (BMI>= 27 kg/m2 at baseline) 
there was observed a treatment difference of 12% for change in BW between semaglutide 2.4 mg 
once weekly and placebo at 52 weeks for completers with a standard deviation of 8.5. We assume 
this also can be expected in the obese HF population in this trial.  
Although the specific magnitude of clinical relevance between groups for change in KCCQ-CSS 
can be deliberated, it is assumed that in this HF population we can expect a treatment difference of 
5 points58 between semaglutide 2.4 mg once weekly and placebo at week 52 with a standard 
deviation of 14 based on the results in the study by Kitzman et al, where a difference of 7 points  
was estimated between 92 completed subjects for KCCQ-OSS randomised to either diet or no diet 
in an obese population with heart failure with preserved ejection fraction adjusted for baseline.44 
Furthermore, in this trial the standard deviation across the groups were approximately 12 using the 
published 95% CIs assuming KCCQ-OSS and KCCQ-CSS have similar variability. Furthermore, 
using results from DEFINE-HF (a HFrEF population) the standard deviation for KCCQ-CSS was 
calculated to be 13.7 and 13.7 for placebo and active group respectively at 3 months also adjusted 
for baseline KCCQ-CSS .59 
In the DEFINE-HF trial based on the same assumptions as above a standard deviation of 72 and 75 
was derived for 6MWD in the placebo group and the active group, respectively.59 By personal 
communication the standard deviation in the PANACHE trial for 6MWD was 60 and in the 
SECRET trial it was much lower with a standard deviation of 40. As a treatment difference of 
30 metres in the 6MWD is considered as having a clinical relevance we will assume this difference 
of 30 metres at week 52 between semaglutide 2.4 mg OW versus placebo with a standard deviation 
of 70. 
Using data from NN9536-4373 a mean ratio of 0.79 and 0.51 (semaglutide 2.4 mg versus placebo) 
was estimated for completers (on treatment) at 20 and 68 weeks adjusted for baseline CRP. A 
coefficient of variation was estimated to be 1.23 using the residual variance on the log scale back 
transformed. We assume a mean ratio of 0.70 for completers between semaglutide 2.4 mg once 
weekly versus placebo in this trial at 52 weeks. 
For the power calculations on the hierarchical composite endpoint, it is assumed that 10 all-cause 
deaths (with a treatment effect corresponding to a hazard ratio of 0.9) and 15 subjects with heart 
failure hospitalisation (with a treatment effect corresponding to a hazard ratio of 0.8) will occur 
during the trial. A correlation of 0.5 between the KCCQ-CSS and 6MWD is assumed for this 
endpoint. The power calculations for this endpoint are based on simulation of 10000 datasets. 
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In relation to treatment effects in non-completers using data from NN9536-4373 we assume that 
25% of subjects discontinue permanently and 60% of these are retrieved at week 52. All subjects in 
the placebo arm are assumed to have same effect as subjects who complete the trial on placebo. 
Retrieved subjects in the semaglutide s.c. 2.4 mg OW arm are assumed to have an effect 
corresponding to half the treatment difference (compared to placebo) of subjects who complete the 
trial on semaglutide s.c. 2.4 mg once weekly. Non-retrieved subjects in the semaglutide s.c. 2.4 mg 
once weekly arm are assumed to have an effect corresponding to placebo. The attenuation of the 
assumed mean differences between treatment groups using these assumptions can be seen in 
Table 9-1. 
Table 9-1 
Assumptions and power for the confirmatory endpoints given with an 
anticipated number of 516 randomised subjects  
Endpoint 
Mean 
difference 
Completers 
Mean  
Difference# 
Standard 
deviation  
Two-sided 
significance 
level (%)*  
Marginal 
Power 
(%) 
Body weight 
-12% 
-9.9% 
8.5 
1 
>99.9% 
KCCQ-CSS 
5.0 points 
4.125 points 
14  
4 
90% 
6MWD 
30 metres 
24.75 metres 
70 
2.5 
96% 
Hierarchical 
composite 
N/A 
N/A 
N/A 
2.5 
91% 
CRP  
 0.70 
Mean ratio 
0.745 
Mean ratio 
1.23 
CV 
1.25 
84% 
CRP is characterised by mean ratio and coefficient of variation (CV) 
#Assumed that 25% discontinue treatment with 60% retrieval with a halved treatment effect in retrieved subjects which 
corresponds to that 75% of subjects have a treatment effect as completers, 15% would have a halved treatment effect as 
completers and 10% would have no treatment effect. *Minimum significance level it can be tested on. 
The sample size in this trial would essentially be governed by the assumptions of the mean 
difference and the standard deviation of KCCQ-CSS. Different scenarios can be observed in 
Table 9-2. 
Table 9-2 
Sample size for KCCQ-CSS according to different assumptions of the mean 
difference and standard deviation with a significance level of 4% and a power of 
90%. 
Standard deviation  
 Mean difference  
Sample size  
13 
5 
304 
14 
5 
352 
15 
5 
404 
13 
4.125 
446 
14 
4.125 
516 
15 
4.125 
592 
13 
4 
474 
14 
4 
548 
15 
4 
628 
 
 
 
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9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised 
Full analysis set (FAS)  
All subjects randomised. Exclusion of data from analyses should be used 
restrictively, and normally no data should be excluded from the FAS. Subjects 
will be analysed according to the randomised treatment 
Safety analysis set (SAS) 
All subjects randomly assigned to trial treatment and who take at least 1 dose of 
trial product. Subjects are analysed according to the treatment they received. 
 
Two observation periods are defined for each subject: 
 In-trial: The in-trial period is defined as the uninterrupted time interval from date of 
randomisation to date of last contact with trial site. 
 On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose 
of trial product has been administered within the prior 2 weeks (14 days). The on-treatment 
period is defined as all times which are considered on-treatment. 
In general, the on-treatment period will therefore be from the date of first trial product 
administration to date of last trial product administration excluding potential off-treatment time 
intervals triggered by at least two consecutive missed doses. 
For the evaluation of AEs, the lag time for each on-treatment time interval is 5 weeks (35 days). 
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods. 
Effect endpoints will be analysed using the FAS; safety endpoints will be analysed using the SAS. 
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be written, including a more technical and detailed 
elaboration of the statistical analyses. The SAP will be finalised before breaking the blind to 
treatment assignment. 
9.4.1 
General considerations 
The comparison presented from a statistical analysis will be semaglutide sc 2.4 mg OW 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. 
The last available and eligible observation at or before randomisation is used as the baseline value.  
Data from all countries and sites will be analysed and reported together. 
9.4.2 
Primary endpoints 
The primary endpoints are change in the KCCQ clinical summary score (points) and change in BW 
in percentage (BW-%) from baseline (week 0) to end of treatment (week 52) as listed in Section 3. 
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All tests are tests of superiority of semaglutide s.c. 2.4 mg once weekly to placebo. 
Analyses addressing the primary estimand 
The following statistical analyses and imputation methods are designed to address the primary 
estimand. 
The primary analysis model for change in the KCCQ-CSS (points) or change in BW (%) is a linear 
regression (ANCOVA) with randomised treatment, and with baseline KCCQ-CSS (points) and 
baseline BW (kg), respectively, as covariates. The factor BMI subgroup (BMI <35.0 kg/m2 versus 
BMI ≥35.0 kg/m2) is included in the model as it is used as a stratification variable in the 
randomisation scheme. 
The estimated treatment difference between semaglutide s.c. 2.4 mg once-weekly and placebo will 
be reported together with the associated two-sided 95% CI and corresponding p-value. All available 
data at week 52 are used and missing values at week 52 will be imputed and the endpoint will be 
derived from the imputed values. The imputation approach for the primary analysis is a multiple 
imputation similar to the one described by McEvoy et al.60 For subjects in the semaglutide s.c. 2.4 
mg OW and the placebo groups, missing primary endpoint measurements at week 52 for non-
retrieved subjects are imputed using assessments from retrieved subjects in each treatment group. 
This will be done according to the timing of last available observation during the on-treatment 
period (LAO-OT) of KCCQ-CSS or BW. Missing measurements for the primary endpoints at week 
52 for subjects on randomised treatment (at week 52) are imputed by sampling from available 
measurements at week 52 from subjects on randomised treatment in the relevant randomised 
treatment arms. Details of the imputation approach are provided in the SAP e.g. variables used in 
the imputation. 
Sensitivity analyses will address the primary estimand using a nonparametric method. 
9.4.3 
Secondary endpoint(s) 
9.4.3.1 
Confirmatory secondary endpoint 
The confirmatory secondary endpoints are change in CRP and 6MWD (metres) from baseline 
(week 0) to end of treatment (week 52) as well as the hierarchical composite endpoint as listed in 
Section 3. 
All tests are tests of superiority of semaglutide s.c. 2.4 mg OW versus placebo. 
Analyses addressing the primary estimand 
The secondary confirmatory endpoints CRP and 6MWD will be analysed using the primary 
imputation approach used for the primary endpoint and to address the primary estimand. The 
statistical model for change in CRP and 6MWD will be the same as for the primary endpoints. The 
linear regression for CRP will be based on the log-transformed values at week 52 and log-
transformed baseline values.   
The analysis of the hierarchical composite endpoint will be based on direct comparisons of each 
subject randomised to semaglutide s.c. 2.4 mg OW versus each subject randomised to placebo 
within each stratum. For each of these pairs, a ‘treatment winner’ based on similar observation time 
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will be declared based on the endpoint hierarchy. The win ratio (i.e. the proportion of winners 
randomised to semaglutide s.c. 2.4 mg OW divided by the winners randomised to placebo) will be 
reported together with the associated two-sided 95% CI and corresponding p-value. Furthermore, 
the contribution of wins from each individual component of the hierarchical composite endpoint 
will be summarised.       
9.4.3.2 
Supportive secondary endpoints 
For details on analyses of additional supportive secondary endpoints, please refer to the SAP. 
9.4.4 
Exploratory endpoints 
For details on analyses of the exploratory endpoints, please refer to the SAP. 
9.4.4.1 
Pharmacokinetic and/or pharmacodynamic 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 HFpEF, obesity 
and T2D. 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 STEP 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. 
9.5 
Interim analyses  
No interim analyses are planned. 
9.6 
Data monitoring committee 
There is no data monitoring committee for this trial  
9.7 
Reporting of the main part of the trial  
Not applicable 
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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: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki62 and applicable International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline63 
o Applicable laws and regulations 
 The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
 Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the clinical trial report (CTR) according to national requirements. 
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects. 
 Before a site is allowed to start screening subjects, written notification from Novo Nordisk must 
be received. 
 The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations 
o ensuring submission of the CTR synopsis to the IRB/IEC 
o 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. 
10.1.3 
Informed consent process 
 The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial. 
 The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
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 Subjects must be informed that their participation is voluntary. 
 Subjects must be informed about their privacy rights.  
 Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines63, Declaration of Helsinki62 and the 
IRB/IEC or site. 
 The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form 
before any trial related activity. 
 The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
 Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
 A copy of the informed consent forms must be provided to the subject. 
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the subject may receive other written information during the 
trial.  
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
 Data protection 
 Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
 The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
 The subject must be informed about his/her privacy rights, including that his/her personal trial 
related data will be used by Novo Nordisk in accordance with local data protection law. The 
disclosure of the data must also be explained to the subject.  
 The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
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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 Table 8-1). 
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.  
10.1.6.3 
Steering committee 
A steering committee will provide scientific and operational leadership for the trial. The committee 
will consist of experts from outside Novo Nordisk, and designated Novo Nordisk employees. The 
committee will operate under a charter agreed with Novo Nordisk. 
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)64, the Food and Drug Administration Amendment 
Act (FDAAA)65, European Commission Requirements1, 66, 67 and other relevant recommendations or 
regulations. If a subject request to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint and is for this 
trial last subject first treatment (LSFT) + 52 weeks corresponding to visit 11. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
11. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
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. 
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 All subject data relating to the trial will be recorded on eCRFs unless transmitted electronically 
to Novo Nordisk or designee (e.g. laboratory and electronic PRO (ePRO) data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
 The following will be provided as paper CRFs: 
o Pregnancy forms 
 The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable:  
o AE forms  
o Safety information forms  
o Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a subject) 
 Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
 The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
10.1.8.2 
Monitoring 
 The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and 
reproduce any record(s) and report(s) that are important to the evaluation of the trial. If the 
electronic medical record does not have a visible audit trail, the investigator must provide the 
monitor with signed and dated printouts. In addition, the relevant site staff should be 
available for discussions at monitoring visits and between monitoring visits (e.g. by 
telephone).  
 Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
 Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
 Monitors will review the subject’s medical records and other source data, to ensure consistency 
and/or identify omissions compared to the CRF.  
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10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database. 
10.1.9 
Source documents 
 All data entered in the eCRF must be verifiable in source documentation other than the CRF. 
 For ePROs, data in the service providers’ database is considered source data. 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
 Data 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.  
 If source data is entered directly in a paper CRF, each data entry or clear series of data entries 
must be signed and dated separately by the trial staff making the entry. 
 It must be possible to verify subject’s medical history in source documents, such as subject’s 
medical record 
 The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested, and who was contacted. 
 Definition of what constitutes source data can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
10.1.10 
Retention of clinical trial documentation 
 Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. 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, eCRF and other subject data will be provided in an electronic 
readable format to the investigator before access is revoked to the systems and/or electronic 
devices supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
electronic readable format or as paper copies or prints) must be retained by the site. A copy 
of all data will be stored by Novo Nordisk. 
 Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
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10.1.11 
Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
 failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
 inadequate recruitment of subjects by the investigator 
 discontinuation of further trial product development. 
10.1.12 
Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). The investigator must be able to provide the necessary information or 
otherwise demonstrate to Novo Nordisk that such technical and organisational safety measures have 
been taken. 
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During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
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.  
For country specific indemnity statements, please refer to Appendix 7, Section 10.7. 
10.1.14 
Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
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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.68 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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10.2 
Appendix 2: Clinical laboratory tests 
 The tests detailed in Table 10-1 will be performed by the central laboratory except otherwise 
stated. 
 All laboratory results from visit 1 will be disclosed to the investigators. For the remaining visits 
no laboratory results will be disclosed to the investigators. 
 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 disclosed laboratory results for concomitant illnesses and AEs. 
 Laboratory samples will be destroyed no later than at finalisation of the CTR except for 
samples collected for the biobank for future use. 
Table 10-1 
Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism 
Visit: 1 
 
HbA1c1 
Biomarkers 
Visit: 1, 7, 11 
 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
 
high sensitivity C-Reactive Protein (hsCRP) 
Pregnancy Testing 
Visit: 1, 2, 4, 5, 7, 8, 9, 10, 
11, 12 
 
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2 
Biobank3 
Visit: 2, 7, 11 
 
Whole blood (for genetic analysis) (visit 2 only) 
 
Serum (for analyses of circulating biomarkers) 
Pharmacokinetics 
Visit: 7, 11 
 
Plasma semaglutide 
Notes: 
1 For screening purposes only, performed at local laboratory at screening 
2 Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
3 Subjects must sign and date a separate informed consent form before samples are collected 
 
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an 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 
 Obesity related surgical procedures 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
 Conditions present prior to the time point from which AEs are collected and anticipated day-
to-day fluctuations of these conditions, including those identified during screening or other 
trial procedures performed before exposure to IMP.  
Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
 Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to 
the procedure is the AE. Exceptions include obesity related surgical procedures where the 
procedure (e.g. bariatric surgery) should be reported as 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 subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalisation are AEs. If a 
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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, diarrhea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious and reported 
as SAEs using the important medical event criterion. 
 The following AEs 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 upper normal limit (UNL) and total bilirubin >2 x UNL where no alternative 
aetiology exists (Hy's law) 
 
 
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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 
 Heart failure hospitalisations or urgent heart failure visits: 
New episode or worsening of existing heart failure leading to an urgent, unscheduled hospital 
admission or clinic/office/emergency department visit 
Adverse events requiring additional data collection 
Acute Pancreatitis  
Diagnosis of acute pancreatitis requires two of the following three features: 
1. abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back) 
2. serum lipase activity (and/or amylase activity) at least three times greater than the upper limit 
of normal 
3. characteristic findings of acute pancreatitis on imaging. 
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
 administration of wrong drug  
Note: Use of wrong 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 higher dose than intended. The administered dose must deviate 
from the intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily occur. 
Note: missed doses or drug pauses are not to be reported as a medication error. 
Misuse and abuse  
 Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
 Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. gastrointestinal adverse events or other), this must be reported on an 
additional AE form. 
 
 
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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 subject identifiers, except for the 
subject number, will be redacted on the copies of the source documents before submission to 
Novo Nordisk. 
 For all non-serious AEs, the applicable forms should be signed when the event is resolved or 
at the end of the trial at the latest. For sign-off of SAE related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
 Novo Nordisk products used as concomitant medication: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as concomitant medication in 
the trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to 
report this AE to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and SAEs 
can be assessed as severe.  
 
Assessment of causality 
 The investigator is obligated to assess the relationship between IMP and the occurrence of 
each AE/SAE. 
 Relationship between an AE/SAE and the relevant IMP should be assessed as:  
 Probable - Good reason and sufficient documentation to assume a causal relationship. 
 Possible - A causal relationship is conceivable and cannot be dismissed. 
 Unlikely - The event is most likely related to aetiology other than the IMP. 
 Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
 The investigator 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 assesses causality for every event before the initial transmission of the SAE data. 
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 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 subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
 Recovering/resolving: The condition is improving, and the subject is expected to recover 
from the event. This term may be applicable in cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE).  
Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
 Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
 Not recovered/not resolved: The condition of the subject has not improved, and the 
symptoms are unchanged, or the outcome is not known.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
 Fatal: This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with a fatal outcome must be reported as an SAE. 
 Unknown: This term is only applicable if the subject is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject die during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology. 
New or updated information will be recorded in the CRF. 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
 Relevant forms (AE and safety information form) must be completed in the eCRF.  
 For reporting and sign-off timelines, see Figure 10-1 below. 
 If the eCRF is unavailable for more than 24 hours, then the site will use the paper AE form, 
and if the eCRF 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 eCRF as soon as it becomes available. 
 After the trial is completed, the trial database will be locked, and thee eCRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
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a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after eCRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
 Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk 
in accordance with Section 10.1.5. 
 For SAEs, initial notification via telephone is acceptable, although it does not replace the 
need for the investigator to complete the AE and safety information form within the 
designated reporting timelines (as illustrated in the figure below): 
 AE form within 24 hours 
 Safety information form within 5 calendar days 
 Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
 The specific event form for AEs requiring additional data collection within 14 calendar days   
 
 
 
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
Documented total hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for 12 months without an alternative medical 
cause.  
 Females ≥ 50 years of age can be considered postmenopausal (irrespective of treatment with a 
hormonal contraception or hormone replacement therapy (HRT)) if they have both: 
 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.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table(s) below:
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Table 10-2 
Highly effective contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
Highly effective methodsb,d that have low user dependency (Failure rate of <1% per year when 
used consistently and correctly): 
 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, d 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 
 Oral/injectable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
 Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the trial treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject. 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical trials. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
d) Contraception should be utilised during the treatment period and for at least 35 days (corresponding to 
time needed to eliminate trial product) after the last dose of trial product.  
Pregnancy testing 
 Additional pregnancy testing should be performed during the treatment period, if required 
locally (Appendix 7, Section 10.7). 
 Women/WOCBP should only be included after a negative highly sensitive urine or serum 
pregnancy test (refer to Appendix 2, Section 10.2). 
 A pregnancy test should be performed at the end of relevant systemic exposure (refer to 
Appendix 2, Section 10.2). 
 Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy 
is otherwise suspected. 
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Collection of pregnancy information  
Female subjects who become pregnant  
 Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this trial. 
 Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy (see Figure 10-2). 
 Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month 
beyond the delivery date. 
 Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any AE in connection with 
pregnancy or elective termination of a pregnancy for medical reasons will be reported as an AE 
or SAE. If relevant, consider adding ‘gestational’, ‘pregnancy related’ or a similar term when 
reporting the AE/SAE. 
 Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
 Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the IMP by the investigator will be reported to Novo Nordisk as described in Section 
10.3. While the investigator is not obligated to actively seek this information in former subjects, 
he or she may learn of an SAE through spontaneous reporting.  
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
Any female subject who becomes pregnant while participating in the trial will discontinue IMP.  
 
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
Technical complaint definition  
 A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does 
not concern the AE itself. 
Examples of technical complaints: 
 Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles 
or contamination) 
 Problems with packaging material including labelling 
 Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form. 
10.5.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must 
be completed. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
 24 hours if related to an SAE  
 5 days calendar for all other technical complaints  
If the eCRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject, the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the eCRF 
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. 
 
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10.6 
Appendix 6: Retention of human biosamples and genetics  
In countries where applicable, the trial will involve collection of human biosamples to be stored in a 
central archive for future use. Subjects must sign and date a separate informed consent form before 
biosamples are collected. 
The following samples will be collected and stored: 
 Whole blood (for genetic analysis) – at baseline (visit 2) 
 Serum (for analysis of circulating biomarkers) – at baseline (visit 2), week 20 (visit 7), and end 
of treatment (visit 11). 
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.  
The biosamples will be stored at a central storage facility contracted by Novo Nordisk. Only Novo 
Nordisk and storage facility employees will be able to access the stored biosamples. The biosamples 
may be transferred to other countries for analysis and will be destroyed at the latest 15 years after 
the trial has been reported. 
Patients may withdraw from the biobank component of the trial at any time, independent of 
participation in the trial. The patient can choose to do so at any given time while in the trial or after 
the end of the trial. If a patient withdraws from the biobank component all stored biosamples 
obtained from their own body will be destroyed. 
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10.7 
Appendix 7: Country-specific requirements  
Argentina:  
 Section 5.2, exclusion criteria #18 and Appendix 4 (Section 10.4): Contraceptive methods and 
pregnancy tests will be reimbursed by the sponsor. Monthly testing with highly sensitive 
urine pregnancy tests is required for woman of childbearing potential (WOCBP). 
 Section 6.7: In reference to treatment after end of trial: the sponsor commits to comply with 
what is stated in point 6.8 of the current local regulation, disposition 6677/10. According to 
it, commits to comply with the following: “For Argentina, after the conclusion of subject´s 
participation in the study, trial doctor will discuss with subjects the best alternatives for 
future treatment. If trial doctor, based on his/her adequately justified medical analysis, 
decides that the Sponsor’s study drug is the best available treatment option for the subject, 
trial doctor will prescribe the study drug, which must be approved by the Ethics Committee. 
The Sponsor (Novo Nordisk Pharma Argentina S.A.) will provide access to the Sponsor’s 
study drug to the subject for the time the Ethics Committee decides or until access is ensured 
by any other means and in accordance with the applicable provisions in Argentina. Subjects 
must visit trial doctor to receive the Sponsor’s study drug and will have to provide 
information about health status and any possible side effects that may have been experienced 
since last visit. 
 
Australia:  
 Comply with Medicines Australia Guidelines for Compensation for Injury Resulting from 
Participation in a Company Sponsored Clinical Trial, version 160104 16 January 2004. 
 
Czech Republic: 
 Section 5.2, exclusion criteria #18 and Appendix 4 (Section 10.4): A monthly pregnancy test 
(urine) is required for all women of childbearing potential.  
 Appendix 2 (Section 10.2), laboratory assessments: In addition to the parameters listed in 
Appendix 2, amylase and lipase will be analysed.  
 Section 8.3 and Appendix 3 (Section 10.3): All AEs, irrespective of seriousness, should be 
collected from the day of randomisation and until the follow-up visit/end of trial visit, at the 
time points specified in the flowchart.  
 
Denmark:   
 Section 5.2, exclusion criteria #18 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 
 
Germany 
 Subject’s full Date of Birth is not allowed to be collected and must be shortened to year of birth 
 Section 1.2 Flowchart, section 5.2, exclusion criteria #18, Appendix 2 (Section 10.2) and 
Appendix 4 (Section 10.4): A monthly pregnancy test (urine) is required for all women of 
childbearing potential. 
 Section 8.3 and Appendix 3 (Section 10.3): All AEs, irrespective of seriousness, should be 
collected from the day of randomisation and until the follow-up visit/end of trial visit, at the 
time points specified in the flowchart.   
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Israel:  
 Section 8.7, 8.8 and Appendix 6 (Section 10.6): No subjects from Israel will participate in the 
optional biobank part of the trial, and no genetic testing will be performed as noted in 
sections 8.7 and 8.8. 
 
Poland:  
 Section 5.2, exclusion criteria #18 and Appendix 4 (Section 10.4): Contraceptive measures 
considered adequate include highly effective contraceptive methods in accordance with the 
Clinical Trial Facilitation Group: Recommendations related to contraception and pregnancy 
testing in clinical trials.  
 Novo Nordisk carries liability for the Trial exclusively in the scope defined by the applicable 
laws and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 2001 
(uniform version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to 
support potential claims for liability attributable to the Trial, Novo Nordisk and Investigator 
are covered by the Insurance Policy issued according to applicable Polish law. 
 
Spain: 
 Appendix 1 (Section 10.1): Retention of clinical trial documentation is 25 years according to 
the new Spanish Royal Decree 1090/2015 
 Section 5.2, exclusion criteria #18 and Appendix 4 (Section 10.4): Contraceptive measures 
considered adequate include highly effective contraceptive methods in accordance with the 
Clinical Trial Facilitation Group: Recommendations related to contraception and pregnancy 
testing in clinical trials.  
 
United Kingdom: 
 Section 5.2, exclusion criteria #18 and Appendix 4 (Section 10.4): Contraceptive measures 
considered adequate include highly effective contraceptive methods in accordance with the 
Clinical Trial Facilitation Group: Recommendations related to contraception and pregnancy 
testing in clinical trials.  
 Section 1.2 Flowchart, section 5.2, exclusion criteria #18, Appendix 2 (Section 10.2) and 
Appendix 4 (Section 10.4): A monthly pregnancy test (urine) is required for all women of 
childbearing potential.  
 
 
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10.8 
Appendix 8: Mitigations to ensure patient safety and data integrity during an 
emergency situation 
Definition and scope of appendix 
In case local restrictions, e.g. due to a COVID-19 outbreak, lead to lock-down of a site, the site 
must contact Novo Nordisk to allow for implementation of mitigations mentioned in this appendix 
based on mutual agreement. 
Table 10-3 indicates the minimum requirements for assessments that should be performed during a 
lock-down, but sites should always try to follow the assessments outlined in Section 1.2 (original 
flowchart) to the extent possible. Implementation of specific mitigations should be based on 
assessment of feasibility at the individual site. 
Sites should comply with local regulations, requirements and/or guidelines. 
Visits 
Screening (Visit 1) and randomisation/baseline (Visit 2) should always be performed as physical 
on-site visits. If a site is unable to perform these visits on-site, screening and randomisation of new 
participants at that site should be on hold until on-site visits are possible. Participants that cannot 
attend on-site visits 1 and 2 should not be included. 
Visits 7 and 11 should be performed as physical on-site visits, if in any way possible. If not, 
assessments can be conducted remotely using telemedicine or as home visits. The visit window for 
visit 11 can be extended for up to 4 weeks. If the assessments at visit 7 cannot be performed on-site, 
using telemedicine or home visits, the visit window can be extended for up to 8 weeks. 
Other on-site visits (Visits 3, 4, 5, 6, 8, 9 and 10) can be converted to telemedicine (video, phone or 
similar) or home visits. 
At each visit the investigator must indicate in the eCRF how the visit was performed and specify the 
reason for the preferred assessment method. 
Assessments 
Local laboratories or diagnostic facilities can be used at the investigator’s discretion if on-site visits 
are not possible or in case of temporary lockdown of the central laboratory. Only findings meeting 
the definition for an AE should be reported in the eCRF, refer to Section 10.1.12 for further details. 
If the assessments indicated in Table 10-3 cannot be performed as on-site visits, using telemedicine 
or at a local laboratory or diagnostic facility, they should be performed at the first possible time 
point following the originally scheduled visit. 
Assessments used for the primary and secondary endpoints at Visits 7 and 11 (weight, outcome 
assessments and lab samples) should be prioritised. In addition, all participants must have ECG 
performed at Visit 11 and all participants of the sub-study must have an echocardiography 
performed at Visit 11. Pregnancy tests can be shipped to the subject of childbearing potential if on-
site visits are not possible. The site is responsible for contracting a suitable courier and costs will be 
reimbursed by Novo Nordisk. It must be documented in medical records that the subject has 
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consented to this process, and, if required locally, the subject might have to sign a separate 
informed consent form. 
Study intervention 
Alternative dispensing methods may be implemented, and details will be communicated and 
documented. The dispensing options will be provided by Novo Nordisk A/S and will be based on 
options and requirements at country level and if permitted by local regulations. 
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Table 10-3 
Minimum assessments following randomisation to be performed during lockdown 
Please refer to Section 1.2 for the full flowchart.  
Procedures marked with a black X should be prioritised. If deemed necessary because of the lockdown, Visits 3, 4, 5, 6, 8, 9 and 10 can be fully converted to 
phone visits and procedures marked with a red X will subsequently be cancelled. 
 
Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
Informed consent and demographya (10.1.3) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria (5.1, 5.2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination (8.2.1) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Medical history/Concomitant illness (8.2.1), Tobacco useb  
 
X 
 
 
 
 
 
 
 
 
 
 
Childbearing potential (10.2, 10.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication (6.5) 
 
Xc 
X 
X 
X 
X 
Xc 
X 
Xc 
X 
Xc 
X 
Body weight (8.1.1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height / BMI (8.1.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
Waist circumference (8.1.1) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Status (PGI-S) for KCCQ (8.1.2) 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
Patient Global Impression of Change (PGI-C) for KCCQ (8.1.2) 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) (8.1.2) 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
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Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
European Quality of Life five Dimensions five Level (EQ-5D-5L) (8.1.2) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Status (PGI-S) for 6MWT (8.1.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Patient Global Impression of Change (PGI-C) for 6MWT (8.1.2) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Six-minute walk test (6MWT) (8.1.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
NYHA classification / Vital Signs (8.2.2, 8.2.4)  
X 
 
 
 
 
 
X 
 
 
 
X 
 
Electrocardiogram (ECG) (8.2.3) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Echocardiography (8.1.3) 
X 
Xd 
 
 
 
 
 
 
 
 
Xd 
 
Laboratory assessments (10.2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Semaglutide plasma concentration (10.2) 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test (only for women of childbearing potential)e (10.2) 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Healthy lifestyle counselling (5.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event and Events for adjudication (8.3, 10.3) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication error, Misuse and Abuse (8.3, 10.3.3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug dispensing (6) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Training in trial product, pen-handling (6.1) 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
Hand Out Directions for Use (6.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
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Screening 
Randomisation 
Maintenance period 
End of 
treatment 
End of trial 
Visit/Phone 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12 
Timing of Visit (Weeks) 
Up to - 2 
0 
4 
8 
12 
16 
20 
28 
36 
44 
52 
57 
Visit Window (Days) 
0 to +13 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
0 to +7 
Hand Out Dose Reminder Card 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Hand Out ID Card  
X 
 
 
 
 
 
 
 
 
 
 
 
Drug Accountability (6.2) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IWRS session 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a) Demography consists of date of birth, sex, race and ethnicity (according to local regulation – Germany: for country-specific requirements, please see Appendix 7 (Section 10.7)). 
b) Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
c) Dose to be collected for loop diuretics. 
d) Only relevant for subjects included in the echocardiographic sub-study. 
e) For women of childbearing potential only. In addition to the planned assessments, urine dipstick pregnancy test should be performed at any time during the trial if a menstrual period is 
missed, or if pregnancy is suspected. (according to local regulation – United Kingdom and Germany: for country-specific requirements, please see Appendix 7 (Section 10.7)). 
 
 
 
 
 
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10.9 
Appendix 9: Abbreviations  
6MWT 
six-minute walk test 
 
6MWD 
six-minute walking distance 
AE 
adverse event 
BMI 
body mass index  
BNP 
brain natriuretic peptide  
BW 
body weight 
CI 
confidence interval  
COVID-19 
Coronavirus disease 2019 
CRF 
case report form 
CRP 
C-Reactive Protein 
CTR 
clinical trial report 
DFU 
direction for use 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EAS 
event adjudication system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life five Dimensions five Level  
FAS 
full analysis set 
FDAAA 
U.S. Food and Drug Administration Amendments Act 
GCP 
Good Clinical Practice 
GLP-1 
glucose like peptide-1 
HbA1c 
haemoglobin A1c 
HF 
heart failure 
HFpEF 
heart failure with preserved ejection fraction 
HFrEF 
heart failure with reduced ejection fraction  
HRT 
hormone replacement therapy 
hsCRP 
high sensitivity C-Reactive Protein 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IV 
intravenous 
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IWRS 
interactive web response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
LA 
left atrial 
LVEDP 
left ventricular end diastolic pressure  
LV 
left ventricular  
LVEF 
left ventricular ejection fraction 
MTC 
medullary thyroid cancer 
NT-proBNP 
N-terminal pro-brain natriuretic peptide  
NYHA 
New York Heart Association  
PA 
pulmonary artery  
PCD 
primary completion date 
PGI-C 
Patient Global Impression of Change  
PGI-S 
Patient Global Impression of Status  
PK 
pharmacokinetic 
PRO 
patient reported outcome 
RA 
receptor agonist  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set  
s.c. 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
type 2 diabetes 
TMM 
trial materials manual 
UNL 
upper normal limit 
VAS 
visual analogue scale 
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 updated protocol is located 
directly before the Table of Contents. 
Protocol version 5.0 (12 February 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 Union1 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 change implemented in the amended protocol is to address comments 
received from the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). 
 
Section # and 
name 
Description of change 
Brief rationale 
Section 10.7: 
Appendix 7 
Country-specific 
Requirements 
Germany 
All AEs, irrespective of seriousness, should be 
collected from the day of randomisation and until 
the follow-up visit/end of trial visit, at the time 
points specified in the flowchart 
See overall 
Rationale 
 
Protocol version 4.0 (21 Jan 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1. 
 
Overall rationale for preparing protocol, version 4.0: 
The overall rationale for the changes implemented in the amended protocol is to account for 
collection of vital status and to include additional blood sampling for PK assessment following 
comments received from the Food and Drug Administration (FDA), US. Plasma semaglutide 
concentrations will be used to describe the exposure-response analysis. In addition, information 
regarding the COVID-19 pandemic was included and some administrative changes have been made. 
 
Section # and name 
Description of change 
Brief rationale 
Section 1.2 Flowchart 
 Correction of minor errors 
 Addition of “Semaglutide 
plasma concentration” row 
 Removal of “Barrier and 
motivation interview” row 
 Footnotes updates 
For clarification and to 
account for inclusion of 
PK samples 
Section 2 Introduction 
Correction of references 
For clarification 
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Section # and name 
Description of change 
Brief rationale 
Section 6.1.1 Medical Devices 
Removal of the sentence, “Subjects 
will have access to training pen-
injectors for cushion injection at the 
clinical site prior to treatment 
dosing.” 
For clarification 
Section 6.5 Concomitant 
medication 
 Addition of COVID-19 vaccine 
to list of medication  
 Addition of text regarding 
weight management drugs 
For inclusion of 
COVID-19 vaccine and 
for clarification 
regarding weight 
management drugs 
Section 7.1 Discontinuation of trial 
treatment 
Removal of text, “A treatment 
discontinuation session must be 
made in IWRS.” 
For clarification 
Section 7.1.1 Temporary 
discontinuation of trial treatment 
 Removal of text, “In such cases 
a treatment discontinuation 
session should not be made in 
the IWRS.” 
 Replacement of text, “however 
treatment discontinuation 
session should not be made in 
IWRS” 
 Replacement of text “If acute 
pancreatitis is confirmed, 
treatment with trial product 
should not be restarted, and a 
treatment discontinuation 
session should be made in 
IWRS.”  
For clarification 
Section 7.2 Subject 
discontinuation/withdrawal from 
the trial 
 Replacement of text, “If acute 
pancreatitis is confirmed, 
treatment with trial product 
should not be restarted, and a 
treatment discontinuation 
session should be made in 
IWRS.” 
 Addition of text regarding vital 
status 
For clarification and to 
account for collection of 
vital status 
Section 7.3 Lost to follow-up 
Addition of text 
To account for 
collection of vital status 
Section 8 Trial assessments and 
procedures 
Removal of bullet point regarding 
barriers and motivation interview 
For clarification 
Section 8.3 Adverse events and 
serious adverse events 
Addition of text 
To include information 
regarding COVID-19 
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Section # and name 
Description of change 
Brief rationale 
Section 8.5 Pharmacokinetics 
Addition of section 
To account for inclusion 
of PK samples 
Section 9.4.4.1 Pharmacokinetic 
and/or pharmacodynamic 
modelling 
Addition of section 
To account for inclusion 
of PK samples 
Section 10.1.12 Responsibilities 
Addition of text 
To align with changes in 
the protocol template 
Section 10.2 Appendix 2, Table 
10-1 
 Addition of text describing 
disclosure of results 
 Addition of PK sampling to 
efficacy laboratory assessments 
For clarification 
regarding the blinding 
plan, and to comply 
with additions to 
Sections 8.5 and 9.4.4.1 
Section 10.5 Appendix 5 
Removal of Section 10.5.3 
Reporting of technical complaints  
For clarification 
Section 10.8 Appendix 8 
Addition of section to address 
mitigations to ensure participant 
safety and integrity during an 
emergency situation 
To include information 
regarding COVID-19 
conduct 
Section 10.9 Appendix 9 
Addition of COVID-19 and PK  
For clarification 
 
Protocol version 3.0 (07 January 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 Union1 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 3: 
The overall rationale for the change implemented in the amended protocol is to address comments 
received from the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). 
 
Section # and 
name 
Description of change 
Brief rationale 
Section 10.7: 
Appendix 7 
Country-specific 
Requirements 
Germany 
A monthly pregnancy test is mandatory for female 
subjects of childbearing potential 
See overall 
rationale 
 
Protocol version 2.0 (05 January 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
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Directive 2001/20/EC of the European Parliament and the Council of the European Union1 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 2: 
The overall rationale for the changes implemented in the amended protocol is to address comments 
received from the Medicines & Healthcare products Regulatory Agency (MHRA). 
 
Section # and 
name 
Description of change 
Brief rationale 
Section 10.7: 
Appendix 7 
Country-specific 
Requirements 
United Kingdom 
A monthly pregnancy test is mandatory for female 
subjects of childbearing potential 
See overall 
rationale 
 
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9.1.1
Protocol Attachment
Protocol Attachment I is located in the Trial Master File.
If applicable, Protocol Attachment II is also located in the Trial Master File.
Content: Global key staff and Country key staff.
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Study ID: EX9536-4665
Clinical Study Report
Appendix 9.1.1
21 June 2023
1.0
Final
CONFIDENTIAL

SAP_003.pdf: 
C o ver P a ge  f or St atistic al A n al ysis Pl a n  
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 4 7 8 8 5 1 1
S p o ns or t rial I D: 
E X 9 5 3 6- 4 6 6 5
Official title of st u d y:  
Effect of se ma gl uti de s.c. 2. 4 m g o nce wee kl y o n f u ncti o n a n d 
s y m pt o ms i n s u bjects wit h o besit y-relate d heart fail ure wit h 
preser ve d ejecti o n fracti o n
D oc u me nt date *  
0 1 Dece m ber 2 0 2 2
* D oc u me nt date refers t o t he date o n w hic h t he d oc u me nt was m ost rece ntl y u p date d.


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1  of 3 8  
 
C O N FI D E N TI A L
E X 9 5 3 6- 4 6 6 5 
St atistic al A n al ysis Pl a n 
Effec t o f se m a gl uti de s. c. 2. 4 m g o n ce w ee kl y o n f u ncti o n a n d 
s y m pt o ms i n s u bjects w it h o besit y-rel a te d h e a rt f ail ure wit h preser ve d 
ejecti o n fr acti o n
Re d acte d st atistic al a n alysis pl a n
incl u des re d acti o n of  c o m p a ny 
c o nfi de n ti al inf or m ati o n. 
. 
Bi ostatistics, G L P- 1 & C V 1 


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2  of 3 8  
 
Ta ble of c o nte nts 
P a ge  
T a ble of c o nte nts ............................................................................................................................................... 2
Versi o n hist or y  .................................................................................................................................................. 3
1  I ntr o d ucti o n ................................................................................................................................................. 5
1. 1  
O bjecti ves a n d e n d p oi nts  .................................................................................................................... 6
1. 1. 1  
Pri mar y o bj ecti ve a n d esti ma n ds  ......................................................................................... 6
1. 1. 2  
Sec o n dar y o bj ecti ves a n d esti ma n ds  ................................................................................... 8
1. 1. 3  
E x pl orat or y o bj ecti ve  ........................................................................................................ 1 0
1. 2  
Trial desi g n  ....................................................................................................................................... 1 1
2  St atistic al h y p ot heses  ................................................................................................................................ 1 2
3  S a m ple size deter mi n ati o n  ........................................................................................................................ 1 4
4  A n al ysis sets  ............................................................................................................................................... 1 5
5  St atistic al a n al yses  ..................................................................................................................................... 1 6
5. 1  
Ge neral c o nsi derati o ns  ...................................................................................................................... 1 6
5. 2  
S u bj ect dis p ositi o n  ............................................................................................................................ 1 7
5. 3  
Pri mar y e n d p oi nts a nal yses  ............................................................................................................... 1 7
5. 3. 1
Defi niti o n of e n d p oi nts  ...................................................................................................... 1 7
5. 3. 2
Mai n a nal ytical a p pr oac h ................................................................................................... 1 7
5. 3. 2. 1  
Pri mar y esti ma n d  ........................................................................................... 1 7
5. 3. 2. 2  
Sec o n dar y esti ma n d  ....................................................................................... 2 0
5. 3. 3
Se nsiti vit y a nal yses  ........................................................................................................... 2 0
5. 3. 4
S u p ple me ntar y a nal yses  .................................................................................................... 2 1
5. 4  
Sec o n dar y e n d p oi nts a nal yses  ........................................................................................................... 2 1
5. 4. 1
C o nfir mat or y sec o n dar y e n d p oi nts  .................................................................................... 2 1
5. 4. 1. 1  
Defi niti o n of e n d p oi nts  .................................................................................. 2 1
5. 4. 1. 2  
Mai n a nal ytical a p pr oac h  ............................................................................... 2 2
5. 4. 1. 3  
Se nsiti vit y a nal ysis  ......................................................................................... 2 3
5. 4. 1. 4  
S u p ple me ntar y a nal yses  ................................................................................. 2 3
5. 4. 2  
S u p p orti ve sec o n dar y e n d p oi nts  ........................................................................................ 2 3
5. 4. 2. 1
Cli nicall y mea ni n gf ul wit hi n -s u bj ect c ha n ge e n d p oi nts ................................ 2 4
5. 5
E x pl orat or y e n d p oi nts a nal ysis  ......................................................................................................... 2 5
5. 6
Safet y a nal yses  .................................................................................................................................. 2 6
5. 7
Ot her a nal yses  ................................................................................................................................... 2 6
5. 7. 1  
S u b g r o u p a nal yses ............................................................................................................. 2 7
5. 7. 2  
P har mac o ki netic m o delli n g  ............................................................................................... 2 7
5. 8
I nteri m a nal yses ................................................................................................................................ 2 7
5. 8. 1  
Da ta m o nit ori n g c o m mittee ............................................................................................... 2 7
6  S u p p orti n g d oc u me nt ati o n  ....................................................................................................................... 2 8
6. 1
A p pe n di x 1: List of a b bre viati o ns  ..................................................................................................... 2 8
6. 2
A p pe n di x 2: C ha n ges t o pr ot oc ol -pla n ne d a nal yses  ......................................................................... 3 0
6. 3
A p pe n di x 3: Defi niti o n a n d calc ulati o n of e n d p oi nts, assess me nts a n d deri vati o ns  ........................ 3 0
6. 4
A p pe n di x 4: Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire a n d sc ori n g  ............................................ 3 3
7  Ref ere nces  .................................................................................................................................................. 3 8
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3  of 3 8  
 
Versi o n hist or y  
T his Statistical A nal ysis Pla n ( S A P) f or trial E X 9 5 3 6-4 6 6 5 is base d o n t he pr ot oc ol versi o n 6 . 0 
date d 9 t h of Se pte m ber  2 0 2 2 .  
T a ble  1 -1  
S A P V ersi o n Hi st or y S u m m a r y 
S A P 
Versi o n  
A p pr o v al 
D ate  
C h a n ge  
R ati o n ale  
1. 0  
See a p pr o val 
date i n t he 
electr o nic 
d oc u me nt 
ma na ge me nt 
s yste m 
N ot A p plica ble  
Ne w d oc u me nt  
2 . 0 
See a p pr o val 
date i n t he 
electr o nic 
d oc u me nt 
ma na ge me nt 
s yste m 
A d de d details o n 
t he classificati o n 
of e ve nts of d eat h 
i n secti o n 5. 1 a n d 
p har mac o ki netic 
m o delli n g  i n 
secti o n 5. 7. 3 . 
T he S A P is u p date d t o reflect c ha n ges i n t he 
pr ot oc ol . 
3. 0  
See a p pr o val 
date i n t he 
electr o nic 
d oc u me nt 
ma na ge me nt 
s yste m 
A d de d pre vi o us 
heart fail ure 
e ve nts as 
i nterc urre nt 
e ve nts i n t he 
statistical 
a nal ys es.    
U p date d d ue t o f ee d-b ac k fr o m  re g ulat or y 
a ut h orities  a d dressi n g heart fail ure e ve nts  ( ur ge nt 
visit  or h os pitalisati o ns)  a d de d as i nterc urre nt 
e ve nts.  
4. 0  
See a p pr o val 
date i n t he 
electr o nic 
d oc u me nt 
ma na ge me nt 
s yste m 
A d de d t he 
hierarc hical 
c o m p osite 
c o nfir mat or y 
e n d p oi nt  a n d 
c ha n ge d 
s u p ple me ntar y 
a nal ysis . M ore 
details pr o vi de d 
f or a nc h or base d 
s u p p orti ve 
sec o n dar y 
e n d p oi nts. U p date 
t o i m p utati o n 
m o del f or 
i nterc urre nt e ve nt. 
T he S A P is u p date d t o reflect c ha n ges i n t he 
pr ot oc ol  i n re gar ds t o t he i ncl usi o n of t he 
hierarc hical c o m p osite e n d p oi nt a n d t o a d dress 
t he u p date d s u p ple me ntar y a nal ysis.  Als o ne w 
e x pl orat or y e n d p oi nt s wit h a c ha n ge s c ore  of 1 5  
f or K C C Q are a d de d. 
M ore details  a n d e x pla nati o n te xt are a d de d f or 
t he t hres h ol ds base d o n P GIs i n t he s u p p orti ve 
sec o n dar y e n d p oi nts secti o n 5. 4. 2 . F urt her m ore, 
t he e n d p oi nts defi ne d b y t hese t hres h ol ds are 
a d de d i n m ore det ail i n t he e n d p oi nt ta bles . 
F urt her m ore, t here has b ee n a n u p d ate t o t he 
i m p utati o n m o del f or i nterc urre nt e ve nts w here 
ti mi n g of last a vaila ble o bser vati o n d uri n g t he o n-
treat me nt peri o d ( L A O-O T) n o w is a c o v ariate i n 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
4  of 3 8  
 
t he im p utati o n m o del i nstea d of a fact or.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
5  of 3 8  
 
1  I ntr o d ucti o n 
T his Statistical A nal ysis Pla n ( S A P) descri bes i n detail t he a nal yses of effi cac y , ot her e n d p oi nts a n d 
assess me nts i n trial E X 9 5 3 6 -4 6 6 5 . E n d p oi nts a n d assess me nts i n t he trial are liste d i n A p pe n di x 
6. 3 . 
S pecificati o ns of ta bles, fi g ures a n d listi n gs ( T F L) a n d ot her s pecificati o ns n ot i ncl u de d i n t his S A P 
will be descri be d i n t he m oc k T F L.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Date:  
1 Dece m ber 2 0 2 2  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
V ersi o n:  
4. 0  
P a ge:  
6  of 3 8  
 
1. 1  
O bjecti ves a n d e n d p oi nts  
T he o bjecti ves a n d esti ma n ds i n t he trial are d escri be d bel o w.  
1. 1. 1  
Pri m ar y o bjecti ve a n d esti m a n ds  
T he pri mar y o bje cti ve is t o i n vesti gate t he effects of se ma gl uti de s.c.  2. 4 m g o nce -wee kl y  o n p h ysic al f u ncti o n, s y m pt o ms a n d b o d y wei g ht c o m pare d wit h 
place b o, b ot h a d d e d t o sta n dar d of care, i n s u bjects wit h  o besit y -relate d H F p E F.  
T he pri mar y a n d s ec o n d a r y esti ma n ds f or t he pri m ar y o bjecti ve are liste d i n Ta ble  1 -1 . 
T a ble  1 -1  
Pri m ar y a n d sec o n d ar y e sti m a n ds f or t he pri m ar y o bjecti v e 
O bjecti ve  
Esti m a n d 
c ate g or y 
Esti m a n d  attri b utes  
 
Tre at me nt 
c o n diti o n  
P o p ul ati o n 
of i nterest  
V ari a ble/ E n d p oi nt  
I nterc urre nt e ve nt str ate g y 
P o p ul ati o n -
Le v el 
S u m m ar y 
M e as ure  
T o i n vesti gate 
t he effects of 
se ma gl uti de 
s.c. 2. 4 m g 
o nce -
wee kl y  o n 
p h ysical 
f u ncti o n, 
s y m pt o ms a n d 
b o d y wei g ht 
c o m pare d 
wit h place b o, 
b ot h a d de d t o 
sta n dar d of 
care, i n 
s u bj ects 
wit h  o besit y -
relate d H F p E F  
Pri m ar y  
Se ma gl uti de 
2. 4 m g or 
place b o,  
b ot h a d de d t o 
sta n dar d-of -
care , re gar dless 
of a d here nce t o 
ra n d o mise d 
treat me nt a n d 
i nitiati o n of 
ot her a nti -
o besit y 
t hera pies 
 
All 
ra n d o mise d 
C ha n ge i n K C C Q 
cli nical s u m mar y 
sc ore fr o m baseli ne 
( wee k 0) t o e n d of 
treat me nt ( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: Data c ollecte d after i nterc urre nt e ve nts use d 
i n a nal ysis (treat me nt p olic y) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or bariatric s ur ger y: Data 
c ollecte d after i nterc urre nt e ve nts use d i n a nal ysis (treat me nt p olic y)  
 
E ve nts of C V -deat h (a) a n d  pre vi o us heart fail ure e ve nt (a) (if data  are n ot 
c ollecte d ): Will be i nc or p orate d i nt o t he K C C Q cli nical s u m mar y sc ore b y 
ascri bi n g t he o utc o me a n u nfa v o ura ble val ue (c o m p osite)   
Mea n 
differe nce of 
se ma gl uti de 
2. 4 m g vers us 
place b o  
C ha n ge i n b o d y 
wei g ht fr o m 
baseli ne ( wee k 0) t o 
e n d of treat me nt 
( wee k 5 2)  
 
D isc o nti n uati o n of trial treat me nt: Data c ollecte d after i nterc urre nt e ve nts use d 
i n a nal ysis (treat me nt p olic y) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or bariatric s ur ger y: Data 
c ollecte d after i nterc urre nt e ve nts use d i n a nal ysis (treat me nt p olic y)  
Mea n 
differe nce of 
se ma gl uti de 
2. 4 m g vers us 
place b o  
Sec o n d ar y  
( b) 
Se ma gl uti de 
2. 4 m g or 
place b o,  
b ot h a d de d t o 
sta n dar d-of -
care , ha d all 
All 
ra n d o mised  
C ha n ge i n K C C Q 
cli nical s u m mar y 
sc ore fr o m baseli ne 
( wee k 0) t o e n d of 
treat me nt ( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: “ ha d s u bj ects a d here d t o treat me nt” 
( h y p ot hetical) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or bariatric s ur ger y: “ ha d t he 
s u bj ect n ot i nitiate d wei g ht ma na ge me nt dr u gs or bariatric s ur ger y” 
( h y p ot hetical) 
 
E ve n ts of deat h: “ Ha d t he s u bj ect n ot die d” ( h y p ot hetical)  
Mea n 
differ e nce of 
se ma gl uti de 
2. 4 m g vers us 
place b o  


Statistical A nal ysis Pla n  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Date:  
1 Dece m ber 2 0 2 2  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
V ersi o n:  
4. 0  
P a ge:  
7  of 3 8  
 
s u bj ects 
a d here d t o 
ra n d o mise d 
treat me nt a n d 
n ot i nitiate d 
ot her a nti -
o besit y 
t hera pies   
C ha n ge i n b o d y 
wei g ht fr o m 
baseli ne ( wee k 0) t o 
e n d of treat me nt 
( wee k 5 2)  
 
D isc o nti n uati o n of trial treat me nt: “ ha d s u bj ects a d here d t o treat me nt” 
( h y p ot hetical) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or bariatric s ur ger y: “ ha d t he 
s u bj ect n ot i nitiate d wei g ht ma na ge me nt dr u gs or bariatric s ur ger y” 
( h y p ot hetical) 
 
E ve nts of deat h: “ Ha d t he s u bj ect n ot die d” ( h y p ot hetical)  
Mea n 
differe nce of 
se ma gl uti de 
2. 4 m g vers us 
place b o  
(a) As deter mi ne d b y t he e ve nt a dj u dicati o n c o m mittee : h eart fail ure is eit her heart fail ure h os pitalizati o n or ur ge nt heart fail ure visit.   
( b) N ot relate d t o a n y c o nfir mat or y h y p ot hesis


Statistical A nal ysis Pla n  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Date:  
1 Dece m ber 2 0 2 2  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
V ersi o n:  
4. 0  
P a ge:  
8  of 3 8  
 
1. 1. 2  
Sec o n d ar y o bjecti ves a n d esti m a n ds  
T he sec o n d ar y o bjecti ve is t o i n vesti gate t he effects of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y o n wal ki n g dista nce , bi o mar ker of i nfla m mati o n,  b o d y 
c o m p ositi o n , disease s pecific as pects, s ocial li mitati o n, a n d healt h-relate d q ualit y of life c o m pare d wit h place b o, b ot h  a d de d t o sta n dar d of care, i n s u bjects 
wit h  o besit y -relate d H F p E F.  
T o i n vesti gate t h e effects of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y i n i m pr o vi n g t he o verall cli nical be nefit c o m pare d wit h pl ace b o, b ot h a d de d t o sta n dar d of 
care, i n s u bje cts wit h o besit y -rel ate d H F p E F. 
T he esti ma n ds f or t he s ec o n dar y o bjecti ve are liste d i n  Ta ble  1 -2 . 
T a ble  1 -2  
E sti m a n ds f or t he sec o n d ar y o bjecti ve  
O bjecti ve  
Esti m a n d 
c ate g or y 
Esti m a n d  attri b utes  
Tre at me nt 
c o n diti o n  
P o p ul ati o n 
of i nterest  
V ari a ble/ E n d p oi nt  
I nterc urre nt e v e nt str ate g y 
P o p ul ati o n -Le v el 
S u m m ar y 
M e as ure  
Sec o n d ar y 
o bjecti ve:  
T o i n vesti gate 
t he effects of 
se ma gl uti de s.c. 
2. 4 m g o nce -
wee kl y o n 
wal ki n g 
dista nce, 
bi o mar ker of 
i nfla m mati o n, 
b o d y 
Pri m ar y  
Se ma gl uti de 
2. 4 m g or 
place b o,  
b ot h a d de d t o 
sta n dar d-of -
care , 
re gar dless of 
a d here nce t o 
ra n d o mise d 
treat me nt a n d 
i nitiati o n of 
ot her a nti -
All 
ra n d o mise d 
 
C ha n ge i n si x-mi n ute wal ki n g dista nce  
fr o m baseli ne ( wee k 0) t o e n d of treat me nt 
( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: Data 
c ollecte d after i nterc urre nt e ve nts use d i n 
a nal ysis (treat me nt p olic y)  
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or 
bariatric s ur ger y: Data c o llect e d after 
i nterc urre nt e ve nts use d i n a nal ysis (treat me nt 
p olic y)  
 
E ve nts of C V -deat h (a) a n d pre vi o us heart fail ure 
e ve nt (a)  (if data are n ot c ollecte d):  Will be 
i nc or p orate d i nt o t he si x-mi n ute wal ki n g 
dista nce b y ascri bi n g t he o utc o me a n 
u nfa v o ura ble  val ue (c o m p osit e)  
Mea n differe nce 
of se ma gl uti de 
2. 4  m g vers us 
place b o  


Statistical A nal ysis Pla n  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Date:  
1 Dece m ber 2 0 2 2  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
V ersi o n:  
4. 0  
P a ge:  
9  of 3 8  
 
c o m p ositi o n, 
disease s pecific 
as pects, s ocial 
li mitati o n, a n d 
healt h -relate d 
q ualit y of life 
c o m pare d wit h 
place b o, b ot h 
a d de d t o 
sta n dard of care, 
i n s u bj ects wit h 
o besit y -relate d 
H F p E F  
o besit y 
t hera pies 
Hierarc hical c o m p osite of: 1 
Ti me t o all -ca use deat h,  
N u m ber of heart fail ure e ve nts re q uiri n g 
h os pitalisati o n or ur ge nt heart fail ure visit,  
Ti me t o first heart fail ure e ve nt re q uiri n g 
h os pitalisati o n or ur ge nt heart fail ure visit,  
Differe nce at least 1 5 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 1 0 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 5 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 3 0 metres i n si x -mi n ute 
wal ki n g dista nce c ha n ge fr o m baseli ne t o 
5 2 wee ks (assesse d b y t he wi n rati o)  
 
D isc o nti n uati o n of trial treat me nt: Data 
c ollecte d after i nterc urre nt e ve nts use d i n 
a nal ysis (treat me nt p olic y)  
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or 
bariatric s ur ger y: Data c ollect e d after 
i nterc urre nt e ve nts use d i n a nal ysis (treat me nt 
p olic y)  
 
T otal wi ns f or  
eac h treat me nt 
gr o u p  
C ha n ge i n C -Reacti ve Pr otei n fr o m 
baseli ne ( wee k -2) t o e n d of treat me nt 
( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: Data 
c ollecte d after i nterc urre nt e ve nts use d i n 
a nal ysis (treat me nt p olic y)  
 
I nitiati o n of ot her wei g ht ma na geme nt dr u gs or 
bariatric s ur ger y: Data c ollect e d after 
i nterc urre nt e ve nts use d i n a nal ysis (treat me nt 
p olic y)  
Ge o metric mea n 
rati o of 
se ma gl uti de 
2. 4  m g vs place b o  
Sec o n d ar y  
( b) 
Se ma gl uti de 
2. 4 m g or 
place b o,  
b ot h a d de d t o 
sta n dar d-of -
care , ha d all 
s u bj ects 
a d here d t o 
All 
ra n d o mise d 
C ha n ge i n si x-mi n ute wal ki n g dista nce  
fr o m baseli ne ( wee k 0) t o e n d of treat me nt 
( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: “ ha d 
s u bj ects ad here d t o treat me nt” ( h y p ot hetical)  
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or 
bariatric s ur ger y: “ ha d t he s u bj ect n ot i nitiate d 
wei g ht ma na ge me nt dr u gs or bariatric s ur ger y” 
( h y p ot hetical) 
 
E ve nts of deat h: “ Ha d t he s u bj ect n ot die d” 
( h y p ot hetical)  
Mea n differe nce 
of se ma gl uti de 
2. 4  m g vers us 
place b o  
                                                 
1 N ote t hat t he differe nt t hres h ol ds of K C C Q -C S S d o n ot c ha n ge t he o verall res ult of t he wi n rati o, b ut it i ncl u de d t o differe ntiate t he i n di vi d ual le vels  


Statistical A nal ysis Pla n  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Date:  
1 Dece m ber 2 0 2 2  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
V ersi o n:  
4. 0  
P a ge:  
1 0  of 3 8  
 
ra n d o mise d 
treat me nt a n d 
n ot i nitiate d 
ot her a nti -
o besit y 
t hera pies  
Hierarc hical c o m p osite of:  
Ti me t o all -ca use deat h,  
N u m ber of heart fail ure e ve nts re q uiri n g 
h os pitalisati o n or ur ge nt heart fail ure visit,  
Ti me t o first heart fail ure e ve nt re q uiri n g 
h os pitalisati o n or ur ge nt heart fail ure visit,  
Differe nce at least 1 5 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 1 0 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 5 i n K C C Q cli nical 
s u m mar y sc ore c ha n ge fr o m b aseli ne t o 5 2 
wee ks,  
Differe nce at least 3 0 metres i n si x -mi n ute 
wal ki n g dista nce c ha n ge fr o m baseli ne t o 
5 2 wee ks (assesse d b y t he wi n rati o)  
 
D isc o nti n uati o n of trial treat me nt: “ ha d 
s u bj ects a d here d t o treat me nt” ( h y p ot hetical) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or 
bariatric s ur ger y: “ ha d t he s u bj ect n ot i nitiate d 
wei g ht ma na ge me nt dr u gs or bariatric s ur ger y” 
( h y p ot hetical) 
 
T otal wi ns f or 
eac h treat me nt 
gr o u p  
C ha n ge i n C -Reacti ve Pr otei n fr o m 
baseli ne ( wee k -2) t o e n d of treat me nt 
( wee k 5 2) 
 
D isc o nti n uati o n of trial treat me nt: “ ha d 
s u bj ects a d here d t o treat me nt” ( h y p ot hetical) 
 
I nitiati o n of ot her wei g ht ma na ge me nt dr u gs or 
bariatric s ur ger y: “ ha d t he s u bj ect n ot i nitiate d 
wei g ht ma na ge me nt dr u gs or bariatric s ur ger y” 
( h y p ot hetical) 
 
E ve nts of deat h: “ Ha d t he s u bj ect n ot die d ” 
( h y p ot hetical)  
Ge o metric mea n 
rati o of 
se ma gl uti de 
2. 4  m g vs place b o  
(a) As deter mi ne d b y t he e ve nt a dj u dicati o n c o m mittee : heart fail ure is eit her heart fail ure h os pitalizati o n or ur ge nt  heart fail ure visit.    
( b) N ot relate d t o a n y c o nfir mat or y h y p ot hesis  
1. 1. 3  
E x pl or at or y o bjecti ve  
T he e x pl orat or y o bj ecti v e is t o i n vesti gate t he effects of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y vers us place b o, b ot h a d de d t o sta n dar d of care, i n s u bjects wit h 
o besit y -relate d H F p E F re gar di n g:  
 Heart fail ure o utc o mes  
 C ha n ge i n me di cati o ns  
 C ha n ge i n  bi o mar kers of m y ocar dial strai n   
 Ec h ocar di o gra p hic p ara meters of heart fail ure (i n a s u bset of s u bjects)   


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 1  of 3 8  
 
1. 2  
Tri al desi g n  
T his is a 5 2 -wee k, ra n d o mise d, place b o -c o ntr olle d, d o u ble bli n d, m ulti -ce ntre cli nical trial 
c o m pari n g se ma gl uti de s.c. 2. 4 m g wit h place b o i n s u bjects wit h o besit y -relate d heart fail ure wit h 
preser ve d eje cti o n fracti o n.  
Eli gi ble s u bjects will be ra n d o mis e d i n a 1: 1 ma n ner t o recei ve eit her se ma gl uti de s.c. 2. 4 m g or 
place b o o nce wee kl y as a d d -o n t o sta n dar d of care (Fi g ure  1 ). 
T he trial i ncl u des a s cre e ni n g visit t o assess t he s u bject’s eli gi bilit y f oll o we d b y a ra n d o misati o n 
visit. A peri o d of 1 6 wee ks of d ose escalati o n is pla n ne d t o mi ni mise gastr oi ntesti nal a d verse e v e nts 
wit h a d ose i ncrease e v er y 4 t h wee k . Hereafter a visit will ta ke place e ver y 8t h wee k u ntil e n d of 
treat me nt ( wee k 5 2). F oll o w u p peri o d is 5 wee ks after e n d of treat me nt.  
A s u bset of 2 4 0 ra n d o mise d s u bjects will u n der g o ec h ocar di o gra p h y assess me nt at ra n d o misati o n t o 
e ns ure at least 1 8 0 s u bjects u n der g oi n g ec h ocar di o gra p h y at t he e n d of treat me nt.   
Ra n d o misati o n will be stratifie d b y B MI i nt o t w o s u b gr o u ps ( B MI < 3 5. 0  k g/ m 2 a n d B MI ≥3 5. 0  
k g/ m 2). 
Fi g ure  1  
A sc he m atic di a gr a m of t he tri al desi g n  
 
 
 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 2  of 3 8  
 
2  St atistic al h y p ot heses  
F or t he pri mar y e n d p oi nts, c ha n ge fr o m baseli ne i n t he K C C Q cli nical s u m mar y s c ore ( C S S) a n d 
c ha n ge fr o m baseli ne i n b o d y w ei g ht,  the f oll o wi n g co nfir mat or y o ne -si de d h y p ot hes es are pla n ne d 
t o be teste d. Let μ se ma gl uti de a n d μ place b o de n ote t he tr ue mea n of c ha n ge fr o m baseli ne f or s e ma gl uti de 
2. 4  m g a n d pla ce b o gr o u p, res pecti vel y . 
 S u peri orit y  of s e ma gl uti de 2. 4 m g v ers us place b o i n  c ha n ge i n K C C Q-C S S fr o m baseli ne 
( wee k 0) t o e n d of tr eat m e nt ( wee k 5 2) will be test e d as : 
𝐻: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒≤𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 vs
𝐻𝐴:𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒> 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 
 
 S u peri orit y  of s e ma gl uti de 2. 4 m g v ers us place b o i n  c ha n ge i n b o d y wei g ht  fr o m baseli ne 
( wee k 0) t o e n d of tr eat me nt ( wee k 5 2)  will be test e d as : 
𝐻: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒≥𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 vs
𝐻𝐴:𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒< 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 
 
O perati o nall y t he h y p ot h eses will be e val u ate d b y t w o -si de d tests. 
 
T he h y p ot h ese s f or t he c o nfir mat or y sec o n d ar y e n d p oi nt, c ha n ge i n si x-mi n ute wal ki n g dista n ce 
(6 M W D)  fr o m baseli ne ( wee k 0) t o e n d of treat me nt ( wee k 5 2) , are t he sa me as f or K C C Q-C S S. 
Si milarl y, t he h y p ot h eses f or t he c o nfir mat or y sec o n dar y e n d p oi nt, rati o t o baseli ne ( wee k -2) at  
e n d of treat m e nt ( wee k 5 2)  i n C -Reacti ve Pr otei n ( C R P) are t he sa me as f or b o d y wei g ht. 
 
T he hierarc hic al e n d p oi nt  is a c o m p osite of deat h, n u m ber of heart fail ure  e ve nts, ti me t o first heart 
fail ure e v e nt, a differe n ce of at least 1 5, 1 0 a n d 5  sc ores i n K C C Q-C S S c ha n ge fr o m b aseli ne  t o 
wee k 5 2  a n d a differe n ce of at least 3 0 metres i n 6 M W D  c ha n ge fr o m b aseli ne t o 5 2 wee ks  (Fi g ure 
2 ). T his will be assesse d usi n g a wi n rati o a p pr oac h. All patie nts ra n d o mise d t o se ma gl uti de  2. 4 m g  
are c o m p are d t o all patie nt ra n d o mise d t o place b o wit hi n eac h strat u m.   
T he stratifie d wi n rati o is calc ulate d as t he t otal n u m ber of wi n s i n t he se ma gl uti de 2. 4 m g gr o u p 
acr oss all strata di vi de d b y t he t otal n u m ber of l osses . A val ue a b o ve o ne i n dicates a fa v o ura bl e 
o utc o me f or se ma gl uti de 2. 4 m g as c o m pare d t o pl ace b o. F or mall y, we c o nsi der t he f oll o wi n g 
h y p ot hesis testi n g f or t he wi n ra ti o statistic: 
𝐻:𝑊𝑅
≤1  
𝐻𝐴:𝑊𝑅
> 1  
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 3  of 3 8  
 
Fi g ure 2  T he c o m p osit e hier arc hic al e n d p oi nt  
 
M ulti plicit y a dj ust me nt  
T he tests of s u peri orit y of se ma gl uti de s.c. 2. 4 m g o nce wee kl y vers us place b o f or t he pri mar y a n d 
c o nfir mat or y sec o n dar y e n d p oi nts are perf or me d usi n g a gra p hical testi n g s yste m ( Fi g ure 3 ) t hat 
preser ves t he o verall st u d y -wis e t y p e I err or of 5 %.  
 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 4  of 3 8  
 
 
 
 
 
 
 
 
 
 
 
K C C Q -C S S: Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire; C R P: C -Reacti ve Pr otei n; 6 M W D: si x -mi n ute wal ki n g 
dista nce. Hierarc hical c o m p osite e n d p oi nt as defi ne d i n Secti o n 1. 1. 2 . 
First, t he m ulti ple pri mar y e n d p oi nts are teste d, w here f or t hese t w o e n d p oi nts t he al p ha is s plit i n 
1 % f or w ei g ht c ha n ge a n d 4 % f or c h a n ge i n K C C Q -C S S. T he tests f or t he m ulti ple e n d p oi nt will 
f oll o w t he wei g hte d H ol m-B o nferr o ni  pr oce d ure 6 ( wit h wei g ht o ne) s uc h t hat if o ne of t he t w o 
e n d p oi nts i s s u peri or t he n t he f ull al p ha ca n b e rec ycle d f or t he ot her e n d p oi nt a n d he nce t he 
re mai ni n g pri mar y e n d p oi nt will be teste d at t he 5 % si g nifica nce l e vel (t w o-si de d). 
If b ot h h y p ot h eses are rejecte d a n d s u p eri orit y is c o nfir me d f or b ot h pri mar y e n d p oi nts, t he n t he 
c o nfir mat or y sec o n dar y e n d p oi nts will be teste d acc or di n g t o t he fl o w a n d wei g hts as s p ecifie d i n 
Fi g ure 3 . T h e 5 % al p ha will be 5 0/ 5 0 s plit bet wee n 6 M W D a n d t he hierarc hical c o m p osite 
e n d p oi nt, suc h  t hat t he hierarc hical c o m p osite e n d p oi nt will be teste d at 2. 5 % si g nifica nce l e vel, 
a n d if s u peri orit y is c o nfir me d, t he 6 M W D will be teste d at 3. 7 5 % si g nifica nce le vel. If s u peri orit y 
is n ot c o nfir me d f or t he hierarc hical c o m p osite e n d p oi nt, t he 6 M W D will be teste d at 2. 5 % 
si g nifica n ce le v el. If s u p eri orit y is c o nfir me d f or b ot h 6 M W D a n d t he hierarc hical c o m p osite 
e n d p oi nt, C R P will be teste d at 5 % si g nifi ca nce le v el, b ut o nl y if 6 M W D is c o nfir me d C R P will be 
teste d at 2. 5 % si g nifica n ce le vel, or if o nl y t h e hierarc hical c o m p osite e n d p oi nt is c o nfir me d, C R P 
will be teste d at 1. 2 5 % si g nifica nce l e vel.  
 
3  
S a m ple size deter mi n ati o n  
See pr ot oc ol Secti o n 9. 2.  
 
Fi g ure 3   
Tests of s u peri orit y of se m a gl uti de s.c. 2. 4 m g o nce wee kl y vers us pl ace b o f or t he 
pri m ar y  a n d c o nfir m at or y sec o n d ar y e n d p oi nts  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 5  of 3 8  
 
4  
A n al ysis set s 
T he f oll o wi n g p o p ul ati o n s are defi ne d : 
 
 
T hree o bser vati o n peri o ds are defi ne d f or eac h s u bject : 
 I n-trial: T he i n-tri al peri o d  is defi ne d as t he ti me i nter val fr o m date of ra n d o misati o n t o  
 Date of last c o nt act wit h trial site  
 Wit h dra wal date f or s u bj ects w h o wit h dra w i nf or me d c o nse nt  
 Date of t he last s u bject-i n vesti gat or/site c o nt act as defi ne d b y i n vesti gat or f or s u bjects w h o 
are l ost t o f oll o w u p  
 Date of deat h f or s u bjects w h o die bef ore a n y of t he a b o ve  
 O n -treat me nt ( wit h trial pr o d uct): A ti me-p oi nt is c o nsi dere d as ‘ o n -tr eat m e nt’ if a n y d ose of 
trial pr o d uct has bee n a d mi nistere d wit hi n t he pri or 2 wee ks ( 1 4 da ys). T he o n -tre at me nt peri o d 
is defi ne d as all ti mes w hic h are c o nsi dere d o n-treat me nt. 
 I n ge neral, t he o n-tr eat m e nt peri o d will t heref ore be fr o m t he dat e of first trial pr o d uct 
a d mi nistrati o n t o date of last trial pr o d uct a d mi nistrati o n e x cl u di n g p ote ntial off -tr eat me nt 
ti me i nter vals tri g gere d b y at least t w o c o nsec uti ve misse d d oses. 
 F or t he e val uati o n of A Es, t he la g ti me f or eac h o n -treat me nt ti me i nter val is 5 wee ks ( 3 5 
da ys).  
 O n -treat me nt wit h o ut ot h er a nti -o besit y t hera pies : T he ti me peri o d w here s u bjects are 
c o nsi dere d t o be treate d wit h trial pr o d uct a n d ha ve n ot i nitiate d ot her wei g ht ma na ge me nt 
dr u gs or bariatric s ur ger y ( i.e. a nti-o besit y t hera pies ). T he peri o d be gi ns at t he date of first trial 
pr o d uct a d mi nistrati o n a n d e n ds at t he earliest dat e of:  
 T he e n d date of t he o n -tr eat me nt o bser vati o n peri o d 
 Initiati o n of ot her a nti -o b esit y t hera pies  
T he i n -trial a n d o n-tr eat me nt peri o ds defi ne t he patie nt years of o bs er vati o n ( P Y O) a n d patie nt 
years of e x p os ure ( P Y E), res pecti vel y, as t he t otal ti me d urati o n i n t he peri o ds . 
P o p ul ati o n  
Descri pti o n  
Ra n d o mise d  
All s u bj ects ra n d o mise d  
F ull a nal ysis set ( F A S)  
All s u bj ects ra n d o mise d. E xcl usi o n of data fr o m a nal yses s h o ul d be use d 
restricti vel y, a n d n or mall y n o data s h o ul d be e xcl u de d fr o m t he F A S. S u bj ects will 
be a nal yse d acc or di n g t o t he ra n d o mise d treat me nt  
Safet y  a nal ysis set ( S A S)  
All s u bj ects ra n d o ml y assi g ne d t o trial treat me nt a n d w h o ta ke at least o ne d ose of 
trial pr o d uct. S u bj ects will be a nal yse d acc or di n g t o t he treat me nt t he y recei ve d f or 
t he maj orit y of t he peri o d t he y were o n treat me nt 
Ec h ocar di o gra p hic a nal ysis set 
( E A S) 
All s u bj ects i n t he s u b -p o p ulati o n of F A S t hat are  fr o m t he sites w here t he 
ec h ocar di o gra p hic s u bst u d y  is c o n d ucte d 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 6  of 3 8  
 
5  St atistic al a n al yses  
5. 1  
Ge ner al c o nsi der ati o ns  
N o v o N or dis k will be res p o nsi ble f or t he statistical a nal ysis a n d re p orti n g. A nal ysis a n d re p orti n g 
will be base d o n p o ole d data fr o m all sites a n d will be perf or me d o n u n -bli n de d data after data base 
releas e. 
Effect e n d p oi nts will be a nal ys e d usi n g t he F A S; safet y e n d p oi nts will be a nal yse d usi n g t he S A S.  
T he c o m paris o n prese nte d fr o m a statistical a nal ysis will be se ma g l uti de 2. 4  m g vers us pl ace b o a n d 
res ults will be prese nte d b y t he esti mate d treat me nt c o ntrast wit h ass ociate d t w o-si de d 9 5 % 
c o nfi de nce i nter vals ( CIs) a n d p-val u es c orres p o n di n g t o t w o -si de d tests of n o differe n ce. 
Data fr o m all c o u ntries a n d sites will b e a nal ys e d a n d re p ort e d t o get her.  
T he last a vaila ble a n d eli gi ble o bser vati o n at or bef ore ra n d o misati o n is use d as t he baseli ne v al ue. 
If n o assess me nts are a v aila ble, t he mea n of baseli ne val ues acr oss all s u bjects is use d as t he 
baseli ne val ue.  
T he stratificati o n fact or is B MI s u b gr o u p (B MI < 3 5. 0 k g/ m 2, B MI ≥3 5. 0 k g/ m 2). Wr o n g 
stratificati o n, e. g. if a s u bject wit h a B MI < 3 5. 0 k g/ m 2 was mista ke nl y ra n d o mise d usi n g t he 
ra n d o misati o n list f or s u bjects wit h a B MI ≥3 5 k g/ m 2, t he act ual val ue of t he stratificati o n fact or 
s h o ul d i n ge neral be use d i n t he a nal ysis (i. e. < 3 5 k g/ m 2 s h o ul d be use d as fact or le v el i n t he 
e x a m ple a b o ve).  
La b orat or y v al ues bel o w t he l o wer li mit of q ua ntificati o n ( L L O Q) will be set t o ½ L L O Q. 
La b orat or y v al ues a b o v e t he u p per li mit of q ua ntificati o n ( U L O Q) will be set t o U L O Q.  
All c o nti n u o us varia bles will be s u m marize d wit h n, mea n, sta n dar d de viati o n, me dia n, ge o metric 
mea n, C V, mi n a n d ma x. W he n rele va nt , n u m ber of val ues n < L L O Q a n d n > U L O Q will als o be 
prese nte d.  
F or eac h s u bject a g i ve n assess me nt at wee k 5 2  ma y b e a v aila ble or missi n g a n d  T a ble  5 -1  
descri bes t he ta x o n o m y f or t his. N ote,  t his is d o ne per assess me nt a n d per s u bject; s u bjects ma y be 
a differe nt t y p e f or differe nt assess me nts (a s u bject ma y ha v e “a vaila ble o n ra n d o mise d treat me nt ” 
f or b o d y wei g ht b ut “ missi n g o n ra n d o mise d tr eat me nt” f or waist circ u mfere nce). 
I n t he s p ecific cas e w here ca use of deat h is n ot deter mi ne d b y t h e e ve nt adj u dicati o n c o m mittee 
(e. g. if t he s u bject w as l ost t o f oll o w-u p a n d hereafter die d) it will be ass u me d t he ca use of deat h is 
C V deat h.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 7  of 3 8  
 
T a ble  5 -1  
T a x o n o m y f or s u bjects b ase d o n wee k 5 2  assess me nts  
Assess me nt  
at w ee k 5 2  
S u bjects o n 
r a n d o mise d tre at me nt 
at w ee k 5 2  
T y pe descri pti o n  
A vaila ble  
Yes  
A v ail a ble o n r a n d o mise d tre at me nt : 
S u bj ects w h o c o m plete t he tri al o n ra n d o mise d treat me nt wit h a n assess me nt at 
wee k 5 2: I ncl u des t h ose t hat st o p a n d restart trial pr o d uct.  
N o  
A v ail a ble b ut disc o nti n ue d   
S u bj ects w h o disc o nti n ue d ra n d o mise d treat me nt pre mat urel y b ut ret ur ne d t o ha ve 
a n assess me nt at wee k 5 2. T hese are als o calle d retrieve d s u bjects. 
Missi n g  
Yes  
Missi n g o n r a n d o mise d tre at me nt : 
S u bj ects w h o c o m plete t he tri al o n ra n d o mise d treat me nt wit h o ut a n assess me nt at 
wee k 5 2: I ncl u des t h ose t hat st o p a n d restart trial pr o d uct.  
N o  
Missi n g a n d disc o nti n ue d : 
S u bj ects w h o disc o nti n ue d ra n d o mise d treat me nt pre mat urel y a n d di d n ot ret ur n t o 
ha ve a n assess me nt at w ee k 5 2. T hese are als o calle d n o n -retrieve d s u bjects. 
5. 2  
S u bject dis p ositi o n  
See m oc k T F Ls.  
5. 3  
Pri m ar y e n d p oi nts a n al yses  
5. 3. 1  
Defi niti o n of e n d p oi nts  
T he pri mar y e n d p oi nts are c ha n ge i n t he K C C Q -C S S  (see A p pe n di x 6. 4 ) a n d c ha n ge i n b o d y 
wei g ht  i n perce nt a ge fr o m baseli ne ( wee k 0) t o e n d of  treat me nt ( wee k 5 2) as liste d i n 
A p pe n d i x 6. 3 . 
C ha n ge fr o m bas eli ne ( wee k 0) t o  e n d of treat me nt ( wee k 5 2)  i n b o d y wei g ht ( %) is defi ne d as 
( b o dy wei g ht at week 5 2 –  b o dy wei g ht at b aseli ne)
b o dy wei g ht at b aseli ne
 × 1 0 0.
5. 3. 2  
M ai n a n al ytic al a p pr o ac h  
5. 3. 2. 1  
Pri m ar y esti m a n d  
I n li ne wit h t he pri mar y esti ma n d strate g y (see Secti o n 1. 1. 1 ), t he pri mar y a nal ysis of t he pri mar y 
e n d p oi nts will be base d o n all ra n d o mise d s u bjects (f ull a nal ysis set) a n d t h e i n-trial o bser v ati o n 
peri o d.  
T he s u peri orit y tests of s e ma gl uti de 2. 4 m g vs. pl ace b o will be carrie d o ut as descri be d i n Se cti o n 2 . 
All a vaila ble data at wee k 5 2 are use d a n d missi n g val u es at wee k 5 2 will be i m p ute d a n d t he 
e n d p oi nt will be deri ve d fr o m t he i m p ute d val ues. Missi n g data will be ha n dle d differe ntl y b ase d o n 
w het her it is missi n g d ue t o a n i nterc urre nt e ve nt or n ot.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 8  of 3 8  
 
T he strate g y f or t he ha n dli n g of i nterc urre nt e ve nts f or t he pri mar y esti ma n d is o utli ne d i n 
Ta ble  5 -2 .  
S u bjects w h o ha ve missi n g K C C Q -C S S val ues at wee k 5 2 d ue t o car di o vas c ular ( C V) d eat h  or 
su bjects w h o ha ve missi n g K C C Q -C S S val ues at wee k 5 2  wit h a  pre vi o us heart fail ure e v e nt , as 
deter mi ne d b y t he e v e nt a dj u dicati o n c o m mittee, will be i m p ute d usi n g a c o m p osite strate g y. M ore 
s pecificall y, a si n gle i m p utati o n a p pr oac h w here t he l o west K C C Q-C S S val ue  acr oss treat me nt 
gr o u ps a n d ti me p oi nts  will be use d. Base d o n t his val ue t he c h a n ge fr o m bas eli ne will be cal c ulate d 
i n di vi d uall y f or t he s u bjects i n sc o pe.  
A ti p pi n g p oi nt a nal ysis will a d dress t he se nsiti vit y of assi g ni n g t hes e u nfa v o ura ble val ues, s ee 
Secti o n 5. 3. 3 . 
T a ble  5 -2  
H a n dli n g of i nterc urre nt e ve nts f or t he pri m ar y esti m a n d  
I nterc urre nt e ve nt 
(e n d p oi nts) 
D at a c ollecti o n  
D at a a n al ysis  
D isc o nti n uati o n of trial treat me nt 
(K C C Q -C S S  a n d b o d y wei g ht ) 
S u bj ects will be f oll o we d, a n d data 
c ollecte d after i nterc urre nt e ve nts  
Data c ollecte d after i nterc urre nt e ve nts 
use d i n a nal ysis (treat me nt  p olic y 
strate g y) 
I nitiati o n of ot her wei g ht 
ma na ge me nt dr u gs or bariatric 
s ur ger y (K C C Q -C S S  a n d b o d y 
wei g ht ) 
C V deat h (c) (K C C Q -C S S  o nl y)  
 
- 
C V deat hs will be i nc or p orate d i nt o t he 
K C C Q -C S S  b y ascri bi n g t he o utc o me 
a n u nfa v o ura ble val ue (c o m p osite 
strate g y) 
Heart fail ure h os pitalizati o n (c) 
(K C C Q -C S S  o nl y)  
Ur ge nt heart fail ure (c) (K C C Q -C S S  
o nl y)  
S u bj ects will be f oll o we d, a n d dat a 
collecte d after i nterc urre nt e ve nts  
If data  are n ot c ollecte d heart fail ure  
e ve nts will be i nc or p orate d i nt o t he 
K C C Q -C S S b y ascri bi n g t he o utc o me 
a n u nfa v ora ble val ue (c o m p osite 
strate g y) 
(c)As deter mi ne d b y t he e ve nt a dj u dicati o n c o m mittee   
S u bjects w h o ha ve missi n g K C C Q -C S S val ues at wee k 5 2 d ue t o ot her reas o ns t ha n C V relate d 
deat h or  pre vi o us heart fail ure  e ve nts  will ha ve t heir val ues i m p ute d usi n g a missi n g at ra n d o m 
( M A R) ass u m pti o n.  
Missi n g b o d y wei g ht val ues d ue t o b ot h C V deat h , n o n -C V deat h  a n d wit h  pre vi o us  heart fail ure  
e ve nts will be i m p ute d usi n g a M A R ass u m pti o n t o all o w bri d gi n g t o t he res ults of t he S T E P 
pr o gra m me.  
M ulti ple i m p ut ati o n of K C C Q -C S S  
Missi n g data f or t he pri m ar y e n d p oi nt t hat d o n ot arise  fr o m i nterc urre nt e ve nts (e. g. l ost t o f oll o w-
u p or wit h dra wal fr o m t he trial)  will be i m p ute d b y m ulti ple i m p utati o n a p pr oac h si milar t o t he o ne 
descri be d b y M c E v o y et al.1  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
1 9  of 3 8  
 
F or s u bjects i n t he se m a gl uti de 2. 4 m g a n d t he place b o gr o u ps, missi n g pri mar y e n d p oi nt 
meas ure me nts at w ee k 5 2 f or n o n -retrie ve d (see Ta ble  5 -1 ) s u bjects are i m p ute d usi n g assess me nts 
fr o m retrie v e d s u bjects i n eac h tr eat me nt gr o u p. T his will be d o ne acc or di n g t o t he ti mi n g of l ast 
a vaila ble o bser vati o n d uri n g t he o n -tr eat me nt peri o d ( L A O-O T) of K C C Q -C S S.  
Missi n g meas ur e me nts f or t he pri mar y e n d p oi nt at wee k 5 2 f or s u bj ects o n ra n d o mise d treat me nt 
(at wee k 5 2) are i m p ute d b y sa m pli n g fr o m a vaila ble meas ure m e nts at wee k 5 2 fr o m s u bjects o n 
ra n d o mise d treat me nt i n t he rele va nt ra n d o mise d treat me nt gr o u p. 
T he m ulti ple i m p utati o n f or K C C Q-C S S is d o ne b y defi ni n g a n i m p utati o n m o del usi n g retri e ve d 
s u bjects fr o m t he f ull a nal ysis set a n d d o ne wit hi n gr o u ps defi ne d b y ra n d o mise d treat me nt a n d t he 
ti mi n g of t he L A O-O T of t he e n d p oi nt. T he m o del will be a li near re gressi o n of K C C Q -C S S at 
wee k 5 2 wit h ge n d er ( male/fe male)  a n d baseli ne B MI ( k g/ m 2) (i n cate g ories < 3 5 k g/ m2, ≥3 5 k g/ m2) 
as fact ors a n d bas eli ne K C C Q -C S S, baseli ne b o d y wei g ht ( k g) , L A O -O T of K C C Q -C S S a n d ti mi n g 
of L A O -O T of K C C Q -C S S as c o variates. N o i nteracti o ns will be i ncl u de d. If t he i m p utatio n m o del 
ca n n ot be fit t he n t he m o del will be re d uce d u ntil t he m o del ca n fit. Re d ucti o n will be d o ne i n a 
fi x e d or der b y first re m o vi n g t he ge n d er a n d t h e n t he baseli ne B MI. If t h e i m p utati o n m o del still 
ca n n ot be fit, t he i m p utati o n will be d o ne re gar dless of t he ra n d o mise d treat me nt ar m. If n o L A O-
O T e xists p ost -baseli ne t he n t he L A O -O T will be t he baseli ne K C C Q -C S S . If a n y s u bjects are o n-
treat me nt a n d ha v e missi n g val u es f or K C C Q-C S S at wee k 5 2, a n i m p utati o n m o del f or missi n g 
K C C Q -C S S meas ure me nts at wee k 5 2 f or t hese s u bjects will als o be defi ne d i n a si milar wa y usi n g 
s u bjects t hat are o n-treat me nt a n d ha ve a vaila ble val ues f or K C C Q-C S S. T he esti mate d p osteri or 
distri b uti o n f or t he para meters (re gressi o n c o effi cie nts a n d vari a nces) i n t he i m p utati o n m o dels are 
t he n use d t o i m p ute missi n g w ee k 5 2 K C C Q -C S S val ues f or eac h ra n d o mise d treat me nt ar m. T his 
will be d o ne 1, 0 0 0 ti mes res ulti n g i n 1, 0 0 0 c o m plete data sets.  
A n al ysis of K C C Q -C S S  
T he c ha n ge fr o m bas eli ne t o wee k 5 2  will be a nal ys e d usi n g a n a nal ys is of c o varia n ce ( A N C O V A) 
wit h ra n d o mise d treat me nt  a n d stratificati o n ( B MI < 3 5. 0 k g/ m 2, B MI ≥3 5. 0  k g/ m 2) as fact ors, a n d 
baseli ne K C C Q -C S S as c o variate f or eac h of t he 1 0 0 0 c o m plete data sets.  T he 1 0 0 0 sets of a n al ysis 
res ults will be c o m bi ne d usi n g R u bi n’s r ule t o dra w i nfere n ce.  
Base d o n N N 9 5 3 6 -4 1 5 3 p hase 2 res ults 1, 0 0 0 c o pies s h o ul d be s ufficie nt  t o esta blis h sta ble res ults. 
If 1, 0 0 0 c o pies are i ns ufficie nt, 1 0, 0 0 0 c o pies will be use d.  T he m ulti ple i m p utati o ns will be 
ge n erat e d usi n g N o v o N or dis k trial n u m ber 9 5 3 64 6 6 5  as see d n u m ber.  I n a d diti o n t o t he see d 
n u m ber, it is s pecifie d t h at t he dataset is s orte d b y s u bject I D.  
T he esti mate d treat me nt differe n ce b et wee n s e ma gl uti de 2. 4 m g a n d place b o will be re p orte d 
t o get her wit h t he ass ociat e d t w o-si de d 9 5 % CI a n d c orres p o n di n g p-v al ue.  
M ulti ple i m p ut ati o n a n d a n al ysis of b o d y wei g ht  
I m p utati o n of missi n g d ata d ue t o i nterc urre nt e ve nts will be perf or me d as descri be d pre vi o usl y i n 
t his secti o n. M ulti ple im p utati o n of b o d y wei g ht will be d o ne i n a si milar ma n ner as f or K C C Q -
C S S, wit h t he c ha n ge t hat baseli ne K C C Q -C S S will n ot be i ncl u de d i n t he i m p utati o n m o del.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 0  of 3 8  
 
I n t he a nal ysis of c h a n ge fr o m baseli ne t o wee k 5 2 i n b o d y wei g ht ( %), bas eli ne b o d y wei g ht ( k g) 
will be use d i nstea d of baseli n e K C C Q-C S S as c o variate.  
 
5. 3. 2. 2  
Sec o n d ar y esti m a n d  
I n li ne wit h t he s ec o n dar y esti ma n d strat e g y descri be d i n Secti o n 1. 1. 1 , t he sec o n dar y esti ma n d f or 
t he pri mar y e n d p oi nts will be base d o n all ra n d o mise d s u bjects (f ull a nal ysis set) a n d t he ‘ o n-
treat me nt wit h o ut ot her a nti -o besit y t hera pies ’ o bs er vati o n peri o d (s ee Secti o n 4 ).  I n t he sec o n dar y 
esti ma n d o bser vati o ns aft er a heart fail ure e v e nt will be use d if c ollecte d.  
T he sec o n d ar y esti ma n d f or t he pri mar y e n d p oi nts a d dresses t he effi cac y of se ma gl uti de 2. 4 m g a n d 
will be assesse d usi n g a mi x e d m o del f or re peate d meas ure me nts ( M M R M). Wee k 5 2  assess me nts 
fr o m retrie v e d s u bjects are n ot use d i n t his a nal ysis. T he M M R M will use assess me nts o nl y fr o m 
s u bjects w h o are ta ki n g t he ra n d o mise d treat me nt u ntil e n d of treatme nt or u ntil first disc o nti n ui n g 
of ra n d o mise d treat me nt.  
T he deri ve d d ate of t he s ec o n d c o nsec uti ve misse d d ose will be use d as t he latest date f or usi n g 
assess me nts i n t h e M M R M. T he assess me nt cl osest i n ti me a n d bef ore t he deri ve d date of t he 
sec o n d co nsec uti ve misse d d ose will be use d as last assess me nt o n ra n d o mise d treat me nt. F or 
s u bjects w h o i nitiate ot her a nti -o besit y t h era pi es , as defi ne d i n Secti o n 4 , bef ore c o m pleti o n or first 
disc o nti n ui n g of ra n d o mise d treat me nt, t he d ate of starti n g t he ot her a nti -o b esit y t hera pies  will be 
use d as latest date f or usi n g ass ess me nts i n t his M M R M.  
Si milarl y, t he assess me nt cl osest i n ti me a n d bef ore t he d ate of st arti n g ot h er a nti -o besit y t h era pi es  
will be use d as last assess me nt o n ra n d o mise d treat me nt.  
T he M M R M will be fitte d usi n g K C C Q -C S S  a n d t he sa me fact or s a n d c o v ariate as f or t he pri mar y 
a nal ysis m o del  (s ee Secti o n 5. 3. 2. 1 , “A nal ysis of K C C Q -C S S”) all neste d wit hi n visit. A n 
u nstr uct ure d c o v aria n ce matri x f or meas ure me nts wit hi n t he sa me s u bject will be use d t o  descri be 
t he varia bilit y f or t he re p eate d meas ure me nts f or a s u bject. 
Fr o m t he M M R M m o del t he esti mate d treat me nt differe n ce b et wee n s e ma gl uti de 2. 4 m g a n d 
place b o will be re p orte d t o get h er wit h t he ass oci ate d t w o -si de d 9 5 % CI a n d c orres p o n di n g p-v al ue.  
A nal ysis of b o d y wei g ht will be d o ne i n t he sa me ma n ner as f or K C C Q -C S S.  
5. 3. 3  
Se nsiti vit y a n al ys es 
Ti p pi n g p oi nt se nsiti vit y a n al yses  
As a se nsiti vit y a nal ysis f or t he pri mar y esti ma n d, a t w o -di me nsi o nal ti p pi n g p oi nt a nal ysis will be 
perf or me d. First, missi n g d ata are i m p ute d acc or di n g t o t he pri mar y m ulti ple i m p utati o n 
a p pr oac h.  T he n, a p e nalt y is a d de d t o t he i m p ute d val ues at e n d of tr eat me nt. T he a p pr oac h is t o 
e x pl ore a ra n ge of pe nalti es f or b ot h treat me nt gr o u ps, a n d t he i m pact t hese w o ul d ha ve o n t he trial 
c o ncl usi o ns.  T his se nsiti vit y a nal ysis e v al uates t h e r o b ust ness of t he s u peri orit y c o n cl usi o ns t o 
de part ures fr o m t he o bser ve d c ha n ge i n K C C Q -C S S  a n d b o d y wei g ht i n b ot h treat me nt gr o u ps. 
A d diti o nall y, a ti p pi n g p oi nt a nal ysis f or K C C Q -C S S will be perf or me d o n i m p ute d val ues d ue t o 
C V deat h  or  pre vi o us heart fail ure e v e nts  i n a si milar ma n ner as f or t he ti p pi n g p oi nt a nal ysis of t he 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 1  of 3 8  
 
m ulti ple i m p ute d val ues. T his se nsiti vit y a n al ysis e val uates t he r o b ust ness of t he s u peri orit y 
c o ncl usi o ns i n a setti n g w here i m p ute d val u es are a d de d p e nalties usi n g i ncreasi n gl y u nfa v o ura bl e 
val ues (i ncl u di n g zer o i n t he w orst -cas e sce nari o).  
5. 3. 4  
S u p ple me nt ar y a n al yses  
S u p ple me nt ar y  a n al yses usi n g r a n k A N C O V A 
T o access t he c o m p osite st rate g y i n relati o n t o missi n g data d ue t o C V deat h, n o n -C V deat h a n d  
heart fail ure e v e nts a n o n -para m etric a p pr oac h will be perf or m e d usi n g t h e ra n k A N C O V A as a 
s u p ple me ntar y a n al ysis f or K C C Q-C S S.  
T he cli nical i m p orta nce of c ha n ge i n K C C Q -C S S will be a p plie d  f or eac h s u bject w here val ues 
wit hi n eac h or der will be ra n ke d acc or di n g t o T a ble  5 -3 . 
T a ble  5 -3  
R a n ki n g of K C C Q -C S S acc or di n g t o  i nterc urre nt a n d f at al e ve nts  
Or der  E n d of tre at me nt ( wee k 5 2) 
cl assific ati o n 
 S u b -or deri n g  
1  
O bser ve d/i m p ute d f oll o wi n g a M A R a 
a p pr oac h 
C ha n ge fr o m baseli ne ra n ke d fr o m hi g hest t o l o west ( n o 
pri orit y bet wee n o bser ve d/i m p ute d val ues)  
2  
Pre vi o us h eart fail ure  e ve nt i n trial (if 
data at wee k 5 2 are n ot c ollecte d)  
Ra n ki n g b y n u m ber of e ve nts ( m ore e ve nts ra n ke d l o west) 
a n d t he n  ra n ki n g b y ti me t o  first e ve nt (s h ortest ti me 
ra n ke d l o west)  
3  
N o n -C V deat hs  
Ra n ki n g b y ti me t o e ve nt (s h ortest ti me ra n ke d l o west)  
4  
C V deat hs  
Ra n ki n g b y ti me t o e ve nt (s h ortest ti me ra n ke d l o west)  
a T he 1 0 0 0 c o m plete data sets ge nerate d f or t he pri mar y i m p utati o n a p pr oac h will be re use d a n d p o ole d t o get her 
s u m marisi n g b y ta ki n g t he mea n of t he res p o nse val ues b y s u bject. Or der re prese nts ra n ki n g fr o m hi g hest t o 
l o west. 
After t he ra n ki n g of val u es, t he  ra n k A N C O V A will be perf or me d, first a dj usti n g f or b aseli ne 
K C C Q -C S S i n a li near re gressi o n, a n d t he n use t h e Va n Eltere n test (stratifie d Wilc o x o n) usi n g 
stratificati o n ( B MI < 3 5 k g/ m2, ≥3 5 k g/ m2) o n t he c orres p o n di n g resi d uals. A (t w o -si de d) p-val ue 
f or t he test of treat me nt differe n ce b et wee n s e ma gl uti de 2. 4 m g a n d place b o will be re p orte d.  
5. 4  
Sec o n d ar y e n d p oi nt s a n al ys es 
5. 4. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
5. 4. 1. 1  
Defi niti o n of e n d p oi nts  
T he c o nfir mat or y sec o n d ar y e n d p oi nts are:  
 C ha n ge i n 6 M W D fr o m baseli ne ( wee k 0)  t o e n d of treat me nt ( wee k 5 2) 
 T he hierarc hic al c o m p osite e n d p oi nt  fr o m baseli ne ( wee k 0) t o e n d of st u d y ( wee k 5 7) 
 C ha n ge i n C R P fr o m bas eli ne ( wee k -2) t o e n d of treat me nt ( wee k 5 2)  
 
A sc he matic o ver vie w of t he e n d p oi nts is i ncl u de d i n A p pe n di x 6. 3 . 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 2  of 3 8  
 
5. 4. 1. 2  
M ai n a n al ytic al a p pr o ac h  
T he s u peri orit y tests of s e ma gl uti de 2. 4 m g vs. pl ace b o will be carrie d o ut i n a hierarc hical or d er as 
descri be d i n Secti o n 2 .  
A n al yses a d dressi n g t he pri m ar y esti m a n d  
O verall, t he attri b utes of t he pri mar y esti ma n d des cri be d i n Secti o n 5. 3. 2. 1  is carrie d o v er t o t he 
c o nfir mat or y a n al ysis of t he sec o n dar y e n d p oi nts  6 M W D  a n d C R P , a n d s pecificall y t he i nterc urre nt 
e ve nt strate g y f or 6 M W D will mi mic w hat was d o ne  f or K C C Q-C S S , w hereas t he i nterc urre nt 
e ve nt strate g y f or C R P will mi mic b o d y wei g ht , see Ta ble  5 -2 . T his mea ns t hat missi n g val ues f or 
6 M W D d ue t o C V deat h or pre vi o us heart fail ure  e ve nt will be i m p ute d usi n g t he l o west 6 M W D 
val ue acr oss treat me nt gr o u ps a n d ti me p oi nts . Base d o n t his val ue t he c ha n ge fr o m baseli ne will be 
calc ulate d i n di vi d uall y f or t he s u bjects i n sc o pe.  
T he a nal ysis will be base d o n all ra n d o mise d s u bjects (f ull a nal ysis set) a n d t he i n-trial o bser vati o n 
peri o d.  
T he c o nfir mat or y sec o n d ar y e n d p oi nts  6 M W D a n d C R P  will be a nal ys e d usi n g t he sa me i m p utati o n 
a p pr oac h as use d f or t he pri mar y e n d p oi nts  a d dressi n g t he pri mar y esti ma n d . T he i m p utati o n m o del 
is t he sa me as descri be d i n Secti o n 5. 3. 2. 1  ( m ulti ple i m p utati o n of K C C Q-C S S) wit h K C C Q -C S S 
re place d b y assess me nts of t he e n d p oi nt t o be a nal ys e d.  
Si milarl y, t he st atistical m o del will be as descri be d i n Secti o n 5. 3. 2. 1  ( b ullet 2: a nal ysis), i. e. 
i ncl u di n g ra n d o mise d tr eat me nt  a n d stratificati o n as fact ors, a n d  ass oci ate d baseli ne as c o v ariate.  
F or C R P b ot h t he de pe n d e nt varia ble  a n d c o variat e will be l o g -tra nsf or m e d a n d t he rati o t o baseli ne 
( wee k -2 ) t o e n d of treat me nt ( wee k 5 2) will be calc ulate d i nstea d of differe nces.  
T he a nal ysis of t he hierarc hical c o m p osite e n d p oi nt will be base d o n direct c o m paris o ns of eac h 
s u bject ra nd o mise d t o se ma gl uti de s.c. 2. 4 m g vers us eac h s u bject ra n d o mise d t o place b o wit hi n 
eac h strat u m. F or eac h of t hese pairs, a ‘treat me nt wi n ner’ bas e d o n si milar o bser vati o n ti me will be 
declare d base d o n t h e e n d p oi nt hierarc h y. T h e wi n rati o (i.e. t he n u m ber of wi n ners ra n d o mise d t o 
se ma gl uti de s. c. 2. 4 m g di vi de d b y t he  n u m ber  of  wi n ner s ra n d o mise d t o pl ace b o) will be re p ort e d 
t o get her wit h t he ass ociat e d t w o-si de d 9 5 % CI a n d c orres p o n di n g p-v al ue. F urt her m ore, t he 
c o ntri b uti o n of wi ns fr o m eac h i n di vi d ual  c o m p o ne nt of t he hierarc hical c o m p osite e n d p oi nt will be 
s u m marise d. 
M issi n g K C C Q-C S S a n d 6 M W D val ues d ue t o ot her reas o ns t ha n C V rel ate d deat h or pre vi o us 
heart fail ure e v e nts will be i m p ute d usi n g t he M A R ass u m pti o n as descri be d i n S ecti o n 5. 3. 2. 1 .  
T he a nal ysis of t he hierarc hical c o m p osite e n d p oi nt will be d o ne usi n g a str atifie d wi n rati o 
a p pr oac h, s ee G a o h o n g D o n g, J. Q. ( 2 0 1 8). T he stratifie d wi n rati o. J o ur n al of Bi o p h ar m ace utic al 
St atistics , 7 7 8-7 9 6.  T he met h o d ca n briefl y b e descri be d as:  
C o nsi der a cli nical trial wit h patie nts ra n d o mise d i nt o t w o gr o u ps wit h 𝐻 strata. Let 𝜇𝑠
(𝑒) a n d 𝑚𝑎
(𝑔) 
de n ote t he n u m ber of patie nts i n t he treat me nt gr o u p a n d t he c o ntr ol gr o u p, res pecti vel y, a n d 
𝑙(𝑢) = 𝑡𝑖
(𝑑) + 𝑒𝜇
(𝑝) t he t otal sa m ple siz e i n t he m t h strat u m (𝑙
= 1 ,2 ,… ,𝑎). We defi ne t he 
wei g ht e d stratifie d wi n rati o as 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 3  of 3 8  
 
𝐻𝜇
= ∑
𝑠(𝑒)𝑚𝑎
(𝑔)
𝑙
𝑢= 1
∑
𝑡(𝑖)𝑑𝑒
(𝜇)
𝑝
𝑙= 1
 
I n t he u nstratifie d sit uati o n (𝑎
= 1 ), t his re d uces t o 𝑐𝑒
(1 )/ 𝑏𝑜
(1 ), t he ori gi nal wi n rati o. Wit h t w o 
strata a n d t he wei g ht defi ne d as 𝐻(𝐴) = 1 / 𝜇(𝑠) ( Ma ntel-Hae nszel),  t he wei g hte d stratifi e d wi n 
rati o is gi ve n b y 
𝑒𝑚
= ∑
𝑎𝑔
(𝑙)/ 𝑢(𝑡)
2
𝑖= 1
∑
𝑑𝑒
(𝜇)/ 𝑝(𝑙)
2
𝑎= 1
 
T he varia n ce is c alc ulate d b y t he as y m pt otic n or m al U statistic a p pr oac h 5.  
A n al yses a d dressi n g t he sec o n d ar y esti m a n d  
A nal ys es  of  c h a n ge i n  6 M W D a n d c ha n ge i n  C R P  will b e d o ne f oll o wi n g t he sa me a p pr oac h as 
descri be d i n Secti o n  5. 3. 2. 2 , w here t he a nal ysis f or c ha n ge i n 6 M W D will mi mic t he a nal ysis f or 
c ha n ge i n K C C Q -C S S a n d t he a nal ysis f or c h a n ge i n C R P will mi mic t he a nal ysis f or c ha n ge i n  
b o d y w ei g ht. C R P will be a nal yse d o n l o g -s cale i n li ne wit h t he strate g y of t he mai n a nal ytical 
ap pr oac h f or C R P. T he a nal ysis will be base d o n all ra n d o mise d s u bjects (f ull a nal ysis set) a n d t he 
‘ o n-treat me nt wit h o ut ot her a nti -o besit y t hera pies ’ o bser vati o n peri o d  
Si milarl y t he hi erarc hic al c o m p osite e n d p oi nt will be base d o n all ra n d o mise d s u bjects (f ull a n al ysis 
set) a n d t he ‘ o n-treat me nt wit h o ut ot her a nti -o besit y t hera pies ’ o bser vati o n peri o d.  
5. 4. 1. 3  
Se nsiti vit y a n al ysis  
Se nsiti vit y a n al ysis f or 6 M W D will f oll o w t he a p pr oac h des cri be d f or K C C Q -C S S i n Secti o n 5. 3. 3  
w here t he ti p pi n g p oi nt a nal yses will be a p plie d usi n g t he sa me m et h o d ol o g y as f or K C C Q-C S S . 
C R P will f oll o w t he a p pr oac h descri be d f or b o d y wei g ht.  
5. 4. 1. 4  
S u p ple me nt ar y a n al yses  
T he s u p ple me ntar y a nal yses f or 6 M W D a n d C R P will f oll o w t he a p pr oac h descri be d i n Secti o n  
5. 3. 4 .  
5. 4. 2  
S u p p orti ve sec o n d ar y e n d p oi nts  
A sc he matic o ver vie w o f t he s u p p orti ve sec o n dar y e n d p oi nts is i ncl u de d i n A p pe n di x 6. 3  a n d a 
brief o ver vi e w is gi ve n i n  Ta ble 5 -4 .  
T he s u p p orti ve  sec o n d ar y e n d p oi nts will be a n al yse d usi n g t he s a me i m p utati o n a p pr oac h as use d  
f or t he c o nfir mat or y sec o n dar y e n d p oi nts a n d t o a d dress t he pri mar y esti ma n d . T he i nterc urre nt 
e ve nt strate g y f or s yst olic bl o o d press ure a n d waist circ u mfere nce will mi mic w hat was d o ne f or 
b o d y w ei g ht, w h ereas t he i nterc urre nt e ve nt strat e g y f or K C C Q o verall s u m mar y s c ore ( K C C Q -
O S S) will mi mic K C C Q -C S S, see Ta ble  5 -2 . T he a nal ysis will be b ase d o n all ra n d o mise d s u bjects 
(f ull a nal ysis set) a n d t he i n-trial o bser vati o n peri o d. 
F or t he c o nti n u o us e n d p oi nts, t he a nal ysis m o del will be wit h r a n d o mise d treat me nt  a n d 
stratificati o n as fact ors, a n d ass ociate d bas eli ne as c o variate.  T he a n al ys es will be o n ori gi nal scale 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 4  of 3 8  
 
(i.e. n o l o g-tra nsf or mati o n). T he res p o n d er ( bi n ar y) e n d p oi nts will be deri ve d fr o m t he 1 0 0 0 
i m p ute d data sets descri b e d i n Sect i o n 5. 3. 2. 1 . F or t he res p o n der e n d p oi nts, eac h of t h e c o m plete 
data sets will be a nal yse d usi n g a l o gistic re gressi o n ( L R) wit h ra n d o mise d  treat me nt a n d 
stratificati o n as fact ors, a n d ass ociate d bas eli ne  val ue  as c o variate. Esti mate d o d ds rati os will be 
l o g-tr a nsf or me d a n d i nfere nce will be dra w n usi n g R u bi n’s r ule. T h e res ults will be bac k -
tra nsf or me d a n d descri be d b y t he o d ds rati o bet wee n treat me nts a n d t h e ass ociate d 9 5 % CI a n d p-
val ue f or n o tr eat me nt differe n ce.  
5. 4. 2. 1  
Cli nic all y me a ni n gf ul wi t hi n-s u bject c h a n ge e n d p oi nts 
T he K C C Q -C S S scale meas ures s y m pt o ms a n d p h ysical  f u ncti o n f or p artici pa nts wit h heart fail ure. 
S u peri orit y wit h res p ect t o K C C Q -C S S is teste d o n t he c o nti n u o us scale i n t he c o nfir mat or y testi n g 
hierarc h y , see Secti o n 2 . If s u peri orit y is de m o nstrate d, t he cli nical r ele va n ce of t he treat me nt effect 
is e val uate d bas e d o n t he pr o p orti o ns of partici pa nts i n eac h treat me nt gr o u p t hat ha ve e x perie nce d 
cli nicall y rele va nt i m pr o ve me nts wit h res pect t o s y m pt o ms a n d p h ysical f u ncti o n as meas ure d b y 
K C C Q -C S S.  
Li ke wis e, s u peri orit y wit h res pec t t o 6 M W T is teste d as a c o nfir mat or y e n d p oi nt. If s u peri orit y is 
de m o nstrate d, t he cli nical rele va nce of t he tr eat me nt effect is e val uate d b as e d o n t he pr o p orti o ns of 
partici pa nts i n eac h treat me nt gr o u p t hat h a ve e x perie nce d cli nicall y rel e va nt i m pr o ve me nts i n 
wal ki n g dista nce.  
T he se cli nicall y m ea ni n gf ul i m pr o ve me nts ca n be c haracterise d as t he s mallest differe n ce i n a n 
e n d p oi nt t hat is percei ve d b y t he s u bject t o be be n eficia l3. I n or der t o c haracterise a m ea ni n gf ul 
wit hi n -s u bject c ha n ge i n K C C Q-C S S a n d 6 M W D t he patie nt gl o b al i m pressi o n of se verit y ( P GI -S)  
will be use d i n a n a nc h or base d a p pr oac h, w here t he P GI -S is t he s o-calle d a nc h ors.  T he res p o n d er 
defi niti o n val ues will be calc ulate d f or K C C Q -C S S a n d 6 M W D b y a n e xter nal ve n d or.  
T he pr o p orti o n of s u bjects i m pr o vi n g e q ual or m ore t ha n t hese t hr es h ol ds base d o n P GI -S will be 
c o nsi dere d as s u p p orti ve sec o n dar y e n d poi nts (see Ta ble 5 -4 ) a n d will be a nal yse d f oll o wi n g t h e 
met h o ds i n Secti o n 5. 4. 2 .   
F urt her m ore,  t o be a bl e t o vis uall y e val u ate t he r o b ust ness of t he res ults base d o n t he P GI-S 1 p oi nt 
i m pr o ve me nt t hres h ol d, t he distri b uti o n of t he c ha n ge i n K C C Q-C S S a n d c ha n ge i n 6 M W D f r o m 
baseli ne will be ill ustrate d i n a n e m pirical C u m ulati ve Distri b uti o n F u ncti o n pl ot b y treat me nt ar ms. 
T o f urt her ai d t his e val uati o n, t he pr o p orti o n of s u bjects i m pr o vi n g e q u al or m ore t ha n t hese 
t hres h ol ds base d o n t he P GI-S 0 p oi nt i m pr o ve me nt a n d P G I-S 2 p oi nt i m pr o ve me nt will be 
a nal ys e d f oll o wi n g t he m et h o ds i n  Secti o n 5. 4. 2 .   
T a ble 5 -4   
St atistic al a n al ysis of s u p p orti ve sec o n d ar y e n d p oi nts  
Title  
St atistic al m o del  
S u bj ect ac hie vi n g 1 0 % wei g ht l oss or m ore ( Yes/ N o)  
L R  
S u bj ect ac hie vi n g 1 5 % wei g ht l oss or m ore ( Yes/ N o)  
L R  
S u bj ect ac hie vi n g 2 0 % wei g ht l oss or m ore ( Yes/ N o)  
L R  
S u bj ect i m pr o vi n g 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect i m pr o vi n g 1 0 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o)  
L R  
C ha n ge i n K C C Q o verall s u m mar y sc ore  
A N C O V A  
C ha n ge i n s yst olic bl o o d press ure ( S B P) ( m m H g)  
A N C O V A  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 5  of 3 8  
 
C ha n ge i n waist circ u mfere nce (c m)  
A N C O V A  
S u bj ects ac hie vi n g C M W S C or m ore i n K C C Q -C S S ( Yes/ N o)                       ( P GI -S)  L R  
S u bj ects ac hie vi n g C M W S C or m ore i n 6 M W D ( Yes/ N o)                              ( P GI -S)  L R  
C M W S C : Cli nicall y mea ni n gf ul wit hi n -s u bject c ha n ge 
5. 5  
E x pl or at or y e n d p oi nts a n al ysis  
T he e x pl orat or y e n d p oi nts i n t he trial are liste d i n Secti o n 6. 3 . T he e x pl orat or y e n d p oi nts t o be 
statisticall y a nal yse d are: 
 C ha n ge i n N T -pr o B N P fr o m baseli ne ( wee k -2) t o e n d of treat me nt ( wee k 5 2)  
 Ti me t o first heart fail ure e ve nt ( h os pitalisati o n or ur ge nt visit)  
 Ec h ocar di o gra p hic s u bst u d y e n d p oi nts  
 C ha n ge i n K C C Q s u bscales fr o m baseli ne ( wee k 0) t o e n d of treat me nt ( wee k 5 2) 
 E n d p oi nts of K C C Q  
 
Re mai ni n g e x pl orat or y e n d p oi nts will be s u m marise d as descri be d i n m oc k T F Ls.  
N T -pr o B N P  
A nal ysis of N T -pr o B N P will be perf or me d as des cri be d i n Secti o n 5. 3. 2. 2  usi n g t he strate g y of t he 
sec o n dar y esti ma n d. T he M M R M will be fitte d usi n g t he sa m e fact or s a n d c o variate , s u bstit uti n g 
K C C Q -C S S at baseli ne wit h (l o g -tr a nsf or me d) N T-pr o B N P as baseli ne,  as f or t he pri mar y a nal ys is 
all neste d wit hi n visit. As i n dicate d, b ot h t he de pe n de nt varia ble a n d c o vari ate will be l o g -
tra nsf or me d a n d t he rati o t o baseli ne ( wee k -2) t o e n d of treat me nt ( wee k 5 2) will be calc ulat e d 
i nstea d of differe nces.  
Ti me t o first he a rt f ail ure e v e nt  
Ti me t o first occ urre nce of a heart fail ure e ve nt fr o m ra n d o misati o n will be a nal yse d usi n g a C o x 
pr o p orti o nal hazar ds m o del stratifie d b y baseli ne B MI ( k g/ m 2) (i n cat e g ori es < 3 5 k g/ m2, ≥3 5 k g/ m2) 
wit h treat me nt as a c o variate. S u bjects wit h o ut a n e ve nt will be ce ns ore d at eit her e n d  of  tr eat me nt 
visit ( wee k 5 2), per ma ne nt disc o nti n uati o n or all -ca use deat h, w hic he v er c o mes first.  
A c u m ulati ve i nci de nce pl ot will be pr o d uce d usi n g t he Nels o n -Aal e n esti mat or a dj usti n g f or 
c o m peti n g ris k (all -ca use deat h) f or t h e t w o treat me nt gr o u ps . T he differe n ce bet wee n t he 
c u m ulati ve i nci de nces at wee k 5 2 f or t he treat me nt gr o u p s will be teste d usi n g a l o g -ra n k test.  
Ec h oc ar di o gr a p hic s u bst u d y  
T he ec h o car di o gra p hic s u bst u d y e n d p oi nts are:  
 C ha n ge i n left atrial v ol u me fr o m baseli ne ( wee k 0) t o e n d of treat me nt ( wee k 5 2)  
 C ha n ge i n left ve ntric ular ( L V) filli n g press ure ( di ast olic f u ncti o n) ( E/e´) fr o m baseli ne ( wee k 
0) t o e n d of treat me nt ( wee k 5 2)  
 C ha n ge i n gl o bal l o n git u di nal strai n fr o m baseli ne ( wee k 0) t o e n d of tr eat me nt ( wee k 5 2) 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 6  of 3 8  
 
A nal ysis of t h e ec h o car di o gra p hic s u bst u d y e n d p oi nts will be perf or me d o n all s u bjects wit h 
o bser ve d val u es at baseli ne a n d at w ee k 5 2  i n t he ec h ocar di o gra p hi c a nal ysis set  usi n g a n 
A N C O V A wit h ra n d o mise d treat me nt a n d stratificati o n ( B MI < 3 5 k g/ m2, ≥3 5 k g/ m2) as fact or a n d 
baseli ne val ue as c o variate . Left atrial v ol u me a n d L V filli n g press ure will be a nal yse d o n l o g-s cale 
i.e. t he rati o bet wee n  e n d  of  treat me nt a n d b aseli n e  will  be  calc ulat e d  i nstea d of  differe n ces,  a n d 
b ot h  t he de pe n de nt  varia ble  a n d c o variate  will  be  l o g-tr a nsf or me d. 
E n d p oi nts of K C C Q  
A sc he matic o ver vie w of t he e x pl orat or y K C C Q e n d p oi nts is i ncl u de d i n A p pe n di x 6. 3  a n d a brief 
o ver vie w is gi ve n i n Ta bl e  5 -5 .  
T a ble  5 -5  
E x pl or ati ve K C C Q  e n d p oi nts 
Title  
St atistic al m o del  
C ha n ge i n K C C Q t otal s y m p t o m sc ore 
A N O V A  
C ha n ge i n K C C Q p h ysical li mitati o ns sc ore  
A N O V A  
C ha n ge i n K C C Q s ocial li mitati o ns sc ore  
A N O V A  
C ha n ge i n K C C Q healt h -relate d q ualit y of life sc ore 
A N O V A  
S u bj ect w orse ni n g 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect w orse ni n g 1 0  p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o) L R  
S u bj ect  i m pr o vi n g 1 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o) L R  
S u bj ect w orse ni n g 1 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore ( Yes/ N o) L R  
S u bj ect i m pr o vi n g 5 p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect i m pr o vi n g 1 0 p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect i m pr o vi n g 1 5  p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect w orse ni n g 5 p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect w orse ni n g 1 0  p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
S u bj ect w orse ni n g 1 5  p oi nts or m ore i n K C C Q o verall  s u m mar y sc ore ( Yes/ N o) 
L R  
 
C o nti n u o us e n d p oi nts will be a nal ys e d usi n g t he s a me i m p utati o n a p pr oac h as use d  f or t he 
c o nfir mat or y sec o n dar y e n d p oi nts a n d t o a d dress t he pri mar y esti ma n d . T h e i nterc urre nt e ve nt 
strate g y will mi mic K C C Q-C S S, see Ta ble  5 -2 . T he a nal ysis will be base d o n all ra n d o mise d 
s u bjects (f ull a nal ysis set) a n d t he i n-trial o bser vati o n peri o d. 
 
T he res p o n der e n d p oi nts of i m pr o vi n g a n d w orse ni n g will be a n al y s e d i n t he sa me ma n ner as 
descri be d f or res p o n d er e n d p oi nts i n Secti o n 5. 4. 2 .  
5. 6  
S afet y a n al yses  
T here are n o s afet y e n d p oi nts i n t he trial.  Safet y assess me nts will be s u m marise d descri pti vel y b y 
treat me nt gr o u p a n d visit. Cate g orical safet y assess me nts  will be s u m maris e d as c o u nts a n d relati ve 
fre q ue n cies. 
5. 7  
Ot her a n al yses  
At t he e n d of treat me nt visit, s u bjects are as ke d w hic h treat me nt (se m a gl uti de or place b o) t hat t he y 
belie ve t he y ha v e recei ve d. T he res ults will be s u m marise d.  
Treat me nt differe n ces at ot her ti me p oi nt s bef ore e n d of treat me nt ( wee k 5 2) f or t he c o nfir mat or y 
e n d p oi nts c o ul d be a nal yse d usi n g t he s ec o n dar y esti ma n d.  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 7  of 3 8  
 
C O VI D -1 9  
A s u p ple me ntar y a n al ysis usi n g t he pri mar y esti ma n d will be perf or me d f or all c o nfir mat or y 
e n d p oi nts e x cl u di n g s u bjects w h o e x perie nce a C O VI D -1 9 relate d a d verse e ve nt.  If less t ha n 5 
s u bjects ha ve e x perie n ce d a C O VI D-1 9 relate d a d verse e v e nt t he a n al ys es will be e x cl u de d.  
A s u p ple me ntar y a n al ysis will be perf or me d usi n g t he pri mar y esti ma n d f or all c o nfir mat or y 
e n d p oi nts e x cl u di n g s u bjects w h o c o-p artici pates i n C O VI D -1 9 vacci nati o n trials. If less t ha n 5 
s u bjects are c o-partici pati n g i n C O VI D -1 9 vacci n ati o n trials t he a nal yses will be e x cl u de d.  
5. 7. 1  
S u b gr o u p a n al yses  
N o  s u b gr o u p a nal yses are pla n ne d t o be re p orte d i n t he trial s pecific st u d y re p ort. 
5. 7. 2  
P h ar m a c o ki netic m o delli n g  
E x p os ure -res p o nse a n al yses will be use d as s u p p orti ve e vi de nce f or t he e val uati o n of efficac y a n d 
safet y a n d f urt her t o s u p p ort t he i n vesti gat e d d ose of se ma gl uti de i n s u bjects w it h H F p E F a n d 
o besit y. Plas ma se ma gl uti de c o nce ntr ati o ns will be use d t o deri ve m o d el -b ase d esti mates of stea d y -
state a vera ge c o nce ntr ati o ns f or eac h s u bject, utilizi n g a p o p ulati o n p har mac o ki netic m o delli n g 
a p pr oac h t h at le vera ges i nf or mati o n fr o m t he S T E P pr o gra m me. Rele va nt efficac y a n d safet y 
e n d p oi nts will be relate d t o stea d y -state a v era ge c o nce ntrati o ns a n d s u bjecte d t o m o del-base d 
e x p os ure-res p o nse a nal ysis. A m o delli n g a nal ysis pla n will be pre pare d pri or t o data base l o c k 
o utli ni n g details of t he a n al yses. T he res ults fr o m t he e x p os ure -res p o ns e a n al ysis will be re p orte d 
se parat el y fr o m t he C T R. 
5. 8  
I nteri m a n al yses 
N o i nteri m a nal yses are pla n ne d.  
5. 8. 1  
D at a m o nit ori n g c o m mittee  
T here is n o data m o nit ori n g c o m mittee f or t his trial.  
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 8  of 3 8  
 
 
6  S u p p orti n g d oc u me nt ati o n  
6. 1  
A p pe n di x 1 : List of a b bre vi ati o ns  
6 M W D  
si x-mi n ute wal ki n g dista nce  
A E  
a d verse e ve nt  
A N C O V A  
a nal ysis of c o varia nce  
B MI  
b o d y mass i n de x  
CI  
c o nfi de nce i nter val  
C O VI D  
c or o na vir us disease  
C R P  
C -Reacti ve Pr otei n  
C S S  
cli nical s u m mar y sc ore  
C V  
car di o vas c ular  
E A S  
ec h ocar di o gra p hi c a nal ysis set  
F A S  
f ull a nal ysis set 
H F p E F  
heart fail ure wit h pres er ve d ejecti o n fracti o n  
K C C Q  
K a nsas C it y C ar di o m y o p at h y Q u esti o n naire  
L A O -O T  
last a vaila ble o bser vati o n d uri n g t he o n -treat me nt peri o d 
L L O Q  
l o wer li mit of q ua ntificati o n 
L R  
l o gistic re gressi o n 
L V  
left ve ntric ular  
M A R  
missi n g at ra n d o m  
M M R M  
mi x e d m o del f or re peate d meas ure me nts  
N T -pr o B N P  N -ter mi nal pr o-brai n natri uretic pe pti de  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O S S  
o verall s u m mar y sc ore  
P GI -S  
patie nt gl o bal i m pressi o n of se verit y 
P GI -C  
patie nt gl o bal i m pressi o n of c ha n ge  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
2 9  of 3 8  
 
 
P Y E  
patie nt years of e x p os ure  
P Y O  
patie nt years of o bs er vati o n  
S A P  
statistical a nal ysis pla n 
S B P  
s yst olic bl o o d press ur e 
S A S  
safet y a n al ysis set 
s.c. 
s u bc uta ne o us 
T F L  
ta bles, fi g ures a n d listi n gs 
U L O Q  
u p per li mit of q ua ntificati o n  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 0  of 3 8  
 
 
6. 2  
A p pe n di x 2: C h a n ges t o pr ot oc ol -pl a n ne d a n al yses  
T he c ha n ges fr o m t he pr ot oc ol of E X 9 5 3 6 -4 6 6 5 are s u m marise d bel o w.   
 T he f oll o wi n g e x pl orat or y e n d p oi nts were a d de d  
 S u bject i m pr o vi n g 1 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore  
 S u bject w orse ni n g 1 5 p oi nts or m ore i n K C C Q cli nical s u m mar y sc ore  
 S u bject i m pr o vi n g 1 5 p oi nts or m ore i n K C C Q o verall s u m mar y sc ore  
 S u bject w orse ni n g 1 5 p o i nts or m ore i n K C C Q o verall s u m mar y sc ore 
 
 
6. 3  
A p pe n di x 3: Defi niti o n a n d c alc ul ati o n of e n d p oi nts, assess me nts a n d deri v ati o ns  
T y pe  
Title  
Ti me fr a me  
U nit  
Det ails  
Pri mar y e n d p oi nt  
C ha n ge i n K C C Q cli nical 
s u m mar y sc ore 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Sc ore ( n o u nit, 
ra n ge; 0-1 0 0)  
 
Pri mar y e n d p oi nt  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
 %  
 
C o nfir mat or y 
sec o n dar y e n d p oi nt 
C ha n ge i n si x-mi n ute wal ki n g 
dista nce ( 6 M W D)  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Metres  
 
C o nfir mat or y 
sec o n dar y e n d p oi nt 
Hierarc hical c o m p osite of:  
Ti me t o all -ca use deat h,  
n u m ber of heart fail ure e ve nts 
re q uiri n g h os pitalisati o n or ur ge nt 
heart fail ure visit,  
ti me t o first heart fail ure e ve nt 
re q uiri n g h os pitalisati o n or ur ge nt 
heart fail ure visit,  
differe nce of at least 1 5 i n K C C Q  
cli nical s u m mar y sc ore c ha n ge 
fr o m baseli ne t o 5 2 wee ks, 
differe nce of at least 1 0 i n K C C Q  
cli nical s u m mar y sc ore  c ha n ge 
fr o m baseli ne t o 5 2 wee ks, 
differe nce of at least 5 i n  K C C Q  
cli nical s u m mar y sc ore  c ha n ge 
fr o m baseli ne t o 5 2 wee ks, 
differe nce of at least 3 0 metres i n 
se x-mi n ute wal ki n g dista nce 
c ha n ge fr o m baseli ne t o 5 2 we e ks 
(assesse d b y t he wi n rati o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of st u d y ( wee k 
5 7)  
T otal wi ns f or 
eac h treat me nt 
gr o u p  
 
C o nfir mat or y 
sec o n dar y e n d p oi nt 
C ha n ge i n C -Reacti ve Pr otei n 
( C R P) 
Fr o m baseli ne ( wee k -
2) t o e n d of treat me nt 
( wee k 5 2) 
Rati o t o 
baseli ne ( n o 
u nit)  
L o g 
tra nsf or me d 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect ac hie vi n g 1 0 % wei g ht 
l oss or m ore ( Yes/ N o)  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
(wee k 5 2)  
C o u nt of 
s u bj ects 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect ac hie vi n g 1 5 % wei g ht 
l oss or m ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
(wee k 5 2 ) 
C o u nt of 
s u bj ects 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect ac hie vi n g 2 0 % wei g ht 
l oss or m ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
(wee k 5 2 ) 
C o u nt of 
s u bj ects 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 1  of 3 8  
 
 
T y pe  
Title  
Ti me fr a me  
U nit  
Det ails  
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect i m pr o vi n g 5 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m ba seli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect i m pr o vi n g 1 0 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
C ha n ge i n K C C Q o verall 
s u m mar y sc ore 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Sc ore ( n o u nit, 
ra n ge 0-1 0 0)  
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
C ha n ge i n s yst olic bl o o d press ure 
( S B P) 
Fr o m baseli ne ( wee k -
2) t o e n d of treat me nt 
( wee k 5 2)  
m m H g  
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
C ha n ge i n waist circ u mfere nc e  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
(wee k  5 2)  
c m 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect ac hie vi n g  t he t hres h ol d 
f or cli nicall y mea ni n gf ul wit hi n-
s u bj ect c ha n ge or m ore  i n K C C Q-
C S S  ( P GI-S)  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
(wee k 5 2)  
C o u nt of 
s u bj ects 
 
S u p p orti ve 
sec o n dar y e n d p oi nt 
S u bj ect ac hie vi n g  t he t hres h ol d 
f or cli nicall y mea ni n gf ul wit hi n-
s u bj ect c ha n ge or m ore  i n 6 M W D 
( P GI-S)  
Fr o m baseli ne ( wee k 0) 
t o e nd of treat me nt 
(wee k 5 2)  
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n a nti h y perte nsi ve 
me dicati o n  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Cate g or y ( n o 
u nit; decrease / 
n o c ha n ge / 
i ncrease) 
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n l o o p di uretic 
me dicati o n  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Cate g or y ( n o 
u nit, decrease / 
n o c ha n ge / 
i ncrease) 
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n N T -pr o B N P  
Fr o m baseli ne ( wee k -
2) t o e n d of treat me nt 
( wee k 5 2) 
Rati o t o 
baseli ne ( n o 
u nit)  
L o g -
tra nsf or me d 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n E Q -5 D -5 L sc ore   
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Sc ore ( n o u nit, 
ra n ge per ite m; 
1 -5)  
 
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  5 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  1 0 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect i m pr o vi n g 1 5 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  1 5 p oi nts or 
m ore i n K C C Q cli nical s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect i m pr o vi n g 5 p oi nts or 
m ore i n K C C Q o verall  s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect i m pr o vi n g 1 0 p oi nts or 
m ore i n K C C Q o verall  s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect i m pr o vi n g 1 5 p o i nts or 
m ore i n K C C Q o verall s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 2  of 3 8  
 
 
T y pe  
Title  
Ti me fr a me  
U nit  
Det ails  
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  5 p oi nts or 
m ore i n K C C Q o verall  s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  1 0 p oi nts or 
m ore i n K C C Q o verall  s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
S u bj ect w orse ni n g  1 5  p oi nts or 
m ore i n K C C Q o verall  s u m mar y 
sc ore ( Yes/ N o) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n s u bscales of K C C Q : 
T otal s y m pt o m sc ore  
P h ysical li mitati o ns sc ore  
S ocial li mitati o ns sc ore  
H ealt h -relate d q ualit y of life 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Sc ore ( n o u nit, 
ra n ge 0-1 0 0)  
 
E x pl orat or y 
e n d p oi nt  
S u bj ect e x perie nci n g 
i m pr o ve me nt i n N Y H A Class 
( Yes/ N o) 
Fr o m baseli ne ( wee k -
2) t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s ubj ects  
 
E x pl orat or y 
e n d p oi nt  
S u bj ect e x perie nci n g deteri orati o n 
i n N Y H A Class ( Yes/ N o) 
Fr o m baseli ne ( wee k -
2) t o e n d of treat me nt 
( wee k 5 2) 
C o u nt of 
s u bj ects 
 
E x pl orat or y 
e n d p oi nt  
Ti me t o first heart fail ure e ve nt 
( h os pitalisati o n or ur ge nt visit) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2) 
Da ys  
 
Ec h oc ar di o gr a p hic s u b -st u dy 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n left atrial v ol u me  
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2 ) 
Rati o t o 
baseli ne ( n o 
u nit)  
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n left ve ntric ular ( L V) 
filli n g press ure ( diast olic 
f u ncti o n) ( E/e´) 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2 ) 
Rati o t o 
baseli ne ( n o 
u nit)  
 
E x pl orat or y 
e n d p oi nt  
C ha n ge i n gl o bal l o n git u di nal 
strai n 
Fr o m baseli ne ( wee k 0) 
t o e n d of treat me nt 
( wee k 5 2 ) 
%  
 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 3  of 3 8  
 
 
6. 4  
A p pe n di x 4: K a ns as Cit y C ar di o m y o p at h y Q uesti o n n aire a n d sc ori n g  
T he K C C Q c o nsists of 2 3 q uesti o ns t hat are ma p pe d i nt o 1 0 s u m mar y sc ores t hat are b ase d o n t he 
as s h o w n i n Fi g ure 4 . Scale sc ores ra n ge fr o m 0 t o 1 0 0 w here hi g h er sc ores i n dicates a better healt h 
stat us wit h re gar ds t o heart failure 4. K C C Q-C S S is a n a vera ge of t he “ p h ysi cal li mitati o n sc ore” a n d 
“t otal s y m pt o m sc ore”, a n d K C C Q -O S S is a n a vera ge of t h e “ p h ysical li mitati o n sc ore,” “t otal 
s y m pt o m sc ore, ” “ q ualit y of lif e score,” a n d “s oci al li mitati o n sc ore” . 
Fi g ure 4   
M a p pi n g of K C C Q  
 
Ite m 
N o.  
Ite m te xt 
Res p o nse scale  
1a  
H o w m uc h are y o u li mite d b y heart 
fail ure i n dressi n g y o urs elf o ver t he 
past 2 wee ks?  
1: E xtre mel y li mite d  
2: Q uite a bit li mite d 
3: M o deratel y li mite d  
4: Sli g htl y  li mite d 
5: N ot at all li mite d  
Missi n g: Li mite d f or ot h er reas o ns or di d n ot d o 
t he acti vit y 
 
1 b  
H o w m uc h are y o u li mite d b y heart 
fail ure i n s h o weri n g/ b at hi n g o ver t h e 
past 2 wee ks  
1c  
H o w m uc h are y o u li mite d b y  heart 
fail ure i n wal ki n g 1 bl oc k o n le vel 
gr o u n d o v er t he p ast 2 w ee ks  
1 d  
H o w m uc h are y o u li mite d b y heart 
fail ure i n d oi n g yar d w or k , h o use w or k 
or carr yi n g gr oceries o ver t he past 2 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 4  of 3 8  
 
 
wee ks  
1 d  
H o w m uc h are y o u li mite d b y heart 
fail ure i n cli m bi n g fli ght of stairs 
wit h o ut st o p pi n g o ver t h e past 2 wee ks  
1f  
H o w m uc h are y o u li mite d b y heart 
fail ure i n h urr yi n g or j o g gi n g o ver t he 
past 2 wee ks  
2  
C o m pare d wit h 2 wee ks a g o, h a ve 
y o ur s y m pt o ms of heart fail ure 
(s h ort ness of breat h, fati g ue, or a n kle 
s welli n g) c ha n ge d? 
1:  M uc h w orse  
2: Sli g htl y w orse  
3: N ot c ha n ge d  
4: Sli g htl y better  
5: M uc h better  
3 : I ha d n o s y m pt o ms o v er t he last 2 wee ks  
3  
O ver t he past 2 w ee ks, h o w ma n y 
ti mes di d y o u h a ve s w elli n g i n y o ur 
feet, a n kles or le gs w he n y o u w o ke u p 
i n t he m or ni n g?  
1: E ver y m or ni n g  
2: 3 or m ore ti mes a wee k, b ur n ot e ver y d a y  
3: 1 -2 ti mes a wee k  
4: L ess t ha n o n ce a wee k  
5: N e ver o ver t he past 2 wee ks  
4  
O ver t he past 2 w ee ks, h o w m uc h has 
s welli n g i n y o ur feet, a n kles or le gs 
b ot here d y o u?  
1: E xtre mel y  b ot h e rs o me 
2: Q uite a bit b ot hers o me  
3: M o deratel y b ot hers o m e  
4: Sli g htl y b ot hers o me  
5: N ot at all b ot hers o me  
5 : I’ ve ha d n o s w elli n g  
5  
O ver t he past 2 w ee ks, o n a vera ge, 
h o w ma n y ti mes has fati g ue li mite d 
y o ur a bilit y t o d o  w hat y o u wa nt?  
1: A ll of t he ti me, 
2: S e veral ti mes per da y  
3: At least o nce a d a y  
4: 3 or m ore ti mes per wee k b ut n ot e ver y d a y  
5: 1 -2 ti mes per wee k  
6: L ess t ha n o n ce a wee k  
7: N e ver o ver t he past 2 wee ks  
6  
O ver t he past 2 w ee ks, h o w m uc h has 
y o ur fati g ue b ot here d y o u?  
1: E xtre mel y b ot h e rs o me 
2: Q uite a bit b ot hers o me  
3: M o deratel y b ot hers o m e  
4: Sli g htl y b ot hers o me  
5: N ot at all b ot hers o me  
5 : I’ ve ha d n o fati g u e 
7  
O ver t he past 2 w ee ks, o n a vera ge, 
h o w ma n y ti mes has s h ort ness of 
breat h li mite d y o ur a bilit y t o d o w hat 
y o u w a nte d?  
1: A ll of t he ti me,  
2: S e veral ti mes per da y  
3: At least o nce a d a y  
4: 3 or m ore ti mes per wee k b ut n ot e ver y d a y  
5: 1 -2 ti mes per wee k  
6: L ess t ha n o n ce a wee k  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 5  of 3 8  
 
 
7: N e ver o ver t he past 2 wee ks  
8  
O ver t he past 2 w ee ks, h o w m uc h has 
y o ur s h ort ness of breat h b ot here d y o u?  
1: E xtre mel y b ot h ers o me  
2: Q uite a bit b ot hers o me  
3: M o deratel y b ot hers o m e  
4: Sli g htl y b ot hers o me  
5: N ot at all b ot hers o me  
5 : I’ ve ha d n o s h ort n ess of breat h  
9  
O ver t he past 2 w ee ks, o n a vera ge, 
h o w ma n y ti mes ha v e y o u bee n f orce d 
t o slee p sitti n g u p i n a c h air or wit h at 
least 3 pill o ws t o pr o p y o u u p beca use 
of s h ort ness of breat h?  
1: E ver y ni g ht  
2: 3 or m ore ti mes a wee k, b ut n ot e ver y da y  
3: 1 -2 ti mes a wee k  
4: Less t ha n o n ce a wee k   
5: Ne ver o ver t he past 2 wee ks  
1 0  
Heart fail ure s y m pt o ms c a n w orse n f or 
a n u m ber of reas o ns. H o w s ure are 
y o u t hat y o u k n o w w h at t o d o, or 
w h o m t o call, if y o ur heart fail ure gets 
w orse?  
1: N ot at all s ure  
2: N ot ver y s ure  
3: S o me w hat s ure  
4: M ostl y s ure  
5: C o m pletel y s ure  
1 1  
H o w well d o y o u u n derst a n d  w hat 
t hi n gs y o u are a ble t o d o t o kee p y o ur 
heart fail ure s y m pt o ms fr o m getti n g 
w orse?  
1: D o n ot u n dersta n d at all  
2: D o n ot u n dersta n d ver y well  
3: S o me w hat u n dersta n d  
4: M ostl y u n d ersta n d  
5: C o m pletel y u n d ersta n d  
1 2  
O ver t he past 2 w ee ks, h o w m uc h has 
y o ur heart fail ure li mite d y o ur 
e nj o y me nt of life?  
1: It has e xtre mel y li mite d m y e nj o y me nt of life  
2: It has li mite d m y e nj o y m e nt of life q uite a bit  
3: It has m o deratel y li mite d m y e nj o y m e nt of life  
4: It has sli g htl y li mite d m y e nj o y me nt of life   
5: It has n ot li mite d m y e nj o y me nt of life at all  
1 3  
If y o u ha d t o s pe n d t he rest of y o ur life 
wit h y o ur heart fail ure t h e wa y it is 
ri g ht n o w, h o w w o ul d y o u feel a b o ut 
t his? 
1: N ot at all satisfie d  
2: M ostl y dissatisfie d  
3: S o me w hat satisfie d  
4: M ostl y s atisfie d 
5: C o m pletel y s atisfie d  
1 4  
O ver t he past 2 w ee ks, h o w ofte n ha ve 
y o u felt disc o ura ge d or d o w n i n t he 
d u m ps beca use of y o ur heart fail ure?  
1: I felt t hat wa y all of t h e ti me  
2: I felt t hat wa y m ost of t he ti me  
3: I occasi o nall y felt t hat wa y  
4: I  rarel y felt t hat wa y 
5: I ne v er felt t hat wa y  
1 5a  
H o w m uc h ha ve y o ur heart fail ure 
li mite d y o ur partici pati o n i n h o b bies, 
recreati o nal a cti vities o ver t he past 2 
wee ks?  
1: Se verel y li mite d  
2: Li mite d q uite a bit  
3: M o deratel y li mite d  
4: Sli g htl y li mite d  
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 6  of 3 8  
 
1 5 b  
H o w m uc h ha ve y o ur heart fail ure 
li mite d y o ur partici pati o n i n w or ki n g 
or d oi n g h o use h ol d c h ores o ver t he 
past 2 wee ks?  
5: Di d n ot li mite d at all  
Missi n g : D oes n ot a p pl y or di d n ot d o f or ot her 
reas o ns 
1 5c  
H o w m uc h ha ve y o ur heart fail ure 
li mite d y o ur partici pati o n i n visiti n g 
fa mil y or frie n ds o ut of y o ur h o me 
o ver t he past 2 w ee ks?  
1 5 d  
H o w m uc h ha ve y o ur heart fail ure 
li mite d y o ur partici pati o n i n i nti mate 
relati o ns hi ps wit h l o ve d o nes o ver t he 
past 2 wee ks?  
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 7  of 3 8  
 
 
 
 
 
 
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
1 Dece m ber 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 6 6 5  
V ersi o n:  
4. 0  
U T N: U 1 1 1 1 -1 2 4 3 -4 3 5 8  
Stat us:  
Fi n al  
E u dra C T N o: 2 0 1 9 -0 0 4 4 5 2 -1 1  
P a ge:  
3 8  of 3 8  
 
 
7  Refere nces  
1.  Mc E v o y B W. Missi n g data i n cli nical trials f or wei g ht ma na ge me nt. J Bi o p har m Stat. 
2 0 1 6; 2 6( 1): 3 0 -6.  
2.  Wa n g D, P oc oc k S. A wi n rati o a p pr oac h t o c o m p ari n g c o nti n u o us n o n -n or mal o utc o mes i n 
cli nical trials. P har m Stat. 2 0 1 6; 1 5( 3): 2 3 8-4 5.  
3.  B yr o m B, Bree d o n P, T ul k ki -Wil ke R, Plat k o J. Mea ni n gf ul c ha n ge: Defi ni n g t he 
i nter preta bilit y of c ha n ges i n e n d p oi nts deri ve d fr o m i nteracti ve a n d m H ealt h tec h n ol o gi es 
i n healt hcare a n d cli nic al researc h. J o ur nal of Re h a bilitati o n a n d Assisti ve Tec h n ol o gies 
E n gi ne eri n g. 2 0 2 0; 7: 2 0 5 5 6 6 8 3 1 9 8 9 2 7 7 8.  
4.  Gree n C P, P orter C B, Bres na ha n D R, S pert us J A. De vel o p me nt a n d e val uati o n of t he 
Ka nsas Cit y Car di o m y o p at h y Q uesti o n naire: a ne w healt h stat us meas ure f or heart fail ure. J 
A m C oll Car di ol. 2  
5.  Ga o h o n g D o n g, J. Q. ( 2 0 1 8). T he stratifie d wi n rati o. J o ur n al of Bi o p h ar m ace utic al 
St atistics , 7 7 8-7 9 6.  
6.  B ur ma n C F, S. C. ( 2 0 0 9). A rec ycli n g fra me w or k f or t he c o nstr ucti o n of B o nferr o ni -b ase d 
m ulti ple tests. St at Me d , 2 8( 5): 7 3 9 -6 1.  
 
 
 
C O N FI D E N TI A L