Clinical trial NCT04564742
Conditions: Acute Myocardial Infarction Heart Failure
Keywords: Myocardial Infarction Cardiovascular Outcome Trial
Sponsor: AstraZeneca
Start date: 2020-12-22; Completion date: 2023-07-05
Enrollment: 4017 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effect of dapagliflozin versus placebo, given once daily in addition to Standard of Care (SoC) therapies for patients with myocardial infarction (MI), for hospitalisation for heart failure (HHF), cardiovascular (CV) death, and other cardiometabolic outcomes.

Detailed description:
This is a multicentre, parallel group double-blind, placebo-controlled phase 3 registry-based randomised controlled trial (R-RCT) in patients without diabetes presenting with myocardial infarction (MI) (ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI)) and evidence of impaired regional or global LV systolic function or definite evidence of Q wave MI on ECG. In the study the effect of dapagliflozin versus placebo, given once daily in addition to SoC therapy will be evaluated for the hospitalisation for HF, CV death, and other cardiometabolic outcomes.

Arms: arm 1: Patients will be randomized 1:1 to either dapagliflozin or placebo arm 2: Placebo matching dapagliflozin
Interventions: intervention 1: Dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Dapagliflozin 10 mg tablets given once daily, per oral use intervention 2: Placebo matching dapagliflozin 10 mg tablets given once daily, per oral use

Protocol documents:
Prot_004.pdf: 
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Clinical Study Protocol
Study Intervention
Dapagliflozin
Study Code
D169DC00001
Version
4.0
Date
23 Feb 2023
A Registry-based, Randomised, Double-blind, Placebo-Controlled 
Cardiovascular Outcomes Trial to Evaluate the Effect of 
Dapagliflozin on Cardiometabolic Outcomes in Patients without 
Diabetes with Acute Myocardial Infarction at Increased Risk for 
Subsequent Development of Heart Failure


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Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number
EudraCT 2020-000664-31
NCT04564742
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D169DC00001
Amendment Number: 3
Study Intervention: Dapagliflozin
Study Phase: 3
Short Title
Dapagliflozin in Patients without DM with acute MI
Acronym: DAPA-MI
Medical Monitor Name and Contact Information will be provided separately
International Coordinating Investigator
Professor Stefan James
, Uppsala University
 Uppsala
Sweden
PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
CSP v.4.0 (Amendment 3)
23-Feb-2023
CSP v.3.0 (Amendment 2)
14-Dec-2021
CSP v.2.0 (Amendment 1)
25-May-2021
CSP v.1.0 (Original Protocol)
16-Apr-2020
Amendment 3 23-Feb-2023
This is a substantial amendment based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
In February 2023, the observed blinded primary endpoint event rate in the DAPA-MI study was 
substantially lower than anticipated. To maximize the scientific value of the study, without 
substantially increasing the sample size or prolonging the study duration,  the primary endpoint 
and the primary analysis method were revised to evaluate the effect of dapagliflozin on a series 
of cardiometabolic outcomes, assessed as a hierarchical composite endpoint using a win-ratio 
analysis. 
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Protocol Title
To reflect the trial will 
evaluate the effect of 
dapagliflozin on 
cardiometabolic 
outcomes.
Changed to reflect the 
revised primary endpoint.
Substantial
1.1 Synopsis
To reflect the trial will 
evaluate the effect of 
dapagliflozin on 
cardiometabolic 
outcomes.
Changed to reflect the 
revised primary endpoint.
Substantial
1.2 Schema
Figure 1 
Study assumptions 
were updated.
To reflect the change in 
study description.
Substantial
2.1 Study Rationale
To reflect the trial will 
evaluate the effect of 
dapagliflozin on 
cardiometabolic 
outcomes.
Changed to reflect the 
revised primary endpoint.
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
2.3 Benefit/Risk 
Assessment
To reflect the addition 
of cardiometabolic 
outcomes in the 
revised primary 
endpoint.
To reflect the revised 
primary endpoint.
Substantial
Table 3 Objectives and 
Endpoints
Objectives and 
endpoints were
updated.
To reflect on how the study 
will be evaluated.
Substantial
4.1 Overall Design 
To reflect hierarchical 
composite endpoint 
approach.
To reflect the revised 
primary endpoint.
Substantial
4.4 End of study definition 
PACD was removed 
and the end of the 
study definition was 
re-defined.
To allow for patients to 
perform closure visits 
before all patients have 
been followed up 3 
months.
Non-substantial
4.6 The Trial Registry 
Collaborators
To clarify MINAP 
access was not 
provided to hospitals in 
Scotland.
Due to revised study 
timelines.
Non-substantial
4.8 Study Committees
Efficacy interim 
analysis was removed.
Not applicable due to the 
revised primary endpoint.
Non-substantial
7.3 Lost to Follow up
PACD was removed 
and the definition of 
lost to follow-up was 
updated.
To align with the modified 
closure of the study.
Non-substantial
8.1 Efficacy Assessments
It was aligned with 
updated objectives and 
endpoints.
To reflect on how the study 
will be evaluated.
Substantial
8.3 Adverse Events and 
Serious Adverse Events
The reference was 
changed to the primary 
endpoint.
To align with revised 
objectives and endpoints.
Substantial
8.11 UnifyTM Mobile 
Software Application
PACD was removed 
and the collection 
schedule with Unify 
app was updated.
To align with the modified 
closure of the study.
Non-substantial
9.1 Statistical Hypotheses
The efficacy interim 
analysis was removed
Previous assumption for 
interim analysis no longer 
applicable.
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
and allocation of alpha 
was updated.
9.2 Sample Size 
Determination
The sample size 
calculation was 
updated.
To align with the revised 
primary endpoint.
Substantial
9.4 Statistical Analyses
Primary and secondary 
endpoints assessments 
were updated.
To align with revised 
objectives and endpoints.
Substantial
9.5 Interim Analyses
Efficacy interim 
analysis was removed.
Previous assumption for 
interim analysis no longer 
applicable.
Substantial
Appendix A1 Regulatory 
and Ethical Considerations
Requirements for 
"Serious Breaches” 
was added.
The update was required to 
comply with regulatory 
and  global company 
requirements.
Non-substantial
Appendix A6 Data Quality 
Assurance
Updated information 
about retention 
timelines of records 
and documents to 
[25 years after study 
archiving or as 
required by local 
regulations].
The update was required to 
comply with global 
company requirement.
Non-substantial


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 6
LIST OF TABLES................................................................................................................ 9
LIST OF FIGURES .............................................................................................................. 9
LIST OF APPENDICES....................................................................................................... 9
1
PROTOCOL SUMMARY................................................................................ 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 16
1.3
Schedule of Activities....................................................................................... 17
2
INTRODUCTION............................................................................................ 22
2.1
Study Rationale ................................................................................................ 22
2.2
Background ...................................................................................................... 23
2.2.1
Dapagliflozin Mode of Action .......................................................................... 23
2.2.2
Cardiovascular Benefits of Dapagliflozin.......................................................... 24
2.3
Benefit/Risk Assessment................................................................................... 25
2.3.1
Risk Assessment............................................................................................... 25
2.3.2
Benefit Assessment........................................................................................... 26
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 26
3
OBJECTIVES AND ENDPOINTS................................................................... 26
4
STUDY DESIGN ............................................................................................. 29
4.1
Overall Design.................................................................................................. 29
4.2
Scientific Rationale for Study Design ............................................................... 30
4.3
Justification for Dose........................................................................................ 31
4.4
End of Study Definition.................................................................................... 31
4.5
The DAPA-MI Clinical Context ....................................................................... 31
4.6
The Trial Registry Collaborators....................................................................... 32
4.6.1
The SWEDEHEART ........................................................................................ 32
4.6.1.1
Scope................................................................................................................ 32
4.6.1.2
Data Collection and Quality Assurance Process ................................................ 32
4.6.2
The NICOR/MINAP Registry........................................................................... 33
4.6.2.1
Scope................................................................................................................ 33
4.6.2.2
Data Collection and Quality Assurance Process ................................................ 34
4.7
The Study-specific R-RCT Framework............................................................. 34
4.8
Study Committees............................................................................................. 35
4.8.1
Executive Committee........................................................................................ 35
4.8.2
Clinical Endpoint Committee............................................................................ 35
4.8.3
Data Monitoring Committee ............................................................................. 35


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5
STUDY POPULATION ................................................................................... 36
5.1
Inclusion Criteria .............................................................................................. 37
5.2
Exclusion Criteria ............................................................................................. 38
5.3
Lifestyle Considerations ................................................................................... 40
5.3.1
Meals and Dietary Restrictions ......................................................................... 40
5.3.2
Caffeine, Alcohol, and Tobacco........................................................................ 40
5.3.3
Activity............................................................................................................. 40
5.4
Screening.......................................................................................................... 40
5.4.1
Procedures for Incorrectly Screened or Randomised Participants ...................... 40
6
STUDY INTERVENTION............................................................................... 41
6.1
Study Intervention(s) Administered .................................................................. 41
6.1.1
Investigational Products.................................................................................... 41
6.1.2
Medical Devices ............................................................................................... 41
6.2
Preparation/Handling/Storage of Interventions.................................................. 42
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 42
6.3.1
Emergency Unblinding ..................................................................................... 43
6.4
Study Intervention Compliance......................................................................... 44
6.5
Concomitant Therapy........................................................................................ 44
6.5.1
Prohibited Medication....................................................................................... 45
6.5.2
Background Medication.................................................................................... 45
6.5.3
Other Concomitant Treatment........................................................................... 45
6.5.4
Recording of Concomitant CV and Glucose Lowering Medications.................. 45
6.5.5
Invasive Cardiac Procedures ............................................................................. 45
6.6
Intervention After the End of the Study............................................................. 46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 46
7.1
Discontinuation of Study Intervention............................................................... 46
7.1.1
Temporary Discontinuation............................................................................... 47
7.1.2
Rechallenge ...................................................................................................... 47
7.1.3
Procedures for Permanent Discontinuation of Study Treatment......................... 47
7.1.4
Evaluation of Volume Status............................................................................. 47
7.1.5
Ketoacidosis in patients with type 2 diabetes mellitus ....................................... 48
7.2
Participant Withdrawal from the Study ............................................................. 49
7.3
Lost to Follow up.............................................................................................. 49
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 50
8.1
Efficacy Assessments........................................................................................ 50
8.1.1
Primary Outcome Assessments......................................................................... 51
8.1.1.1
Hospitalisation for Heart Failure ....................................................................... 51
8.1.1.2
Classification of Death...................................................................................... 51
8.1.2
Secondary Outcome Assessments ..................................................................... 51
8.1.3
Exploratory/Tertiary Outcome Assessments...................................................... 52
8.2
Safety Assessments........................................................................................... 53


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8.2.1
Blood Pressure.................................................................................................. 53
8.2.2
Clinical Safety Laboratory Assessments............................................................ 53
8.2.3
Other Safety Assessments................................................................................. 53
8.2.3.1
Body Mass Index.............................................................................................. 53
8.2.4
CleverCap LiteTM - Device deficiencies ............................................................ 53
8.3
Adverse Events and Serious Adverse Events..................................................... 54
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 54
8.3.2
Follow-up of Reportable AEs............................................................................ 55
8.3.3
Causality Collection.......................................................................................... 55
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 56
8.3.5
Adverse Events Based on Examinations and Tests............................................ 56
8.3.6
Hy’s Law.......................................................................................................... 56
8.3.7
Disease Progression.......................................................................................... 56
8.3.8
Disease-Under study......................................................................................... 57
8.3.9
Reporting of Serious Adverse Events................................................................ 57
8.3.10
Pregnancy......................................................................................................... 58
8.3.10.1
Maternal Exposure............................................................................................ 58
8.3.10.2
Paternal Exposure............................................................................................. 58
8.3.11
Medication Error............................................................................................... 58
8.3.12
Medical Device Deficiencies............................................................................. 59
8.4
Overdose .......................................................................................................... 59
8.5
Human Biological Samples............................................................................... 59
8.5.1
Pharmacokinetics.............................................................................................. 59
8.5.2
Immunogenicity Assessments ........................................................................... 60
8.5.3
Pharmacodynamics........................................................................................... 60
8.6
Human Biological Sample Biomarkers ............................................................. 60
8.7
Optional Genomics Initiative Sample................................................................ 60
8.8
Medical Resource Utilisation and Health Economics ........................................ 60
8.9
Study Plan and Timing of Procedures ............................................................... 60
8.9.1
Prerequisites ..................................................................................................... 60
8.9.2
Visit 1: Screening and Randomisation (Day 1).................................................. 60
8.9.3
Visit 2: Early Follow-visit, Week 8 (±14 days) ................................................. 61
8.9.4
Visit 3: The Second Follow-up Visit, Year 1 (±1 month) .................................. 62
8.9.5
Visit 4, 5, 6 etc: Study-specific Visit(s), Month 22 (±1 month) and Thereafter 
Occurring Every 10th Month Until Study Closure Visit .................................... 62
8.9.6
Premature Treatment Discontinuation Visit....................................................... 63
8.9.7
Study Closure Visit........................................................................................... 63
8.9.8
Unscheduled Visits ........................................................................................... 64
8.10
Clinical Trial Data Model ................................................................................. 64
8.11
UnifyTM Mobile Software Application .............................................................. 64
9
STATISTICAL CONSIDERATIONS............................................................... 65
9.1
Statistical Hypotheses....................................................................................... 65
9.2
Sample Size Determination............................................................................... 66


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9.3
Populations for Analyses .................................................................................. 66
9.4
Statistical Analyses........................................................................................... 67
9.4.1
General Considerations..................................................................................... 67
9.4.2
Efficacy ............................................................................................................ 67
9.4.2.1
Primary Endpoint(s).......................................................................................... 67
9.4.2.2
Secondary Endpoint(s)...................................................................................... 68
9.4.2.3
Tertiary/Exploratory Endpoint(s) ...................................................................... 68
9.4.2.4
Withdrawal From Study/Study Drug, Intercurrent Events and Estimand ........... 68
9.4.2.5
Subgroups......................................................................................................... 69
9.4.3
Safety ............................................................................................................... 69
9.4.4
Methods for Multiplicity Control ...................................................................... 69
9.5
Interim Analyses............................................................................................... 70
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 70
11
REFERENCES................................................................................................. 87
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 18
Table 2
Risk Assessment...................................................................................... 25
Table 3
Objectives and Endpoints......................................................................... 27
Table 4
Investigational Products........................................................................... 41
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 16
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 71
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 78
Appendix C
Abbreviations .......................................................................................... 82
Appendix D
EQ-5D-5L Health Questionnaire.............................................................. 85
Appendix E
Protocol Amendment History................................................................... 87


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title
A Registry-based, Randomised, Double-blind, Placebo-Controlled Cardiovascular Outcomes 
Trial to Evaluate the Effect of Dapagliflozin on Cardiometabolic Outcomes in Patients 
without Diabetes with Acute Myocardial Infarction at Increased Risk for Subsequent 
Development of Heart Failure
Short Title
Dapagliflozin in Patients without DM with acute MI
Rationale
Approximately 7 million individuals suffer a myocardial infarction (MI) annually, and 
survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, CV 
death and for developing heart failure (HF) (Piepoli et al 2016). The development of HF 
following an acute myocardial ischaemia episode is strongly associated with incapacitating 
symptoms, poor functional status, reduced health-related quality of life and unfavourable 
long-term prognosis (Nieminen et al 2015, Nunez-Gil et al 2010) . HF is also one of the 
leading causes of all hospital admissions, generating substantial costs for health care systems. 
Therefore, MI therapies that could prevent the development of HF as well as reoccurrence of 
major CV events represent a large and unmet medical need.
Sodium glucose co-transporter 2 inhibition with dapagliflozin is associated with several 
known or postulated cardioprotective effects. In large outcome studies, treatment with 
dapagliflozin have been shown to prevent HF events and CV death in type 2 diabetes mellitus 
(T2DM) patients  at high risk for, or with established atherosclerotic CV disease(Wiviott et al 
2019), and it has also been confirmed that dapagliflozin constitutes an effective treatment 
option in patients with established HF and reduced ejection fraction with and without T2DM 
(McMurray et al 2019). Observations from mechanistic studies have demonstrated 
multifaceted CV protective effects of dapagliflozin including influence on cardiac loading 
conditions (ie, reduced preload and afterload) (Lan et al 2019), energy substrate utilisation and 
left ventricular remodelling processes ─ which may also be of clinical benefit in the early 
phase after a MI (Lahnwong et al 2018; Santos-Gallego et al 2019).
This study will evaluate the effect of dapagliflozin 10 mg versus placebo, given once daily in 
addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of 
hospitalisation for HF (HHF) or CV death.
In February 2023, the study was revised to evaluate the effect of dapagliflozin 10 mg versus 
placebo, given once daily in addition to Standard of Care (SoC) therapies for patients with MI, 


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on hospitalisation for HF (HHF), CV death, and other cardiometabolic outcomes via a 
hierarchical composite endpoint (consists of incidence of non-fatal MI, AF/flutter event, new 
onset of T2DM, severity of heart failure symptoms assessed using NYHA class, as well as 
≥5% weight loss).
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM, symptoms of HF as measured 
by NYHA class, as well as reduced Body weight, in 
relation to placebo
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
7.
Body weight decrease of at least 5% at last 
visit
Secondary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM and symptoms of HF as 
measured by NYHA class, in relation to placebo
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
To demonstrate the superiority of dapagliflozin 
10 mg once daily (QD) versus dapagliflozin 10 mg 
placebo to match in reducing the incidence of CV 
death or HHF when added to SoC in non-diabetic 
patients with myocardial infarction and impaired left 
ventricular systolic function during the index MI 
hospitalisation
Time to the first occurrence of any of the components 
of this composite:
•
HHF
•
CV death


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Objectives
Endpoints
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing MI, stroke or CV 
death (MACE) when added to SoC
Time to the first occurrence of any of the components 
of this composite:
•
MI
•
Stroke (incl. ischaemic, haemorrhagic and 
undetermined stroke)
•
CV death
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of CV 
death when added to SoC
Time to CV death
To investigate whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of fatal 
or non-fatal MI when added to SoC
Time to the first occurrence of a fatal or a non-fatal 
MI
To determine whether dapagliflozin 10 mg QD, 
compared with placebo, reduces the incidence of new 
onset T2DM in MI patients when added to SoC
Time to new onset of T2DM
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing Body Weight when 
added to SoC
Change from baseline in Body weight
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of  
hospitalisation for any cause when added to SoC
Time to hospitalisation for any cause
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of all-
cause mortality when added to SoC
Time to death of any cause
Tertiary/Exploratory
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety
To evaluate the safety of dapagliflozin 10 mg QD in 
clinically stable patients with ST segment elevation 
myocardial infarction (ST)- or non-ST elevation 
myocardial infarction initiated on post-MI therapies 
and without an established diagnosis of type 1 
diabetes mellitus (T1DM) or T2DM
Adverse events defined as events that lead to:
•
death; or 
•
hospitalisation
For Tertiary/Exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
This is a multicentre, parallel group, event-driven, registry-based randomised controlled trial 
(R-RCT), double-blind, placebo-controlled phase 3 study in patients without diabetes 
CCI
CCI


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presenting with myocardial infarction (MI) (STEMI or NSTEMI) and impaired regional or 
global LV systolic function or definite evidence of Q wave MI on ECG. The study is 
conducted in Sweden and in the United Kingdom (UK) and will randomise about 6400 
patients. In the study the effect of dapagliflozin 10 mg versus placebo, given once daily in 
addition to SoC therapy will be evaluated for the prevention of hospitalisation for HF or CV 
death. The study will utilise 2 high-quality national, population-based clinical registries: (1) 
the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart 
disease Evaluated According to Recommended Therapies (Jernberg et al 2010) and (2) the 
UK-based Myocardial Ischaemia National Audit Project (Herret et al 2010). 
The R-RCT contains a framework, which allows for randomisation and blinding and enables a 
pragmatic data collection using existing clinical registry data with readily available trial 
infrastructure facilitating data and endpoint collection. The study design is intended to ensure 
a robust yet streamlined trial capable of producing high-quality evidence of clinical 
effectiveness and safety.
In February 2023, to address substantially lower than anticipated observed blinded primary 
endpoint event rate among recruited patients, the study was modified from an event-driven 
time-to-event approach to a hierarchical composite endpoint approach. The effect of 
dapagliflozin 10 mg versus placebo, given once daily in addition to SoC therapy will be 
evaluated for cardiometabolic outcomes. Accordingly, the sample size was re-calculated and 
reduced from about 6400 to approximately 4000 patients.
Disclosure Statement
This is a parallel group treatment study with 2 arms that is participant and investigator 
blinded.
Number of Participants
Patients admitted with MI to Coronary care units will be consecutively screened for 
participation to achieve at least 6400 randomly assigned to study intervention and 6400 
evaluable participants.
Screened a
Estimated 6400 participants
Randomly assigned
Estimated 6400 participants
Evaluable participants
Estimated 6400 participants
a
See Section 5.4 for definition.
In February 2023, the study was modified, and estimated number of screened, randomly 
assigned, and evaluable participants were re-calculated and reduced from 6400 to 
approximately 4000 accordingly.


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Intervention Groups and Duration
The study will compare treatment with dapagliflozin 10 mg once daily with dapagliflozin 
10 mg placebo to match in parallel treatment arms and at a 1:1 randomisation ratio. This study 
is event driven. The anticipated duration of the study is approximately 30 months with an 
estimated median treatment period for a patient of 21 months. The study closure procedures 
will be initiated when the predetermined number of primary endpoints are predicted to have 
occurred (n = 722) ie, the primary analysis censoring date. The study duration may be 
changed if the event rate or randomisation rate is different than anticipated. The study may be 
terminated early if either a clear beneficial or harmful effect of the study treatment is detected 
during the Data Monitoring Committee review.
In February 2023, the study was modified from an event-driven time-to-event approach to a 
hierarchical composite endpoint approach. The sample size was re-calculated and reduced 
from about 6400 to approximately 4000 patients and the median treatment period for a patient 
of 21 months was changed to a minimum follow-up time of 3 months for each patient.
Data Monitoring Committee: Yes
Statistical Methods
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint. Assuming a true hazard 
ratio of 0.80 between dapagliflozin and placebo, using a 2-sided alpha of 5%, 722 primary 
endpoint events will provide a statistical power of 85% for the test of the primary composite 
endpoint. This is based on an overall 1:1 allocation between dapagliflozin and placebo.
The study is event driven. With an annual event rate of 7.5% in the placebo treatment group, 
6400 patients are estimated to provide the required number of primary events, based on an 
anticipated recruitment period of 18 months and an average follow-up period of 
approximately 21 months. The sample size, duration of recruitment period, and total study 
duration may change depending on the recruitment rate and event rate of the primary 
endpoint. 
All patients who have been randomised to study treatment will be included in the Full 
Analysis Set irrespective of their protocol adherence and continued participation in the study. 
The primary variable is the time to first event included in the primary composite endpoint. 
The primary analysis will be based on the intention to treat principle using the Full Analysis 
Set, using events confirmed by adjudication.
In the analysis of the primary composite endpoint, treatments (dapagliflozin versus placebo) 
will be compared using a Cox proportional hazards model with a factor for treatment group. 
The p-value, hazard ratio and 95% confidence interval will be reported. An interim analysis is 


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planned to be performed when 2/3 of the primary endpoints are adjudicated, using a Haybittle-
Peto rule. The interim analysis will assess superiority of dapagliflozin to placebo.
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilised. No multiplicity control is placed on the exploratory 
endpoints.
In February 2023, the primary objective of the study was revised to determine if the clinical 
benefit of dapagliflozin is superior in relation to placebo and this objective will be assessed 
with a hierarchical composite endpoint and analysed using the win-ratio method. Assuming a 
true win-ratio of 1.20 between dapagliflozin and placebo, 4000 patients will provide a 
statistical power of 80% for the test of the primary composite endpoint. This is based on an 
overall 1:1 allocation between dapagliflozin and placebo.
All patients who have been randomised to study treatment will be included in the Full 
Analysis Set irrespective of their protocol adherence and continued participation in the study. 
The primary variable is a hierarchical composite endpoint, consisting of 7 components, 
assessed in the order of clinical importance, and will be analysed with the win-ratio method. 
The primary analysis will be based on the intention to treat principle using the Full Analysis 
Set.
1.2
Schema
Figure 1
Study Design


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SoC, Standard of Care, LV, left ventricular; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; 
MI, myocardial infarction; STEMI, ST-elevation myocardial infarction; NSTEMI, non ST-elevation myocardial 
infarction; R, randomisation; UK, United Kingdom; RRR, Relative Risk Reduction; MINAP, Myocardial 
Ischaemia National Audit Project; SWEDEHEART, Swedish Web-system for Enhancement and Development of 
Evidence-based care in Heart disease Evaluated According to Recommended Therapies
SoC, Standard of Care, LV, left ventricular; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; 
MI, myocardial infarction; STEMI, ST-elevation myocardial infarction; NSTEMI, non ST-elevation myocardial 
infarction; R, randomisation; UK, United Kingdom; MINAP, Myocardial Ischaemia National Audit Project; 
SWEDEHEART, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart 
disease Evaluated According to Recommended Therapies


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1.3
Schedule of Activities
Table 1
Schedule of Activities
Procedure a
Screening 
within 7 days 
(+3 days) after 
MI and prior to 
randomisation
Intervention period
Premature 
treatment 
discontinuation 
visit (PTDV)
Study 
Closure 
Visit
(SCV)
Details in CSP 
section or 
Appendix
Day 1
(within 7 (+3) 
days from MI)
Week 8
(±14 days)
Year 1 
(±1 month)
Month 22 and 
onwards
(±1 month)
Visit
NA
1
2
3
4+
Visit type
Randomisation
1st routine 
follow-up
2nd routine 
follow-up
Study-specific visit 
(every 10th month 
until SCV)
Informed consent
X
Section 5.1
Inclusion and 
exclusion criteria
X
Sections 5.1
and 5.2
STEMI/NSTEMI 
(index MI)
X
NA
Reperfusion 
treatment (index 
MI)
X
NA
Demography 
X
NA
Medical history b
X
NA
Relevant risk 
factors c
X
X
X
X
X
X
NA
Systolic and 
diastolic BP
X
X
X
X
X
X
NA
Weight
X
X
X
X
X
X
NA
Height
X
NA


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Table 1
Schedule of Activities
Procedure a
Screening 
within 7 days 
(+3 days) after 
MI and prior to 
randomisation
Intervention period
Premature 
treatment 
discontinuation 
visit (PTDV)
Study 
Closure 
Visit
(SCV)
Details in CSP 
section or 
Appendix
Day 1
(within 7 (+3) 
days from MI)
Week 8
(±14 days)
Year 1 
(±1 month)
Month 22 and 
onwards
(±1 month)
Visit
NA
1
2
3
4+
NYHA 
Classification (I-
IV)
X
X
X
X
X
NA
CCS angina class 
(I-IV)
X
X
X
X
X
NA
LVEF 
assessment d
X
NA
Troponin (peak 
value)
X
Sections 8.1.2, 
8.9.2
Serum creatinine 
for estimated 
glomerular 
filtration rate 
(eGFR)
X
NA
Pregnancy test (β-
hCG) e
X
NA
HbA1c
X
X
X
X
X
X
Sections 8.1, 
8.9
ECG
X
X
X
X
X
X
NA
Efficacy 
endpoints f
X
X
X
X
X
Section 8.1, 
Appendix A 7,
Safety events g
X
X
X
X
X
X
Section 8.3, 
Appendix B


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Table 1
Schedule of Activities
Procedure a
Screening 
within 7 days 
(+3 days) after 
MI and prior to 
randomisation
Intervention period
Premature 
treatment 
discontinuation 
visit (PTDV)
Study 
Closure 
Visit
(SCV)
Details in CSP 
section or 
Appendix
Day 1
(within 7 (+3) 
days from MI)
Week 8
(±14 days)
Year 1 
(±1 month)
Month 22 and 
onwards
(±1 month)
Visit
NA
1
2
3
4+
Additional
revascularisation 
therapy 
(PCI/CABG) 
X
X
X
X
X
X
NA
ICD implantation
X
X
X
X
X
N/A
EQ-5D-3L 
(Sweden only) h
X
X
Section 8.11
Device 
deficiencies
X
=============================
X
X
Section 8.2.4
Concomitant 
medication i
X
=============================
X
X
Section 6.5
Study intervention 
dispensed 
/collected
X j
X
X k
X k
Section 6.1
a
Procedures conducted as part of the participant’s routine clinical management (eg, blood tests, ECG, LVEF) and obtained before signing of the ICF may be 
utilised for screening or baseline purposes provided the procedures met the protocol-specified criteria and were performed within the time frame defined in 
the SoA.
b
Previous MI, Previous stroke, Previous HF, Previous PCI, Previous cardiac surgery, Prehospital CPR, history of Atrial Fibrillation/Atrial flutter.
c
Smoking, hypertension, dyslipidaemia (defined as statin treatment), From Visit 2 and onwards only smoking and diabetes.
d
From Visit 2 and onwards only if new LVEF evaluation has been performed in clinical routine.
e
Women of childbearing potential only.
f
Efficacy events, any potential heart failure hospitalisation and all fatal events will be sent for adjudication to evaluate if fulfilling criteria for endpoint event. 
In addition, MI and stroke endpoints as judged by the Investigator will be reported (for Guidance of definitions for MI and Stroke endpoints see Appendix 
A 7)
g
Serious adverse events (defined as adverse events that leads to hospitalisation or death), will be collected from randomisation.


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h
Version used in SEPHIA registry. EQ-5D-5L will be collected from Unify App users (in both UK and Sweden).  
i
ASA, Statins, ACE inhibitors/ARB, Antiplatelets other than ASA, Anticoagulants, Beta Blockers, MRA, Oral diabetic treatment, Insulin, Diuretics.
j
Study Intervention dispensation only.
k
Study Intervention collection only.
ACE inhibitors, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; ASA, acetylsalicyclic acid; BP, blood pressure; β-hCG, Beta human
chorionic gonadotropin; CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society; CPR, cardiopulmonary resuscitation; CSP, Clinical 
Study Protocol; NA, not applicable; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; EQ-5D-3L, EuroQol five-dimensional three-level 
questionnaire; HbA1c, glycated haemoglobin; HF, Heart Failure; ICD, implantable cardioverter defibrillator ; ICF, Informed Consent Form; IRT, Interactive 
Response Technology; LVEF, Left Ventricular Ejection Fraction; MI, myocardial infarction; MRA, Mineralocorticoid receptor antagonist ; NSTEMI, non-ST 
segment elevation myocardial infarction; NYHA, New York Heart Association; PCI percutaneous coronary intervention; PTDV, premature treatment 
discontinuation visit; SCV, study closure visit; SoA. Schedule of Activities; STEMI, ST segment elevation myocardial infarction.


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2
INTRODUCTION
An estimated 18 million individuals die from cardiovascular (CV) diseases annually, which 
accounts for approximately 30% of all global deaths, and places CV disease both as the 
leading global cause for years of life lost and as the leading cause of total number of deaths 
(Collaborators 2017). Acute MI is a major contributor to CV morbidity and mortality, globally 
estimated to occur in 7 million individuals annually (Piepoli et al 2016). The 1-year mortality 
for MI is estimated at 10%, and the risk for suffering a second major adverse CV event 
(MACE) among MI survivors is estimated at 20% within 1 year after the event (Piepoli et al 
2016).
In parallel with a gradual implementation of new, effective and guideline-supported MI 
treatments, such as percutaneous coronary intervention (PCI), dual antiplatelet therapy, statins 
and angiotensin-converting enzyme (ACE) inhibitors, the overall prognosis following MI has 
substantially improved over time (Szummer et al 2017; Szummer et al 2018; Townsend et al 
2015). However, this observed improvement in MI prognosis seems to have reached a plateau 
during recent years, coinciding with a period where few new breakthrough treatment concepts 
have been introduced within the MI treatment paradigm (Szummer et al 2017; Szummer et al 
2018).
Survivors of MI thus remain at substantial risk for new MACE, CV death (Jernberg et al 
2015) and for developing HF (Desta et al 2017). The development of HF following an MI 
episode is strongly associated with burdensome symptoms, poor functional status and reduced 
health-related quality of life (Nieminen et al 2015), and portend an unfavourable long term 
prognosis (Nunez-Gil et al 2010; Steg et al 2004; Wang et al 2016). Heart failure is also one 
of the leading causes of all hospital admissions, bringing on substantial costs for the health 
care systems. The current therapeutic strategies available to minimise the risk for development 
of HF following MI were all introduced more than a decade ago and include early reperfusion 
therapy, early initiation and proper dose-titration of ACE inhibitors/angiotensin II receptor 
blockers (ARBs) and aldosterone receptor antagonists, and careful evaluation and re-
evaluation of indications for beta-blocker therapy during and after the MI hospitalisation. 
Despite these advancements, MI patients remain at high CV risk and at high risk for 
developing HF. Therefore, MI therapies that could prevent the development of HF and 
reoccurrence of major CV events represent a large and partly unmet medical need.
2.1
Study Rationale
There is an unmet medical need in patients who have suffered a MI. Dapagliflozin treatment 
(and other sodium glucose co-transporter 2 [SGLT2]) has shown CV health benefits in 
patients with type 2 diabetes mellitus (T2DM) and either established atherosclerotic CV 
disease or CV risk factors. Recent confirmatory evidence has shown such benefits also in 
patients without diabetes with chronic HF and reduced ejection fraction. This study seeks to 


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determine dapagliflozin’s potential in the early prevention of serious complications, 
hospitalisations for HF or CV death, immediately following a MI.
In February 2023, it was concluded the observed primary endpoint event rate in the DAPA-MI 
study was substantially lower than anticipated. Therefore, it was decided to revise the primary 
endpoint to evaluate the effect of dapagliflozin on cardiometabolic outcomes, assessed by a 
hierarchical composite endpoint and a Win-ratio analysis.
2.2
Background
The development of HF following an acute myocardial ischaemia episode is strongly 
associated with incapacitating symptoms, poor functional status, reduced health-related 
quality of life and unfavourable long-term prognosis (Nieminen et al 2015, Nunez-Gil et al 
2010). Therefore, MI therapies that could prevent the development of HF as well as 
reoccurrence of major CV events represent a large and unmet medical need. In large outcome 
studies, treatment with dapagliflozin have been shown to prevent HF events and CV death in 
T2DM patients at high risk for, or with established atherosclerotic CV disease (Wiviott et al 
2019), and it has also been confirmed that dapagliflozin constitutes an effective treatment 
option in patients with established HF and reduced ejection fraction (HFrEF) with and without 
T2DM (McMurray et al 2019).
2.2.1
Dapagliflozin Mode of Action
For a detailed description of the chemistry, pharmacology, efficacy, and safety of 
dapagliflozin please refer to the Investigator’s Brochure (IB). 
Dapagliflozin is the first in a class of compounds referred to as SGLT2 inhibitors. SGLT2 is 
localised to the renal proximal tubule where it reabsorbs about 90% of the ~ 180 g of glucose 
normally filtered through the glomeruli each day (Sarafidis et al 2019; Zhang and Liu 2016). 
SGLT2 inhibition therefore leads to pharmacologically controlled glucosuria. Dapagliflozin is 
a highly potent, selective, and reversible oral SGLT2 inhibitor. A pharmacokinetic half-life of 
12.5 hours, due to the C-aryl glucoside-derived chemical structure, allows for the oral 
administration of dapagliflozin once daily. In patients with diabetes, SGLT2 inhibition 
reduces renal glucose reabsorption and consequently increases urinary excretion of excess 
glucose, reduces fasting and postprandial glucose, and reduces circulating glycated 
haemoglobin (HbA1c). The persistent loss of calories via the urine results in a negative energy 
balance and in the reduction of total body fat and weight loss. Dapagliflozin also induces 
diuresis, natriuresis, and decreases blood pressure (BP) without concomitantly trigger an 
increase in sympathetic tone. Dapagliflozin was originally developed to improve glycaemic 
control in adult patients with T2DM. Subsequent clinical development programmes have 
assessed dapagliflozin in the clinical management of type 1 diabetes mellitus (T1DM), and 
dapagliflozin’s cardiorenal benefits in diabetic and non-diabetic subjects, including those with 
HF and chronic kidney disease (CKD). As of 4 October 2019, more than 20000 subjects have 


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been treated in clinical trials (CTs) with dapagliflozin for T2DM, more than 1000 subjects for 
T1DM, and more than 4000 subjects for HF.
2.2.2
Cardiovascular Benefits of Dapagliflozin
Dapagliflozin have been extensively studied in phase IIb and phase III drug development 
programmes, and has been shown to exert protective cardiorenal effects in patients with 
diabetes and established atherosclerotic CV disease or CV risk factors, reducing the incidence 
of hospitalisation for heart failure (HHF) and CV death (Wiviott et al 2019), and attenuating 
progression to CKD (Mosenzon et al 2019). Furthermore, in a pre-specified subgroup analysis 
of patients with T2DM and a history of MI included in the DECLARE-TIMI 58 trial, 
dapagliflozin also reduced the risk of the composite of MI, ischaemic stroke or CV death 
(hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.72-0.99) (Furtado et al 2019).
In addition to dapagliflozin’s positive glycaemic and CV protective health benefits in patients 
with diabetes, evidence suggests that the observed CV benefits from SGLT2 inhibition in 
patients with diabetes mellitus is best explained by multifaceted positive actions on 
pathophysiological factors linked with CV disease, that to a large extent are uncoupled from 
the blood glucose lowering effect per se. The effects are likely driven by adaptive changes 
inflicted by the continuous loss of glucose but are catalysed by diabetes-independent factors 
such as reduced sodium load, circulating blood volume, BP and body weight. This concept is 
further supported by the observation that the principal CV health benefits from SGLT2 
inhibition in the major outcome trials in T2DM conducted hitherto were observed very early 
during the study courses (ie, before any effect of blood glucose lowering on CV outcomes 
could be expected). It is therefore highly plausible, that the observed CV benefits of SGLT2 
inhibition may extend outside the scope of diabetes mellitus populations, a hypothesis that 
was recently confirmed in a large outcome trial in patients with HF and reduced ejection 
fraction, the DAPA-HF trial (McMurray et al 2019). Data from healthy volunteers also shows 
that by inhibiting SGLT2, dapagliflozin effectively blocks the reabsorption of sodium and 
glucose in the kidney in healthy subjects, indicating that the drug mechanism works in patients 
both with and without diabetes.
Although the exact causal mechanisms responsible for the broadly observed CV benefit of 
dapagliflozin is still incompletely understood, there are several proposed mechanisms of 
action—uncoupled from the glucose lowering effect— by which SGLT2 inhibitors can act as 
cardioprotective agents. These includes but are not limited to: (1) a diuretic effect with a 
preferential effect on interstitial volume congestion  (Hallow et al 2018), (2) Positive 
hemodynamic effects due to improvement in left ventricular loading conditions (ie, reduced 
preload and afterload) (Lan et al 2019), (3) positive influence on left ventricular remodelling 
following MI, as demonstrated in non-diabetic animal models (Lahnwong et al 2018, Santos-
Gallego et al 2019), (4) increase in haematocrit levels and thus oxygen transporting capacity 
due to decreased plasma volume and an erythropoietin-induced increase in erythrocyte counts 


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(Sarafidis et al 2019), (5) mitigation of excess neurohormonal activation and extent of 
myocardial damage following a MI (Lahnwong et al 2018) and (6) continuous off-target 
inhibition of sodium-proton antiporters by SGLT2 inhibitors, an action that potentially 
mimic’s ischaemic preconditioning mechanisms that may protect cardiomyocytes during 
hypoxic conditions (McCullough et al 2018).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
dapagliflozin can be found in the IB.
The expected benefits in the post MI population is based on that SGLT2 inhibition with 
dapagliflozin is associated with several known or postulated cardioprotective effects. In large 
outcome studies, treatment with dapagliflozin have been shown to prevent HF events and CV 
death in T2DM patients at high risk for, or with established atherosclerotic CV disease, and it 
has also been confirmed that dapagliflozin constitutes an effective treatment option in patients 
with established HFrEF with and without T2DM. Observations from mechanistic studies have 
demonstrated multifaceted CV protective effects of dapagliflozin including influence on 
cardiac loading conditions, energy substrate utilisation and left ventricular remodelling 
processes ─ which may also be of clinical benefit in the early phase after a MI.
The safety profile for dapagliflozin is very well characterised. The risk profile in the post MI 
population is expected to be similar to the known safety profile. In the DECLARE-TIMI 58 
trial dapagliflozin 10 mg was evaluated generating comprehensive safety data in a high-risk 
CV risk T2DM population including patients with established CV disease. Regarding post MI 
patients an analysis was performed of the subgroups of patients in the DECLARE-TIMI 58 
trial with prior MI at baseline (n = 3,584) versus no prior MI (n = 13,576). The safety 
outcomes in the dapagliflozin-treated patients were similar between subgroups (Furtado et al 
2019, Wiviott et al 2019). The DAPA-HF study randomised patients with HFrEF (n = 4,744) 
including both patients without diabetes (≈55%) and patients with T2DM at baseline (≈45%). 
The safety and tolerability were generally consistent between patients with T2DM and 
patients without diabetes (McMurray et al 2019).
2.3.1
Risk Assessment
Table 2
Risk Assessment
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Study intervention
Hypotension
Dapagliflozin causes an osmotic 
diuresis, which may lead to 
hypotension. In addition, many 
drugs introduced post-MI, as per 
Inclusion criteria:
Patients should be hemodynamically 
stable at randomisation (no episodes of 


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Table 2
Risk Assessment
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
clinical routines, are affecting 
blood pressure.
symptomatic hypotension, or 
arrhythmia with hemodynamic 
compromise in the last 24 hours).
Study procedures
Visit schedule/time between 
visits
Being a pragmatic trial, timing of 
visits is aligned with routine 
clinical practice.
In addition to the visits according to 
clinical routine the first year, patients 
will be followed up with visits every 
10th month until study completion. 
Patients can contact site personnel as 
needed also between visits.
MI, Myocardial Infarction; BP, blood pressure
2.3.2
Benefit Assessment
All MI patients in the study will be optimally treated according to Standard of Care (SoC), and 
dapagliflozin or placebo will be added on top of this treatment. The hypothesis is that 
dapagliflozin will reduce hospitalisation for HF or CV mortality in patients randomised to 
active drug. Furthermore, dapagliflozin is also known to decrease body weight (or prevent 
weight gain) as well as lowering BP and is believed to be nephroprotective through 
mechanisms uncoupled from the blood glucose lowering effect per se. These effects of 
dapagliflozin could all potentially be of benefit in the target population that have recently 
suffered an MI. All patients participating in CTs irrespective of whether treated with active 
treatment or not, generally receive closer medical attention.
In February 2023, the primary endpoint was revised to assess the potential benefit of 
dapagliflozin in the target population on HHF, CV death, and other cardiometabolic outcomes.
2.3.3
Overall Benefit: Risk Conclusion
Participation in this study should present a minimal and acceptable risk to patients who meet 
the inclusion/exclusion (I/E) criteria and consent to take part in the study, with regard to the 
substantial non-clinical and clinical experience with dapagliflozin, the potential CV benefit 
that the drug is hypothesised to exert in the target population due to its mechanism of action, 
and the generally safe and well tolerated character of the drug. The well-tolerated character is 
also consistent in a T2DM population with established CV disease and prior MI, as well as in 
a HFrEF population without diabetes.
3
OBJECTIVES AND ENDPOINTS
The table below presents study Objectives and Endpoints.


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Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM, symptoms of HF as measured 
by NYHA class, as well as reduced Body weight, in 
relation to placebo
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
7.
Body weight decrease of at least 5% at last 
visit
Secondary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM and symptoms of HF as 
measured by NYHA class, in relation to placebo
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
To demonstrate the superiority of dapagliflozin
10 mg once daily (QD) versus dapagliflozin 10 mg 
placebo to match in reducing the incidence of CV 
death or HHF when added to SoC in non-diabetic 
patients with myocardial infarction and impaired left 
ventricular systolic function during the index MI 
hospitalisation
Time to the first occurrence of any of the components 
of this composite:
•
HHF
•
CV death
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing MI, stroke or CV 
death (MACE) when added to SoC
Time to the first occurrence of any of the components 
of this composite:
•
MI
•
Stroke (incl. ischaemic, haemorrhagic and 
undetermined stroke)
•
CV death


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Table 3
Objectives and Endpoints
Objectives
Endpoints
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of CV 
death when added to SoC
Time to CV death
To investigate whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of fatal 
or non-fatal MI when added to SoC
Time to the first occurrence of a fatal or a non-fatal 
MI
To determine whether dapagliflozin 10 mg QD, 
compared with placebo, reduces the incidence of new 
onset T2DM in MI patients when added to SoC
Time to new onset of T2DM
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing Body Weight when 
added to SoC
Change from baseline in Body weight
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of  
hospitalisation for any cause when added to SoC
Time to hospitalisation for any cause
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of all-
cause mortality when added to SoC
Time to death of any cause
Tertiary/Exploratory
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Table 3
Objectives and Endpoints
Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety
To evaluate the safety of dapagliflozin 10 mg QD in 
clinically stable patients with ST segment elevation 
myocardial infarction (ST)- or non-ST elevation 
myocardial infarction initiated on post-MI therapies 
and without an established diagnosis of type 1 
diabetes mellitus (T1DM) or T2DM
Adverse events defined as events that lead to:
•
death; or 
•
hospitalisation
4
STUDY DESIGN
4.1
Overall Design
This is a multicentre, parallel group, event-driven, registry-based, randomised, double-blind, 
placebo-controlled phase 3 study in non-diabetic patients presenting with MI (STEMI or 
CCI
CCI


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NSTEMI) and impaired regional or global LV systolic function or definite evidence of Q 
wave MI on ECG. The study is conducted in Sweden and in the UK. The study addresses a 
clear unmet medical need in patients with MI (post-MI HF development) and will evaluate the 
effect of dapagliflozin 10 mg versus placebo, given once daily in addition to SoC therapy, for 
the prevention of hospitalisation for HF or CV death. The innovative trial design uses a 
registry-based randomised controlled trial (R-RCT) framework (Lauer and D'Agostino 2013; 
Nyberg and Hedman 2019), a trial concept not previously used in drug development 
programmes with the intent of regulatory approval. Based on the availability of adequate web-
based registries with full coverage of the target population and available infrastructure for the 
specific trial requirements, the study will be conducted in Sweden and the United Kingdom, 
and will utilise 2 high-quality national, population-based clinical registries: (1) the Swedish 
Web-system for Enhancement and Development of Evidence-based care in Heart disease 
Evaluated According to Recommended Therapies (SWEDEHEART) (Jernberg et al 2010) and 
(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP) (Herret et al 2010). 
This R-RCT adheres to an innovative trial design integrated within 2 national population-
based health quality registries and therefore will be conducted in the setting of routine clinical 
practice. The R-RCT contains a framework, which allows for randomisation and blinding and 
enables a pragmatic data collection using existing clinical registry data with readily available 
trial infrastructure facilitating data and endpoint collection. The study design is intended to 
ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical 
effectiveness and safety.
For an overview of the study design, see Figure 1. For details on treatments given during the 
study, refer to Section 6.1.
For details on what is included in the efficacy and safety endpoints, refer to Section 3
Objectives and Endpoints.
In February 2023, the study was modified from an event-driven time-to-event approach to a 
hierarchical composite endpoint approach. The effect of dapagliflozin 10 mg versus placebo, 
given once daily in addition to SoC therapy will be evaluated for the HHF, CV death, and
other cardiometabolic outcomes.
4.2
Scientific Rationale for Study Design
This multi-centre trial has been designed as an R-RCT that combines traditional study design 
elements within a pragmatic trial framework to provide high quality evidence on the potential 
benefit of dapagliflozin when administered in the early phase after MI. Traditional design 
elements such as randomisation and double blinding will minimise potential bias while the 
pragmatic and streamlined trial elements are expected to capture a broad MI population that 
will increase external validity and generalisability of study results and at the same time limit 


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study burden on patients and investigators by usage of existing healthcare infrastructure and 
enabled by  continuous clinical quality registries used in routine health care.
4.3
Justification for Dose
The marketed dose (10 mg QD) of dapagliflozin has been demonstrated to be well tolerated 
and effective both for the treatment of T2DM and chronic HF. From a pharmacokinetic and 
pharmacodynamic perspective, 10 mg dapagliflozin is appropriate for use in the target 
population with recent MI at high risk for developing HF, as this dose is expected to near 
maximally inhibit SGLT2 and thus exert an adaptive bodily response to the treatment that 
translate to the strongest CV benefit. In most previous double-blind studies of dapagliflozin in 
T2DM, the 10 mg dose of dapagliflozin was found to be more effective and with comparative 
safety as the 2.5 mg and 5 mg doses. Furthermore, the use of only 1 dose (ie, 10 mg QD) of 
dapagliflozin in this study fit well with the pragmatic trial framework, as dispense of different 
doses of study drug would complicate the drug delivery process.
4.4
End of Study Definition
The end of study is defined as the last visit of the last subject undergoing the study. A subject 
is considered to have completed the study when he/she has completed his/her event 
assessment on or after the primary analysis censoring date (PACD).
The executive committee and AstraZeneca (AZ) will monitor the accrual of endpoint events 
and when appropriate define the PACD at which time at least the pre-defined target number of 
722 subjects with adjudicated events for the primary composite endpoint is expected to have 
occurred. The study sites will be instructed to plan for study closure visits to be performed 
within approximately 8 weeks after PACD.
In February 2023, it was decided to remove PACD from the study. As a consequence, the 
definition of the end of study was modified to the last visit of the last subject undergoing the 
study. A subject is considered to have completed the study when he/she has completed his/her 
close-out visit.
The executive committee and AstraZeneca (AZ) will monitor the accrual of patients and when 
appropriate define a certain date at which time the close-out period will start and the study 
sites should commence with the study closing visits. The close-out period will extend for at 
least 10 weeks.
4.5
The DAPA-MI Clinical Context
In Sweden, MI patients are discharged from hospital typically after 2 to 4 days. In routine 
clinical care, all patients are planned for a visit to a specialised secondary prevention nurse 12 


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weeks after discharge to check symptoms, assess adherence and potential side effects to 
medications, and perform up-titration of medication doses. If there are issues, the discharging 
doctor or the doctor with the assigned patient responsibility is consulted. This doctor will 
typically be responsible for the dedicated secondary prevention visit at 6 to 10 weeks post 
discharge (SEPHIA (the national registry of secondary prevention) visit 1) as well as the 12 
months follow-up visit (SEPHIA visit 2). 
In UK practice, there is more heterogeneity between sites in terms of duration of hospital stay 
and follow-up arrangements. Generally, patients receive follow-up with the cardiac 
rehabilitation team, and most have a single outpatient clinic follow-up with a clinician or 
nurse specialist between 4 and 12 weeks, following which they are mostly discharged back to 
the care of their general practitioner. However, for the purpose of this study visits will be 
scheduled at 6 to10 weeks post discharge. Some sites have started to implement arrangements 
for 12 months follow-up.
For any trial-specific issue, the site investigator will always be informed, thereby maintaining 
the investigator-patient relationship throughout the study period. All study patients will have 
the opportunity to contact the research nurses who will have direct contact with the site 
investigators.
4.6
The Trial Registry Collaborators
4.6.1
The SWEDEHEART
4.6.1.1
Scope
The SWEDEHEART was launched December 2009 following a merger between (1) the 
national registry of acute cardiac care (RIKS-HIA), (2) the Swedish coronary angiography and 
angioplasty registry, (3) the Swedish heart surgery registry and (4) the national registry of 
secondary prevention (SEPHIA) (Jernberg et al 2010). The SWEDEHEART registry is 
financed by the Swedish government and the Swedish Association of Local Authorities and 
Regions (the public health care provider), and is supported by the Swedish Heart Association, 
the National Board of Health and Welfare and the Swedish Heart and Lung Foundation. 
Participating hospitals are not reimbursed by the registry and costs of local data entry are 
borne by their internal budget. Uppsala Clinical Research Center (UCR) has developed the 
web services for the registry and is responsible for administration, quality controls, and 
statistical reports. 
4.6.1.2
Data Collection and Quality Assurance Process
The SWEDEHEART includes all patients admitted to cardiac intensive care units with 
confirmed MI, and all hospitals in Sweden providing care for MI patients participate in the 
registry collaboration. All patients are informed about their participation in the registry and 
maintain the right to opt out from participation. The registry is web-based with all data 
registered online by the caregiver, where after data is transferred in an encrypted format to a 


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secure central server. The whole process of care is kept together in one master record, also in 
cases where the patient is transferred between different units and hospitals. The registry 
system has error checking routines for range and consistency. Variable definitions are easily 
available for the user when data are entered, and to reach a high degree of completeness, most 
of the variables are mandatory. Each hospital can monitor site data completeness online, and 
the accuracy of imputed data elements are regularly subjected to central monitoring/audits.
For patients with MI, information is collected prospectively for more than 100 variables and 
include patient demographics, admission logistics, risk factors, past medical history, medical 
treatment prior to admission, electrocardiographic changes, biochemical markers, other 
clinical features and investigations, medical treatment in hospital, interventions, hospital 
outcome, discharge diagnoses and discharge medications. For MI patients undergoing 
coronary angiography/angioplasty, approximately 150 additional variables are registered. For 
patients who have been hospitalised for MI, a follow-up visit is performed after 6 to 10 weeks 
and again after 12 months. From these visits approximately 75 new variables are added in the 
SEPHIA sub registry. The registry platform is interlinked with the Swedish National 
Population Registry, providing monthly automated updates on time of death. For the present 
study, a selection of variables, harmonised with variables from the MINAP registry, will 
continuously be extracted from the registry to the electronic case report form (eCRF) system.
4.6.2
The NICOR/MINAP Registry
4.6.2.1
Scope
The National Institute for Cardiovascular Outcomes Research (NICOR) is a quality 
improvement and research organisation that collects data and produces analysis to enable UK 
hospitals and healthcare improvement bodies to monitor and improve the quality of care and 
outcomes of CV patients. NICOR manages 6 national clinical audits in the UK and is a cross-
functional partnership of clinicians, IT experts, analysts, academics and data managers. 
NICOR provides project, technical and analytical support for the clinical audits and registries. 
One of the 6 registries that is governed by NICOR is the MINAP, a national registry of 
patients admitted to hospitals in England and Wales with acute coronary syndromes (ACS). 
The MINAP registry was established in 1998 to provide participating hospitals with a 
common mechanism for auditing performance against defined standards of ACS care. By mid-
2002 all hospitals providing care for ACS in England and Wales were participating in the 
registry. Registry oversight is provided by a steering group that represents key stakeholders, 
including professional bodies, patient groups and the national government. The MINAP 
registry is funded by the Department of Health and receives no commercial funding. The costs 
of local data entry are borne by the participating hospitals. Scotland does not take part in 
MINAP, but hospitals in Scotland can participate in the study, being provided access to the 
MINAP registry to enter data for those patients who have consented to the study.


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In February 2023, given the decision to alter the estimated date for the last subject recruited, 
as well as delays in the administrative and technical processes required, hospitals in Scotland 
were not provided with access to the MINAP registry.
4.6.2.2
Data Collection and Quality Assurance Process
The MINAP includes all patients admitted with confirmed MI, and all hospitals in England 
and Wales providing care for MI patients participate in the registry collaboration. A password-
protected webservice is used for data entry and data are uploaded to central servers using 
encrypted transfer protocols. Patients are identiﬁed from their unique National Health Service 
(NHS) number, which is pseudonymized within the database. The MINAP data entry set-up 
has automated error-checking routines, including range and consistency checks, and the 
accuracy of imputed data elements are regularly subjected to monitoring/audits. Online data 
completeness views are readily available for sites participating in the registry. The registry 
maintains a data dictionary, containing explanatory details for each unique variable entry.
The MINAP dataset comprises over 100 separate ﬁelds covering patient demographics, 
admission method, clinical features and investigations, medical history, drug treatment before 
admission, details of reperfusion treatment method, drug treatment in hospital, clinical 
complications, hospital outcome, discharge diagnosis and discharge pharmacotherapy. 
MINAP does not collect follow-up data but is linked to the Ofﬁce for National Statistics’ 
registry and uses each patient’s unique NHS number to obtain regular mortality updates. All 
patients maintain the right to opt out from participation. For the present study a selection of 
variables, harmonised with variables from the SWEDEHEART registry, will continuously be 
extracted from the registry to the eCRF system.
4.7
The Study-specific R-RCT Framework
The trial will be randomised and double-blind, conducted as an integrated part of normal 
clinic workflow and is expected to deliver scientifically robust data in accordance with Good 
Clinical Practice (GCP) and fulfilling the required standards for regulatory compliance.
This R-RCT utilises the platform of already-existing high-quality health registries (described 
in Sections 4.6.1 and 4.6.2) to  randomise and follow study participants during study course 
(Nyberg and Hedman 2019). Due to structural similarities between registries in terms of 
technical set-up and variable capture, these 2 registries allow the CT to be driven by a single 
set of technical solutions, and to provide consistent data from both registries. The DAPA-MI 
R-RCT is a stand-alone web-application managing trial processes such as patient 
randomisation. Continuous capture of relevant efficacy and safety endpoints, within the 
clinical routine platform is performed via data exports from the SWEDEHEART and UK 
MINAP registries. The DAPA-MI R-RCT application is used for collection of study-specific 
baseline data (not included in the MINAP or SWEDEHEART registries), for confirmation of 
patient eligibility, and for randomisation. A Site Screening Log including all patients entered 


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in the web application can be downloaded. In addition, a Site Subject and Enrolment log can 
be downloaded by the site personnel listing all randomised patients at their site. 
After randomisation an export of baseline variables from the applicable registry into the eCRF 
system is performed. In Sweden, part of the follow-up data from 6 to 10 weeks and 12 months 
post MI hospitalisation will also be collected by exporting data from SWEDEHEART into the 
eCRF system. The UK part of study requires the implementation of study-specific follow-up 
routines due to lack of a registry-supported clinical routine for follow-up visits in the MINAP 
registry. The follow-up in the UK will replicate the follow-up routine in Sweden. Data capture 
from follow-up visits after 12 months will be performed directly in the eCRF in both UK and 
Sweden. Vital status will be collected by exports from the registries in both countries 
throughout the study.
4.8
Study Committees
4.8.1
Executive Committee
The Executive Committee (EC) will be responsible for the overall design, including the 
development of the protocol and any protocol amendments, supervision, interpretation and 
reporting (presentations at international congresses and publications in peer reviewed 
journals) of the study. The EC will make recommendations to AZ regarding early stopping or 
modifications of the study based on the information received from the Data Monitoring 
Committee (DMC). The EC will be comprised of designated international academic leaders 
and non-voting members of the Sponsor, and will operate under a separate EC charter.
4.8.2
Clinical Endpoint Committee
An independent, blinded Clinical Endpoint Committee (CEC) will be appointed jointly by the 
Sponsors and the academic leadership of the study. The CEC will adjudicate the primary 
endpoint. Investigators will report potential events via eCRFs in real time. Once a potential 
event has been identified, a complete package of information will be collected with the goal to 
send to the CEC within 2 weeks of identification. A packet would be considered complete and 
allow for assessment if all required data are present. The CEC reviewers would set a target to 
evaluate the complete package within 4 weeks of receipt. Additional details are provided in 
the CEC charter.
4.8.3
Data Monitoring Committee
An independent DMC will be appointed jointly by the Sponsors and the academic leadership 
of the study. The DMC will be responsible for safeguarding the interests of the patients in the 
outcome study by assessing the safety of the intervention during the trial, and for reviewing 
the overall conduct of the CT. They will review overall safety in the trial. In addition, the 
DMC will have the responsibility to assess the efficacy data of the interim analysis and decide 
if stopping guidelines are met. An Independent statistical group will have access to the 


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individual treatment codes and will be able to merge these with the collected study data and 
provide to the DMC while the study is ongoing. The DMC charter will be prepared to detail 
precise roles and responsibilities and procedures to ensure maintenance of the blinding and 
integrity of the study in the review of accumulating data and interactions with the Executive 
Committee. Additional details are provided in the DMC charter.
In February 2023, the efficacy interim analysis was removed.
5
STUDY POPULATION
The target population includes adult male and female patients in Sweden and in the UK, 
presenting with ST- or non-ST elevation MI (STEMI or NSTEMI). Patients should be 
clinically stable and initiated on post-MI therapies according to established international and 
local guidelines at the time of consent and prior to the randomisation, to both satisfy the 
adequate SoC and the safety of participants. In this stable phase patients can, for prognostic 
enrichment purposes, be included if they have signs of impaired regional or global LV systolic 
function on echocardiogram, radionuclide ventriculogram, contrast angiography or cardiac 
MRI OR definitive evidence on ECG of Q wave MI (defined as presence of Q waves in 2 or 
more contiguous leads, excluding leads III and aVR, and meeting all of the following criteria: 
at least 1.5 mm in depth; at least 30 ms in duration; and, if R wave present, more than 25% of 
the size of the subsequent R wave). 
The estimated glomerular filtration rate (eGFR) should be ≥20 mL/min/1.73 m2.
Eligible patients should not have an established diagnosis of T1DM or T2DM at time of 
admission for the index event. The main reason for this is that CV benefit from SGLT2 
inhibition in T2DM is already established in previous trials, and it is therefore hard to claim 
equipoise in a type 2 diabetes post-MI population (Section 7.1). Type 2 diabetic patients can 
according to the European Society of Cardiology (ESC)/European Association for the Study 
of Diabetes (EASD) (Cosentino et al 2019) and other guidelines be on SGLT2 inhibitors or 
expected to become eligible for such therapy during the trial course. Further, a main 
underlying hypothesis in the study is that the beneficial cardioprotective effects of 
dapagliflozin appear independent of the glycaemic effects and can therefore be expected in a 
non-diabetic patient population. 
No patients with chronic symptomatic HF with a prior HHF within the last year and known 
reduced ejection fraction (LVEF ≤40%) will be included, as these patients are likely to 
become eligible for dapagliflozin treatment during the trial course.
The patient population will be recruited while hospitalised for MI in routine specialist care 
within cardiology departments in the UK and Sweden. Only patients that fulfill inclusion 
criteria, have no exclusion criteria and provide written informed consent for study 


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participation will be randomised. Two national, population-based clinical registries 
SWEDEHEART and the MINAP will constitute the study platform. This register framework 
will be used for (1) randomisation of patients and (2) for integral parts of the study follow-up 
routines.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should meet all the inclusion criteria and none of the exclusion criteria for this 
study to be screened/randomised to a study intervention. Under no circumstances, can there be 
exceptions to this rule. 
In this protocol, “screened” subjects are defined as those who fulfil I/E criteria and sign 
informed consent. “Randomised” subjects are defined as those who undergo randomisation 
and receive a randomisation number.
For procedures for withdrawal of incorrectly screened subjects refer to Section 5.4.1.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥18 at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Confirmed MI, either STEMI or NSTEMI, according to the fourth universal definition of 
MI (Thygesen et al 2019), within the preceding 7 days, or 10 days if earlier randomisation 
is not feasible.
3
Evidence of impaired regional or global LV systolic function at any timepoint during 
current MI-related hospitalisation (established with echocardiogram, radionuclide 
ventriculogram, contrast angiography or cardiac MRI) OR definitive evidence on ECG of 
Q wave MI (defined as presence of Q waves in 2 or more contiguous leads, excluding 
leads III and aVR, and meeting all the following criteria: at least 1.5mm in depth; at least 
30 ms in duration; and, if R wave present, more than 25% of the size of the subsequent R 
wave).
4
Haemodynamically stable at randomisation (no episodes of symptomatic hypotension, or 
arrhythmia with haemodynamic compromise in the last 24 hours).
Sex
5
Male or female


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Informed Consent
6
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol
7
Provision of signed and dated, written informed consent prior to any mandatory study 
specific procedures, sampling, and analyses. 
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Known T1DM or T2DM at the time for admission. Patients with hyperglycaemia, but 
without a diagnosis of diabetes mellitus prior to the index event, are eligible at the 
discretion of the Investigator. Patients who present with signs and symptoms consistent 
with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of 
breath should be assessed for ketoacidosis, and if ketoacidosis is confirmed the patient 
should not be randomised.
2
Chronic symptomatic HF with a prior HHF within the last year and known reduced 
ejection fraction (LVEF ≤40%), documented before the current MI hospitalisation.
3
Severe (eGFR < 20 mL/min/1.73 m2 by local laboratory), unstable or rapidly progressing 
renal disease at the time of randomisation.
4
Severe hepatic impairment (Child-Pugh class C) at the time of inclusion into the trial.
5
Active malignancy requiring treatment at the time of screening, except for basal cell- or 
squamous cell carcinoma of the skin, presumed possible to treat successfully.
6
Any non-CV condition, eg, malignancy, with a life expectancy of less than 2 years based 
on the investigator´s clinical judgement.
Prior/Concomitant Therapy
7
Currently on treatment, or with an indication for treatment, with a SGLT2-inhibitor.
8
Known intolerance to dapagliflozin.
Prior/Concurrent Clinical Study Experience
9
Participation in another study with a non-approved investigational drug or blinded 
treatment with a CV or glucose lowering medication.


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Other Exclusions
10 Involvement in the planning and/or conduct of the study (applies to AZ staff, UCR staff 
and/or staff at the study site).
11 Judgement by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements, or 
any condition in the opinion of the Investigator that would make participation unsafe or 
unsuitable.
12 Previous randomisation in the present study. 
13 Women of childbearing potential (ie, those who are not chemically or surgically sterilised 
or postmenopausal):
(a) Who are not willing to use a highly effective method of contraception (described 
below), OR
(b) Who have a positive pregnancy test, OR
(c) Who are breast-feeding.
Highly effective birth control methods include: sexual abstinence [periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to investigational medicinal product (IMP), and withdrawal are not 
acceptable methods of contraception], a vasectomised partner, bilateral tubal occlusion. 
Medically accepted method of contraception that is considered as highly effective ie, combined 
(estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine 
hormone-releasing system (IUS). Women of childbearing potential must agree to use one 
highly effective methods of birth control, as defined above, from screening throughout the 
study and to within 16 weeks after last dose of study drug, and must have a negative 
pregnancy test result at Visit 1.
Women not of childbearing potential are defined as women who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are 
postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic 
for 12 months. The age-specific requirements that apply are as follows:

Women < 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and have follicle-stimulating hormone levels in the postmenopausal range

Women ≥50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment


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5.3
Lifestyle Considerations
Not applicable.
5.3.1
Meals and Dietary Restrictions
Not applicable.
5.3.2
Caffeine, Alcohol, and Tobacco
Not applicable.
5.3.3
Activity
Not applicable.
5.4
Screening
Screening
"Screened" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process.
Potential participants are defined as patients who enter the registries due to an MI 
hospitalisation (and therefore to be considered for trial participation). The registries will be 
considered as the potential participants log, covering all MI patients that enters the registries. 
Individuals who meet the eligibility criteria will be offered to participate in this study.
Those who do not meet the criteria for participation in this study may be considered for trial 
participation during any future MI events.
Screen Failures
Participants who are screened but are not randomly assigned in the study (do not get 
randomisation code), are considered “screen failures”.
5.4.1
Procedures for Incorrectly Screened or Randomised Participants
Patients who fail to meet the eligibility criteria should not, under any circumstances, be
screened or receive study medication. There can be no exceptions to this rule. Patients who are 
screened, but subsequently found not to meet all the eligibility criteria must not be randomised 
or initiated on treatment and must be withdrawn from the study. Where a patient does not 
meet all the eligibility criteria but is randomised in error, or incorrectly started on treatment, 
the Investigator should inform the AZ study physician immediately, and a discussion should 
occur between the AZ study physician and the investigator regarding whether to continue or 
discontinue the patient from treatment. Study treatment must be discontinued in all cases 
where continued treatment is deemed to pose a safety risk to the patient. In those cases where 


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continuation of study therapy is judged not to present a concern related to safety and disease 
management, the therapy should be continued. The rationale for continuing or stopping study 
therapy must be clearly documented in medical records by the Investigator. Regardless of 
what is decided about IP, all randomised patients should remain in the study and the patients 
should continue to be followed up in accordance with defined study procedures.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. Study intervention in this study refers to dapagliflozin 10 mg or matching 
placebo.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Table 4
Investigational Products
ARM name
Treatment 1
Treatment 2
Intervention name:
Dapagliflozin 10 mg
Placebo to match
Type
Drug
Drug
Dose Formulation:
Green, plain, diamond shaped, 
film coated tablets 10 mg
Green, plain, diamond 
shaped, film coated tablets
Unit Dose Strength
10 mg
placebo
Dose Level:
10 mg once daily
once daily
Route of administration 
Per oral
Per oral
Use
experimental
placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Packaging and labelling
Study treatment will be 
provided in bottles. Each bottle 
will be labelled in accordance 
with GMP Annex 13 and per 
country regulatory 
requirement.
Study treatment will be 
provided in bottles. Each 
bottle will be labelled in 
accordance with GMP 
Annex 13 and per country 
regulatory requirement.
Provider
AstraZeneca
AstraZeneca
IMP, investigational medicinal product; NIMP, non-investigational medicinal product; GMP, Good 
Manufacturing Practice.
6.1.2
Medical Devices
Not applicable.


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6.2
Preparation/Handling/Storage of Interventions
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and that any discrepancies are 
reported and resolved before use of the study treatment.
Only randomised subjects in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the investigator and authorised site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
The investigator will retain the returned medication until the AZ representative or delegate 
collects it, along with any medication not dispensed. The AZ representative or delegate will 
advise on the appropriate method for destruction of unused study medication.
Study medication will be dispensed to patients in AZ standard bottles according to the normal 
packing procedure for CT material. Delegated study personnel at the sites will exchange the 
AZ standard caps to CleverCap LiteTM caps for the patient when the study treatment is first 
dispensed. During this process, the original aluminium lining (seal) welded to the bottle 
during the packing step at AZ will remain intact and the tablets will therefore remain protected 
until the patient breaks the lining and takes the first tablet. The change of cap will have no 
impact on the stability and quality of the tablets. 
When the new study medication will be dispensed, the original CleverCap LiteTM will be 
transferred to the new bottle by the site personnel.
Study drug may be delivered to the patient’s home if the patient cannot travel to the site due to 
the COVID-19 pandemic. In this instance, the patient will be provided with instruction on 
how to replace the standard cap with CleverCap LiteTM on the new bottle. 
Detailed procedure of the cap replacement and documentation will be described in the Site 
Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
All subjects will be centrally assigned to the study treatment using a computerised 
randomisation functionality webservice supported by the generic R-RCT framework. This 
computerised randomisation procedure will ascertain allocation concealment and will assign 
the participants 1:1 to dapagliflozin or matching placebo, and the treatment allocation 


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generated within the R-RCT framework will be automatically and blindly communicated to an 
interactive response technology (IRT) at the Sponsor that in turn will govern the dispense of 
study drug.
The randomisation will be stratified by country (Sweden and UK).
The study will be blinded to both patients and Investigators/site staff. The IRT will provide to 
the Investigator(s) the kit identification number to be allocated to the patient at the dispensing 
visit. Study intervention will be dispensed at the study visits summarised in the Schedule of 
Activities (SoA). Routines for this will be described in the IRT user manual that will be 
provided to each centre.
The IRT will provide to the investigator(s) or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit.
Routines for this will be described in the IRT user manual that will be provided to each centre.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The investigator documents and reports the action to AZ, without revealing the treatment 
given to participant to the AZ staff.
AZ retains the right to break the code for serious adverse events (SAEs) that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. Randomisation codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.
6.3.1
Emergency Unblinding
The IRT will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition, the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified within 24 hours after 
breaking the blind. The investigator documents and reports the action to AZ, without revealing 
the treatment given to participant to the AZ staff.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment allocation. Individual 
treatment codes, indicating the treatment allocation for each randomised patient, will be 
available to the Investigator(s) from the IRT. Routines for unblinding will be described in the 


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IRT user manual that will be provided to each centre. If the web-based IRT system is not 
working, unblinding remains possible via a telephone support helpdesk provided by the IRT 
vendor, available 24 hours per day, 365 days per year. The telephone number for this helpdesk 
is found in the IRT user manual and on the Patient Card which should be kept by the patient. 
The number of individuals at the study site who become aware of the treatment status should 
be kept to an absolute minimum, including keeping the patient blinded if possible. Treatment 
with IP should be continued, or re-initiated if interrupted, if considered appropriate.
6.4
Study Intervention Compliance
Treatment compliance will be regularly assessed by the AZ study team and will use “smart 
pill bottle” technology. The study treatment bottles containing dapagliflozin or matching 
placebo will be fitted with the CleverCap Lite™ technology, a system that can provide the 
date and time of every bottle access. Data on treatment compliance from the CleverCap Lite™ 
system will be wirelessly (using the 3G network) pushed to a central reporting/analytics portal 
in encrypted format and supervised by the AZ study team. The analytics portal provides 
individual participant data on exceptions and potential violations from scheduled study 
treatment dosing. Unexpected dose interruption and/or multiple bottle accesses during the 
same day will trigger appropriate action from the AZ study team. Detailed process will be 
described in the Monitoring Plan. Data from the CleverCap Lite™ system on the confirmed 
treatment protocol violation (time for and duration of the dose interruption) will be 
documented as described in the Monitoring Plan.
6.5
Concomitant Therapy
All patients should be treated according to regional standards of care for MI. Beyond 
provision of emergency MI care and appropriate reperfusion strategies, this also includes 
advice on lifestyle interventions aimed at smoking cessation, optimal BP control, diet and 
weight control, and increased physical activity. In addition, pharmacological mitigation of 
associated CV risk factors (eg, BP, lipid-lowering therapies and antithrombotic treatment(s)) 
represents key risk-reducing measures that should be offered to all patients. Further specific 
guideline-recommended pharmacologic MI therapies (beta blockers, renin-angiotensin system 
blockers and mineralocorticoid antagonists) should, in the absence of contraindications for 
their use, be initiated and properly dos-titrated in eligible patients according to the ESC 
guidelines for STEMI and NSTEMI patients, respectively (Ibanez et al 2018; Roffi at al 
2016).The Sponsor will provide an optional study-specific smartphone application to all 
participants in an effort to educate patients about MI and recommended lifestyle changes 
(refer to Section 8.11 for details about the study-supporting smartphone application). 
Background medications will not be provided by the Sponsor.


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6.5.1
Prohibited Medication
Concomitant treatment (ie, treatment in combination with study drug) with open label SGLT2 
inhibitors eg, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin and 
luseogliflozin and fix dose combinations containing these drugs is prohibited. Also, in 
situations when the patient is not on IP, treatment with open label SGLT2 inhibitors during the 
study could interfere with the interpretation of study results and should therefore not be given 
unless all other possibilities to treat the patient properly has been considered.
6.5.2
Background Medication
The patient should receive SoC therapies indicated in the early and subsequent phase after MI 
as judged by the Investigator and consistent with international and local guidelines. Standard 
evidence-based treatments to be considered include (1) antithrombotic treatment (aspirin, 
P2Y12 inhibitors and/or rivaroxaban in guideline-recommended combinations and treatment 
durations, including individual bleeding risks in decision-making), (2) BP management and 
cardioprotective agents (beta-blockers, ACE inhibitors / ARBs, mineralocorticoid/aldosterone 
receptor antagonists, as guided by BP levels and LV function during the MI hospitalisation) 
and (3) lipid management (statins, ezetimide, bile acid sequestrants, fibrates, omega 3 fatty 
acids and PCSK-9 inhibitors, as indicated to meet clinically established treatment goals in 
terms of S-LDL and S-TG reduction). In MI patients with concomitant non-valvular atrial 
fibrillation, oral anticoagulation should be maintained (or added) to antiplatelet(s) according 
to initial MI management strategy (invasive/conservative) and presumed bleeding risk, at the 
discretion of the Investigator. A proton pump inhibitor should also be considered in all MI 
patients with a higher than average presumed gastrointestinal bleeding risk.
6.5.3
Other Concomitant Treatment
Medication other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator.
6.5.4
Recording of Concomitant CV and Glucose Lowering Medications
Adherence to relevant CV medications (eg, antithrombotic, lipid-lowering, and 
antihypertensive/cardioprotective agents) will be recorded throughout the study, using the 
routine clinical registry medication data capture. The same workflow will be used to record 
any initiation of diabetes treatment (peroral glucose lowering agent or insulin). In addition, all 
concomitant medications will be recorded at the time of any reportable adverse events (AEs). 
6.5.5
Invasive Cardiac Procedures
Additional clinically driven invasive cardiac procedures (PCI/coronary artery bypass grafting 
[CABG]) will be captured within the established registry workflow or recorded in the eCRF 
system.


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6.6
Intervention After the End of the Study
Post-study treatment will not be provided by the Sponsor.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
Subjects may be discontinued from Study Intervention in the following situations:

Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment

AE

Severe non-compliance with the Clinical Study Protocol

If a patient develops T2DM during the trial, the decision whether or not to discontinue the 
investigational treatment rests with the Investigator. The protocol allows that a patient 
that develops T2DM during the trial is started on other glucose lowering medications than 
SGLT2 inhibitors. If the Investigator decides that an SGLT2 inhibitor is the only option to 
treat the patient properly, then the investigational product should be discontinued.

Diabetic ketoacidosis (DKA): Consider temporarily interrupting IP if DKA is suspected. 
If DKA is confirmed, IP should be discontinued permanently.

If a patient develops type 1 diabetes during the trial, the investigational treatment should 
be permanently discontinued

If a patient becomes pregnant during the study, the investigational treatment should be 
discontinued immediately, and an AZ representative should be contacted

If a patient during the trial is enrolled in another clinical study with non-approved 
investigational drug administered
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Discontinuation of Study treatment, for any reason, does not impact on the subject´s 
participation in the study. The subject should continue attending subsequent study visits and 
data collection should continue according to the study protocol. If the subject does not agree 
to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information. This could be a telephone contact with the 
subject, a contact with a relative or treating physician, or information from medical records. 
The approach taken should be recorded in the medical records. A subject that agrees to 


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modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.
7.1.1
Temporary Discontinuation
Temporary interruption of IP may be considered in patients thought to be at substantial risk of 
volume depletion/hypotension, such as:
1
patients with an acute medical illness potentially causing volume depletion because of 
inadequate fluid intake or fluid/blood loss (eg, gastroenteritis, gastrointestinal 
haemorrhage), or
2
patients undergoing major surgery.
During such circumstances, the IP should be re-initiated as soon as the reason for the 
temporary discontinuation decision is concluded. Temporary discontinuation will be 
monitored via CleverCap Lite™ portal.
7.1.2
Rechallenge
Patients who have temporarily discontinued IP can resume treatment as soon as, in the opinion 
of the Investigator, the patient’s condition is stable and the patient wishes to resume. No 
minimum time period is necessary before treatment can resume. Whenever possible, restart of 
randomised study medication should be encouraged, even if a premature treatment 
discontinuation visit (PTDV) was previously completed.
7.1.3
Procedures for Permanent Discontinuation of Study Treatment
The investigator should instruct the subject to contact the site before or at the time of stopping 
study treatment. The preferred follow-up approach for all patients who prematurely and 
permanently discontinue IP is that the patient undergoes the PTDV and then continues study 
visits according to plan (refer to Table 1). The PTDV should be done as soon as possible after 
last IP dose.  
The date of last intake of Study treatment should be documented in the eCRF. All Study 
treatment should be returned by the subject at their next on-site study visit or unscheduled 
visit.
7.1.4
Evaluation of Volume Status
Hypotension/Volume Depletion
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should have their regular medication reviewed, and consideration given to 
reducing the dose of, or stopping concomitant non-essential medications, as assessed on an 
individual basis, including diuretics and drugs that lower BP (except essential treatments – see 


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below). The need for conventional diuretics (or the dose of diuretic used) should be re-
evaluated considering the patient’s symptoms and signs. Hypotension may also occur with 
other BP lowering drugs and once again the need for (and dose of) non-essential agents of this 
type (eg, calcium channel blockers, alpha adrenoceptor antagonists and nitrates) should also 
be reconsidered.
Essential Treatments
Essential disease modifying/evidence-based treatments such as beta blockers, angiotensin 
converting enzyme (ACE) inhibitor or ARBs and mineralocorticoid receptor antagonists, 
should NOT be reduced in dose or discontinued unless all other measures fail to improve the 
patient’s situation. In acute situations it may be acceptable to interrupt treatment on a 
temporary basis in certain circumstances (eg, an ACE inhibitor/ARB if the patient has 
experienced a significant deterioration in renal function, a betablocker if the patient is unduly 
bradycardic or hypotensive, a mineralcorticoid receptor antagonistMRA if the patient has 
hyperkalaemia).
Unexpected Acute Declines in Renal Function
Dapagliflozin is a SGLT2 inhibitor, which by its mechanism of action reduces the 
reabsorption of glucose and sodium in the proximal tubules in the kidney. SGLT2 inhibition 
has a mild diuretic effect and an initial haemodynamic change with an initial increase in 
creatinine may occur and should NOT normally result in IP interruption or discontinuation.
If an unexpected, acute decline in kidney function is observed, the patient should be evaluated. 
Volume depletion, hypotension, inter-current medical problems and concomitant drugs may 
cause increases in blood creatinine. Urinary tract infection and urinary obstruction should be 
considered (the latter especially in men). Several drugs may cause a decline in kidney 
function, especially non-steroidal anti-inflammatory drugs and certain antibiotics such as 
trimethoprim. If any drug is suspected of causing or contributing to worsening kidney 
function, their use should be reconsidered.
7.1.5
Ketoacidosis in patients with type 2 diabetes mellitus
There have been reports of ketoacidosis, including diabetic ketoacidosis (DKA), in patients 
with type 2 diabetes mellitus taking dapagliflozin and other SGLT2 inhibitors in previous 
studies.  Patients with type 2 diabetes mellitus on investigational treatment who present with 
signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, 
malaise and shortness of breath should be assessed for ketoacidosis, even if blood glucose 
levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, discontinuation or 
temporary interruption of the investigational treatment should be considered and the patient 
should be promptly evaluated.


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7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, a PTDV visit should be conducted, 
as shown in the SoA. See SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

A subject who withdraws consent will always be asked about the reason(s) and the 
presence of any AE. AEs as defined in the trial (AEs leading to hospitalisation) will be 
reported. The Investigator will follow up subjects as medically indicated. 
7.3
Lost to Follow up
A participant will be considered potentially lost to follow-up if he or she repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site.
The term lost to follow-up will be limited to only patients with unknown vital status at study 
end (if not dead, patients need to have a date last known alive on or after the PACD).
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed potentially lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, repeated 
telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.


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
Efforts to reach the subject should continue until the end of the study. If these efforts to 
re-establish contact with the subject prove unsuccessful, additional allowed approaches 
for recovering vital status is by using the available interlinkage procedures with the 
different national registry sources (as outlined in Sections 4.2.1 and 4.2.2). 

Suggested language, when follow-up status of participant is critical to study outcomes:
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented, and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
In February 2023, it was decided to remove PACD from the study. As a consequence, the 
definition of lost to follow-up was updated and limited to only patients with unknown vital 
status at the study end (patients not confirmed as either dead or alive at their individual 
closing visit).
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. All screened patients will be entered in the 
randomisation application and captured in the screening log within the application. See 
description of the screening log in Section 4.7.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
tests, ECG, LVEF) and obtained before signing of the ICF may be utilised for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
8.1
Efficacy Assessments
Potential endpoint events will be identified (1) when questioning the patient about his/her 
overall health and symptoms and (2) through information received through standard medical 
practice (including findings on physical examination, medical imaging, and laboratory data). 


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Investigators will be encouraged to have a low threshold to submit any potential/possible 
event that might represent an endpoint. If the event is subject to adjudication, relevant source 
documents will be assembled. The source documents and relevant eCRF data will then be sent 
for central adjudication. Detailed instructions regarding endpoint reporting will be provided to 
the study sites. Additional details about the evaluations of potential endpoint events will be 
described in the clinical event adjudication charter.
8.1.1
Primary Outcome Assessments
The following potential endpoints should be reported, and source documents submitted for 
central adjudication:

All potential HHF events

All deaths
8.1.1.1
Hospitalisation for Heart Failure
All potential HHF endpoint should be recorded in the eCRF and submitted to the CEC for 
adjudication. The CEC will adjudicate the events as specified in the CEC Charter.
8.1.1.2
Classification of Death
The CEC members will adjudicate and classify all deaths based on definitions described in the 
CEC charter. For the purpose of the efficacy analysis, deaths will be subclassified by CV, 
non-CV and undetermined cause of death.
8.1.2
Secondary Outcome Assessments
1
The secondary endpoints of MI and stroke, constituting either a stand-alone secondary 
endpoint or part of composite endpoint will rely on investigator reporting and will not be 
subject to central adjudication. The rationale for this is that diagnoses of MI and stroke 
are well-defined in broadly accepted guidelines and defined by objective routine 
diagnosis procedures (ECG and cardiac troponin levels to diagnose MI; and brain 
imaging to support stroke diagnosis, for guidance see Appendix A 7). 
(a) Fatal or non-fatal MI
(b) Stroke (including ischaemic, haemorrhagic, and undetermined stroke)
2
For the secondary endpoint exploring whether dapagliflozin 10 mg QD, compared with 
placebo, reduces the incidence of new onset T2DM in MI patients when added to SoC, 
this will rely on investigator reporting and is defined as: 1) reporting of new onset type 2 
diabetes mellitus (T2DM) necessitating initiation of treatment with glucose lowering 
agent OR 2) HbA1c ≥6.5% (48 mmol/mol) measured by local laboratory at 2 consecutive 
time points.




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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
Investigators will record data on AEs leading to hospitalisation or death at the scheduled study 
visits and study closure visit. Data collection for fatal events will be performed also through 
registry checks. Deaths in both Sweden and the UK are routinely captured by their respective 
population registries and automatically added to SWEDEHEART and requested for linkage 
with the MINAP data. 
All participating patients will be treated according to regional standards of care for MI and 
according to clinical routines at the participating study sites. During the course of the study all 
patients, at all participating sites, will have the opportunity to have direct contact with study 
nurses dedicated to this study.
8.2.1
Blood Pressure
Blood pressure will be assessed in accordance with normal clinical routines at time points 
specified in the SoA (Table 1).
8.2.2
Clinical Safety Laboratory Assessments
No clinical safety laboratory tests will be performed within the study. However, assessment of 
laboratory tests, including serum creatinine, according to clinical practise is recommended. 
For information on how AEs based on laboratory tests should be recorded and reported, refer 
to Section 8.3.5.
8.2.3
Other Safety Assessments
8.2.3.1
Body Mass Index
BMI will be calculated from height and weight at the time points specified in the SoA 
(Table 1).
8.2.4
CleverCap LiteTM - Device deficiencies
In this study any deficiency observed with the CleverCapTM Lite device will be collected and 
reported to the manufacturer.
A device deficiency is an inadequacy of a device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and information supplied by the manufacturer.
The manufacturers complaint report will be used to collect the deficiency.


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8.3
Adverse Events and Serious Adverse Events
In this study only AEs leading to hospitalisation or death will be collected.
With regard to the primary efficacy events of HHF and CV death, all deaths and all potential 
HF hospitalisation events will be centrally adjudicated, as indicated in Section 8.1. If events of 
HHF are negatively adjudicated, they will be re-routed as AEs. For the other efficacy 
endpoints, the investigators will assess if the events are to be reported as endpoint events or 
re-routed as AEs. 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE leading to hospitalisation or death. For information on 
how to follow/up AEs see Section 8.3.2.
In February 2023, it was decided that the composite of HHF or CV death will no longer be the 
primary endpoint of the study. No other change to this section.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Reportable AEs will be collected from the time of randomisation, throughout the treatment 
period and including the follow-up period until the study closure visit.
All reportable AEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Section 8.3.9. The investigator will submit any updated AE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek reportable AEs in former study subjects. 
However, if the investigator learns of any AE leading to hospitalisation or death, at any time 
after a subject’s last visit and he/she considers the event to be reasonably related to the Study 
treatment or study participation, the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of reportable AEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B 3.


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8.3.2
Follow-up of Reportable AEs
After the initial SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All reportable AEs will be followed until resolution, stabilisation, 
the event is otherwise explained, or the subject is lost to follow-up. 
Any reportable AEs that are unresolved at the study closure visit are followed up by the 
Investigator for as long as medically indicated, but without further recording in the case report 
form (CRF). AZ retains the right to request additional information for any subject with 
ongoing SAE(s) at the end of the study, if judged necessary.
Reportable adverse event variables
The following variables will be collected for each reportable AE ie, AEs leading to 
hospitalisation or death:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity 

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

Outcome

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to hospitalisation or death

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication'

Description of AE
8.3.3
Causality Collection
The investigator should assess causal relationship between Investigational Product and each 
reportable AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’.


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Causal relationship should also be assessed for other medication and study procedures. Note 
that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs leading to hospitalisation spontaneously reported by the participant or reported in 
response to the open question from the study site staff: ‘Have you had any health problems 
since the previous visit/you were last asked?’, ‘Have you been hospitalised due to any of these 
health problems?’ or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated examinations should only be 
reported as AEs if they fulfil any criteria for AEs reporting according to this protocol. 
If deterioration in an examination is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s) if leading to hospitalisation or death.
Deterioration in an examination which is unequivocally due to disease progression, should not 
be reported as an AE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE if fulfilling 
hospitalisation criterion unless unequivocally related to the disease under study (Sections 
8.3.8).
8.3.6
Hy’s Law
Not applicable.
8.3.7
Disease Progression
Not applicable.


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8.3.8
Disease-Under study
Events of adjudicated hospitalisation for HF, non-fatal or fatal MI, non-fatal or fatal stroke 
and all-cause mortality will be defined as endpoint events. These events will not be reported to 
health authorities as SAEs as they are considered part of the natural history of the disease 
under study.
8.3.9
Reporting of Serious Adverse Events
All AEs leading to hospitalisation or death have to be reported, whether or not considered 
causally related to the investigational product, or to the study procedure(s) and will be 
recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AZ representatives within 1 day ie, immediately but no later than 24 hours of 
when he or she becomes aware of it.
The designated AZ representative will work with the investigator to ensure that all the 
necessary information is provided to the AZ Patient Safety data entry site within 1 calendar 
day of initial receipt for fatal and life-threatening events and within 5 calendar days of initial 
receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AZ representatives of any follow-up information on a previously reported SAE within 1 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the investigators or other site personnel indicate a reportable AE in the eCRF system, an 
automated email alert is sent to the designated AZ representative.
If the eCRF system is not available, then the investigator or other study site staff reports a 
SAE to the appropriate AZ representative by telephone.
The AZ representative will advise the investigator/study site staff how to proceed. 
Investigators or other site personnel send relevant eCRF modules by fax to the designated AZ 
representative.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
The reference document for definition of expectedness/listedness is the IB for the AZ drug.


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8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AZ except for:

If the pregnancy is discovered before the study subject has received any study drug.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.10.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly/birth defect) should be followed up and documented even 
if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AZ representatives within 1day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AZ representative works with the Investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar days for 
SAEs (Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
In the CRF the PREGREP module is used to report the pregnancy. The PREGOUT is used to 
report the outcome of the pregnancy.
8.3.10.2
Paternal Exposure
Not applicable.
8.3.11
Medication Error
Medication errors with AZ IP are collected in all studies where medication error is possible. 
Refer to the project specific safety requirements (PSSR) or other appropriate project document 
for specific considerations for collection of medication errors.


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For guidance, refer to AZ Standard Operating Procedure ‘Reporting of Individual Safety 
Events in Clinical Studies.’
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AZ representatives within one day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AZ representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (hospitalisations initial and follow up) calendar days if there is a reportable 
AE associated with the medication error (Section 8.3.9) 
The definition of a Medication Error can be found in Appendix B. 
8.3.12
Medical Device Deficiencies
Not applicable.
8.4
Overdose
An overdose with associated AEs is recorded if the AE leads to hospitalisation or death and 
the AE diagnosis/symptoms will be reported on the relevant AE modules in the CRF.
Dapagliflozin has been well tolerated at doses of up to 500 mg/day in single-dose testing in 
healthy volunteers and up to 100 mg/day in repeat-dose testing for 14 days in healthy 
volunteers and patients with T2DM. If an overdose is suspected, monitoring of vital functions 
as well as treatment should be performed as appropriate.
If an overdose on an AZ study drug results in an AE leading to hospitalisation or death then 
the Investigator or other site personnel inform appropriate AZ representatives immediately, or 
no later than 24 hours of when he or she becomes aware of it.
The designated AZ representative works with the Investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site.
For overdoses associated with AEs leading to hospitalisation or death, the standard reporting 
timelines apply, refer to Section 8.3.9.
8.5
Human Biological Samples
Not applicable.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.


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8.5.2
Immunogenicity Assessments
Not applicable.
8.5.3
Pharmacodynamics
Not applicable.
8.6
Human Biological Sample Biomarkers
Biomarkers are not evaluated in this study.
8.7
Optional Genomics Initiative Sample
Not applicable.
8.8
Medical Resource Utilisation and Health Economics
Health Economics/Medical Resource Utilisation parameters are not evaluated in this study.
8.9
Study Plan and Timing of Procedures
8.9.1
Prerequisites
The listed study-specific measures outlined below assumes:
1
That all study participants are carefully followed according to the routine 
SWEDEHEART and MINAP hospitalisation and follow-up protocols.
2
That all sites that participates in the study are compliant with the SWEDEHEART and 
MINAP routines, and that all variables are accurately collected by sites throughout the 
study. 
3
For the post-MI follow-up in the UK, the SEPHIA follow-up routines and variables 
content will be replicated but will be captured by direct entries on eCRF pages in the 
eCRF system. 
4
That all participating centres maintain a dedicated screening log, 
8.9.2
Visit 1: Screening and Randomisation (Day 1)

The RIKS-HIA/MINAP variables are recorded according to clinical routine including 
local blood samples as dictated by the registry, of which the following samples are 
mandatory for study purpose: 

Troponin (peak value)

HbA1c

S-creatinine (to be used to calculate eGFR; at local laboratory)

Patient signs the ICF before any study-specific procedures.

In women with childbearing potential, a negative pregnancy test needs to be confirmed 
prior to screening.


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
The investigator will assess the inclusion and exclusion criteria.

LVEF assessment (if part of routine care)

Index MI characteristics: ECG (STEMI/NSTEMI), any reperfusion treatment

Required demographic data

Height and weight

Systolic and diastolic BP

Relevant Medical history

Relevant Risk factors

Relevant CV and glucose lowering medication

Any potential efficacy endpoint or safety event will be recorded.

The patient will be consented, assigned an E-code and randomised in the R-RCT data 
module, where after the E-code and randomisation number along with date of birth will 
be pushed to the IRT system that in turn will allocate the randomised treatment.

IP will be dispensed via IRT to the patient, including assigning the Clever Cap LiteTM for 
each patient on the first pill bottle. The patient will be instructed to take the IP in 
accordance with protocol without interruptions and to bring all dispensed bottles and the 
CleverCap LiteTM to all study visits, and to report any device deficiencies with the 
CleverCap LiteTM. The first IP dose is intended to be taken on the randomization day.
8.9.3
Visit 2: Early Follow-visit, Week 8 (±14 days)

The investigator or delegate will record all SEPHIA variables, including local blood 
samples as dictated by the registry. In the UK, variables and local lab samples identical to 
the SEPHIA process will be captured by Investigators as direct entries in the eCRF.

ECG

Systolic and diastolic BP

Weight

Relevant Risk factors

NYHA Classification and CCS angina class

EuroQol five-dimensional three-level questionnaire (EQ-5D-3L) (in Sweden only)

HbA1c local lab sample is mandatory for study purposes.

Relevant CV and glucose lowering medication 

Any potential efficacy endpoint or safety event will be recorded.

Any revascularisation therapy (PCI/CABG) or ICD implantation

New IP will be dispensed via IRT to the patient. The patient will be reminded to take the 
IP in accordance with protocol and without interruptions, and to report any device 
deficiencies with the CleverCap LiteTM.


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8.9.4
Visit 3: The Second Follow-up Visit, Year 1 (±1 month)

The investigator or delegate will record all SEPHIA variables, including local blood 
samples as dictated by the registry. In the UK, variables and local lab samples identical to 
the SEPHIA process will be captured by Investigators as direct entries in the eCRF.

ECG

Systolic and diastolic BP

Relevant Risk factors

Weight

NYHA Classification and CCS angina class

EQ-5D-3L (in Sweden only)

HbA1c local lab sample is mandatory for study purposes.

Relevant CV and glucose lowering medication 

Any potential efficacy endpoint or safety event will be recorded

Any revascularisation therapy (PCI/CABG) or ICD implantation

New IP will be dispensed via IRT to the patient. The patient will be reminded to take the 
IP in accordance with protocol and without interruptions, and to report any device 
deficiencies with the CleverCap LiteTM.
8.9.5
Visit 4, 5, 6 etc: Study-specific Visit(s), Month 22 (±1 month) and 
Thereafter Occurring Every 10th Month Until Study Closure Visit

At this visit, variables and local lab samples identical to the SEPHIA follow-up visit 
process during the first-year post-randomisation will be captured by Investigators, but as 
direct entries in the eCRF.

HbA1c local lab sample is mandatory for study purposes.

NYHA Classification and CCS angina class

ECG

Systolic and diastolic BP

Weight

Relevant Risk factors

Weight

Relevant CV and glucose lowering medication 

Any potential efficacy endpoint or safety event will be recorded.

Any revascularisation therapy (PCI/CABG) or ICD implantation

New IP will be dispensed via IRT to the patient.

The patient will be reminded to take the IP in accordance with protocol and without 
interruptions, and to report any device deficiencies with the CleverCap LiteTM.


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8.9.6
Premature Treatment Discontinuation Visit
Patients who prematurely and permanently discontinue treatment with study medication 
should return for a PTDV, which will be done as soon as possible after last IP dose (refer to 
Section 7.1.3).

At this visit, variables and local lab samples identical to the SEPHIA follow-up visit 
process will be captured by Investigators, but as direct entries in the eCRF.

HbA1c local lab sample is mandatory for study purposes.

NYHA Classification and CCS angina class

ECG

Systolic and diastolic BP

Relevant Risk factors

Weight

Relevant CV and anti-hyperglycaemic medication 

Any potential efficacy endpoint or safety event will be recorded.

Any revascularisation therapy (PCI/CABG) or ICD implantation

The patient will return remaining IP and report any device deficiencies with the 
CleverCap LiteTM.

After stopping IP the investigator should ensure that the patient is treated according to 
standard clinical practice and ascertain there is a proper medical follow-up plan in place.
8.9.7
Study Closure Visit

At this visit, variables and local lab samples identical to the SEPHIA follow-up visit 
process will be captured by Investigators, but as direct entries in the eCRF.

HbA1c local lab sample is mandatory for study purposes.

ECG

Systolic and diastolic BP

Relevant Risk factors

NYHA Classification and CCS angina class

Weight

Relevant CV and glucose lowering medication 

Any potential efficacy endpoint or safety event will be recorded.

Any revascularisation therapy (PCI/CABG) or ICD implantation

The patient will return remaining IP and report any device deficiencies with the 
CleverCap LiteTM.

After stopping IP, the investigator should ensure that the patient is treated according to 
standard clinical practice and ascertain there is a proper medical follow-up plan in place.


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8.9.8
Unscheduled Visits
An unscheduled visit may occur in-between scheduled visits eg, to follow up on potential 
endpoint or safety events.
8.10
Clinical Trial Data Model
The investigator will ensure that data are accurately recorded in the registries 
(SWEDEHEART/MINAP) for all subjects at every scheduled contact and according to the 
established variable definitions in the registries. The investigator will also ensure that any 
additional study-specific data is accurately recorded in on eCRFs. Data collected from both 
the web-based registry services and from eCRFs will be managed by an Electronic Data 
Capture System that will be used for data collection and query handling.  
The investigator ensures the accuracy, completeness, and timelines of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue Study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. At site level a specific log to record details of all potential 
participants will be kept to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the subject’s routine clinical management and obtained before 
signing of the ICF (eg, evaluation of LVEF during the current hospitalisation) may be utilised 
for screening or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the time frame defined in the SoA.
8.11
UnifyTM Mobile Software Application
The UnifyTM mobile software application, and associated website system, will provide digital 
support to patients from screening through to, and including, follow-up. The system will 
provide patients and site study staff with information and tools relevant to the conduct of the 
study in accordance with this protocol. This will comprise treatment medication reminders, 
clinical visit reminders, primary endpoint reporting functionality, educational content relating 
to the disease and medication, and ability to collect EQ-5D-5L data.


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MI patients will be asked to complete the EQ-5D-5L quality of life questionnaire 3 days after 
discharge and every month until PACD. The EQ-5D-5L will be administered using the 
UnifyTM mobile software application. Analysis and reporting of the EQ-5D-5L data will be 
presented in a separate report.
AZ (or those acting on behalf of AZ) will set-up clinical sites and invite site staff to use 
UnifyTM by email but will not have the ability to view any patient level system data during the 
trial. Any data collected will be used for UnifyTM system functionality only and is not 
considered to be CT data. 
AZ will own any system data collected which may be used after the trial to make 
improvements to UnifyTM. System data collected will be retained for a period of 10 years after 
trial closure.
The use of the UnifyTM mobile software application is optional for the patient and captured in 
the ICF.
In February 2023, it was decided that the composite of HHF or CV death will no longer be the 
primary endpoint, but the endpoint reporting functionality of those events will continue. It was 
also decided to remove PACD from the study. As a consequence, patients (only active users of 
Unify application) will be asked to complete the EQ-5D-5L questionnaire every month until 
their individual closing visit, instead of until PACD.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
To control the overall type I error rate at 5% 2-sided, the significance level will be adjusted 
for one interim analysis of efficacy performed by the DMC. For the primary endpoint the 
following null hypothesis will be tested at the 4.98% 2-sided significance level:
H0: Win-Ratio [dapagliflozin:placebo] = 1
versus the alternative hypothesis
H1: Win-Ratio [dapagliflozin:placebo] ≠1
In February 2023, it was decided to remove the efficacy interim analysis and to test the 
primary endpoint at 5% 2-sided significance level at the end of the study.


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9.2
Sample Size Determination
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint. Assuming a true hazard 
ratio of 0.80 between dapagliflozin and placebo, using a 2-sided alpha of 4.98% (adjusted for 
interim analysis), 722 patients with primary endpoint events will provide a statistical power of 
85% for the test of the primary composite endpoint. This is based on an overall 1:1 allocation 
between dapagliflozin and placebo. The assumed HR of 0.80 is considered as clinically 
relevant and has taken into account the HF outcomes in the MI sub-group in the DECLARE 
trial. The critical hazard ratio for achieving statistical significance is estimated to be 0.864.
The study is event-driven. With an estimated annual placebo event rate of 7.5% (from an 
observational database within the SWEDEHEART registry) for the primary composite 
endpoint, 6400 patients are estimated to provide the required number of primary events, based 
on an anticipated accrual period of 18 months and a total study duration of approximately 30 
months, and considering an estimated annual drop-out rate at 1% during the study. The sample 
size, duration of recruitment period, and total study duration may change depending on the 
recruitment rate and event rate of the primary endpoint. 
In February 2023, the primary objective of the study was revised to determine if the clinical 
benefit of dapagliflozin is superior in relation to placebo and this objective will be assessed 
with a hierarchical composite endpoint and analysed using the win-ratio method. Assuming a 
true win-ratio of 1.20 between dapagliflozin and placebo, 4000 patients will provide a 
statistical power of 80%, based on simulations, for the test of the primary composite endpoint, 
using a 2-sided alpha of 5%. This is based on an overall 1:1 allocation between dapagliflozin 
and placebo. The assumed win-ratio of 1.20 is considered clinically relevant.
9.3
Populations for Analyses
For purposes of analysis, the following populations are defined: 
Full analysis set (Intention to Treat principle)
All patients who have been randomised to study treatment will be included in the Full 
Analysis Set (FAS) irrespective of their protocol adherence and continued participation in the 
study. Patients will be analysed according to their randomised IP assignment, irrespective of 
the treatment actually received. The FAS will be considered the primary analysis set for the 
primary and secondary efficacy variables and for the exploratory efficacy variables.
Safety analysis set
All randomised patients who received at least one dose of study treatment will be included in 
the safety population. Patients will be analysed according to the treatment actually received. 
For any patients given incorrect treatment, ie, randomised to 1 of the treatment groups but 


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actually given the other treatment, the treatment group will be allocated as follows: patients 
who got both incorrect and correct treatment will be analysed according to their randomised 
treatment. Patients who got only the incorrect treatment will be analysed according to that 
treatment.
The safety analysis set will be considered the primary analysis set for all safety variables.
9.4
Statistical Analyses
The statistical analysis plan will be finalised prior to data base lock (DBL) and it will include 
a more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints.
9.4.1
General Considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violations have been identified and documented.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint(s)
The primary variable is the time to first event included in the primary composite endpoint. 
The primary analysis will be based on the intention to treat (ITT) principle using the FAS, 
including events with onset on or prior to PACD, adjudicated and confirmed by the CEC 
committee.
In the analysis of the primary composite endpoint, treatments (dapagliflozin versus placebo) 
will be compared using a Cox proportional hazards model with a factor for treatment group, 
stratified by country.
The individual components included in the primary composite endpoint will also be analysed 
separately, in the same way as the composite. Analyses of CV death, either as a component of 
a composite or on its own, will include deaths adjudicated as CV cause as well as deaths 
adjudicated as undetermined cause.
Kaplan-Meier (KM) estimates of the cumulative proportion of patients with events will be 
calculated and plotted per treatment group, with the number of patients at risk indicated below 
the plot at specific time points.
In February 2023, it was decided to remove PACD from the study, and as a consequence, all 
data collected on or before each patient’s individual closing visit will be considered. Also, the 
primary endpoint was revised to a hierarchical composite endpoint consisting of the following 
components in the following order of clinical importance: Death, HF events, non-fatal MI, 


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Atrial fibrillation/flutter events, new onset of T2DM, symptoms of HF as measured by NYHA 
class at last visit, as well as body weight loss at least 5% at last visit. The primary endpoint 
will be assessed using the win-ratio method and each patient in the treatment group will be 
compared with each patient in the control group to determine the winner/loser/tie within each 
pair across the multiple outcomes. The win-ratio and corresponding 95% confidence interval 
will be reported.
9.4.2.2
Secondary Endpoint(s)
The secondary variables are the time to first event included in the composite endpoint of CV 
death, MI and stroke, time to first fatal or non-fatal MI, time to death of any cause, time to CV 
death and new onset type 2 diabetes. The secondary analyses will be based on the ITT 
principle using the FAS, using MIs and strokes as reported by the investigators, and CV death 
as adjudicated and confirmed by CEC.
The secondary variables will be analysed in the similar manner as the primary variable.
In February 2023, the following was decided:
The key secondary endpoint will be the same as the primary endpoint, but only with 6 
components excluding the body weight component and will be analysed in the similar manner 
as the revised primary endpoint.
The composite of HHF and CV death was added as a secondary composite endpoint.
Time to hospitalisation for any cause was added as a secondary endpoint.
Change from baseline to last visit in body weight was added as a secondary endpoint.
9.4.2.3
Tertiary/Exploratory Endpoint(s)
Analyses for the exploratory endpoints will be defined in the statistical analysis plan (SAP).
9.4.2.4
Withdrawal From Study/Study Drug, Intercurrent Events and Estimand
It is important to distinguish between non-adherence with, or withdrawal from, randomised 
treatment and discontinuation from the trial. A randomised patient can withdraw from the 
study but not from the analysis, and according to the intention to treat principle, all data will 
be included. The potential impact of intercurrent events (events that occur after treatment 
initiation and either preclude observation of the variable or affect its interpretation [eg, 
discontinuation of treatment, switching treatment, terminal events such as death, lost to 
follow-up or withdrawn consent]) is anticipated to be low and with even distribution between 
the treatment arms. The primary and secondary objectives are event-based and will be 
evaluated under the treatment policy estimand to reflect the effect of the initially assigned 
randomised study drug, irrespective of adherence to randomised study treatment. Specifically, 


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the analyses will be performed for the full analysis set including all events that occurred on or 
prior to PACD, including events following premature discontinuation of study drug.
In February 2023, it was decided that the analyses will be performed for the full analysis set 
including all data collected on or prior to the date of each patient’s individual closing visit.
9.4.2.5
Subgroups
Subgroups of special interest will be pre-specified in the SAP. Subgroup analyses for primary 
and secondary efficacy endpoints will be assessed using the Cox regression model.
In February 2023, this section was updated to read:
Subgroups of special interest will be pre-specified in the SAP. Subgroup analyses for primary 
and key secondary efficacy endpoint as well as for the composite of HHF or CV death 
(secondary endpoint) will be assessed.
9.4.3
Safety
The number and percent of patients with AEs leading to hospitalisation or death, will be 
summarised by treatment group. For safety analyses, summaries will be provided using both 
on-treatment observations and using all observations regardless of whether patients are on or 
of study treatment.
9.4.4
Methods for Multiplicity Control
The significance level of alpha to be used for the final analysis will be adjusted for the interim 
analysis to control the overall type I error at 0.05 (2-sided). The primary endpoint will be 
tested for the final analysis at a 2-sided alpha level of 0.0498. Multiplicity across primary and 
secondary endpoints will be accounted for by utilising a pre-specified hierarchical order of the 
primary and secondary endpoints. The secondary all-cause mortality endpoint will be tested 
outside the multiple testing procedure. A separate alpha spending function will be used for the 
secondary endpoints. For more details around multiplicity see SAP. 
In February 2023, this section was revised. The primary endpoint will be tested at a 2-sided
alpha level of 0.05. Multiplicity across primary and secondary endpoints will be accounted for
by utilising a pre-specified hierarchical order of the primary and secondary endpoints. The
secondary all-cause mortality endpoint will be tested outside the multiple testing procedure.
For more details see SAP.
The secondary endpoints will be tested in the same order as listed in table 3, objectives and
endpoints.


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9.5
Interim Analyses 
An interim analysis is planned to be performed when approximately 2/3 of the primary events 
have been adjudicated. The interim analysis will assess superiority of dapagliflozin to placebo. 
The interim analysis will use a 1-sided alpha level of 0.001. At the interim analysis, the 
primary composite endpoint will be first tested at the specified alpha level. If superiority is 
achieved for the primary endpoint, then the superiority of dapagliflozin to placebo on CV 
death will be tested at a 1-sided alpha level of 0.001. If CV death also is significant, and with 
an appropriate margin, then an action is triggered whereby the DMC will evaluate the totality 
of the available efficacy data and safety data, to determine if benefit is unequivocal and 
overwhelming such that the DMC recommends ending the study. See SAP for more details.
In February 2023, it was decided to remove the efficacy interim analysis from the study.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AZ will be responsible for obtaining the required authorisations to conduct the study from 
the concerned Regulatory Authority. This responsibility may be delegated to a Contract 
Research Organisation but the accountability remains with AZ.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [IB or state other documents] and will notify the IRB/IEC, 
if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.


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
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are able 
to identify the occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
regulations (CFR) 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.


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
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 6
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF (either transferred 
from the registry or entered manually) unless transmitted to the sponsor or designee 
electronically (eg, laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.


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
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca Global retention and Disposal 
(GRAD) Schedule. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.
A 7
Guidance for Definition of Acute Myocardial Infarction and 
Stroke
Guidance for Definition of Acute Myocardial Infarction
The definition is based on Fourth Universal MI definition (Thygesen et al 2019). The term 
acute MI should be used when there is evidence of myocardial necrosis in a clinical setting 
consistent with acute myocardial ischaemia. Under these conditions any 1 of the following 
criteria meets the diagnosis for MI:

Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin 
[cTn]) with at least 1 value above the 99th percentile upper reference limit (URL) and 
with at least 1 of the following:

Symptoms of ischaemia

New or presumed new significant ST-segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB)

Development of pathological Q waves in the ECG

Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality

Identification of an intracoronary thrombus by angiography or autopsy

Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new 
ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers 
were obtained, or before cardiac biomarker values would be increased

PCI-related MI is arbitrarily defined by elevation of cTn values (> 5 x 99th percentile 
URL) in patients with normal baseline values (≤99th percentile URL) or a rise of cTn 
values > 20% if the baseline values are elevated and are stable or falling. In addition, 
either


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
symptoms suggestive of myocardial ischaemia, or

new ischaemic ECG changes, or

angiographic findings consistent with a procedural complication, or

imaging demonstration of new loss of viable myocardium or new regional wall 
motion abnormality are required

Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker 
values with at least 1 value above the 99th percentile URL

CABG- related MI is arbitrarily defined by elevation of cardiac biomarker values (> 10 x 
99th percentile URL) in patients with normal baseline cTn values (≤99th percentile URL). 
In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic 
documented new graft or new native coronary artery occlusion, or (iii) imaging evidence 
of new loss of viable myocardium or new regional wall motion abnormality.
Guidance for Definition of Stroke
The definition is based on the standardised definitions for endpoints (Hicks et al 2015). Stroke 
is defined as an acute episode of focal or global neurological dysfunction caused by cerebral 
vascular injury as a result of infarction or haemorrhage not caused by trauma. Investigators 
will classify strokes into 1 of 3 mutually exclusive categories: ischaemic, haemorrhagic, or 
undetermined. Whenever possible, stroke diagnoses should be confirmed using neuroimaging 
(CT or MRI) to minimise the number of strokes classified as “undetermined”.
Ischaemic Stroke
An acute episode of focal cerebral dysfunction caused by cerebral infarction. Either of the 
following is considered to be an ischaemic stroke:

Rapid onset (or existence on awakening) of a new focal neurological deficit with clinical 
or imaging evidence of infarction and not attributable to a non-ischaemic aetiology (not 
associated with brain infection, trauma, tumour, seizure, severe metabolic disease, or 
degenerative neurological disease)

Rapid worsening of an existing focal neurological deficit (eg, the index stroke event) that 
is judged by the Investigator to be attributable to a new infarction or extension of a 
previous infarction in the same vascular bed, based on persisting symptoms or imaging 
evidence of infarction and no evidence of a non-ischaemic aetiology. In case imaging is 
inconclusive, persistent symptoms is defined as duration of ≥24 hours or until death
Haemorrhagic Stroke
An acute episode of focal or global cerebral dysfunction caused by intraparenchymal, 
intraventricular, or subarachnoid haemorrhage not caused by trauma. Subdural haematomas 
are ICH events but not strokes.


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Undetermined Category of Stroke
An acute episode of focal or global neurological dysfunction caused by presumed brain 
vascular injury as a result of haemorrhage or infarction but with insufficient information to 
allow categorisation as either ischaemic or haemorrhagic. Strokes of undetermined category 
will be analysed as ischaemic strokes.
References:
Thygesen et al. European Heart Journal (2019) 40, 237–269.
Hicks et al. Circulation (2015) 132(4):302-61.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study.
Also, current medical records must be available.

Definition of what constitutes source data can be found in Monitoring Plan.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first participant consented and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The study may be stopped if, in the 
judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that: 

meet individual stopping criteria or are otherwise considered significant, 

are assessed as causally related to study drug,

are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 


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Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
The investigator may initiate study-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 study site by the sponsor 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, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. The investigator should assist and facilitate 
transferal of participants to another site for follow up in the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a participant or clinical 
study participant administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent 1 of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as SAEs. If 
no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used. In 
certain situations, however, medical judgement on an individual event basis should be applied 
to clarify that the malignant tumour event should be assessed and reported as a Non-Serious 
AE. For example, if the tumour is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant 
tumour, the AE may not fulfil the attributes for being assessed as Serious, although reporting 
of the progression of the malignant tumour as an AE is valid and should occur. Also, some 
types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalisation, may be assessed as Non-Serious; examples in adults include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.


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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent 1 or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
Intensity Rating Scale

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 


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several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AZ would not normally recommend or support a rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest 
a causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AZ study drug that either causes harm to the participant or has the 
potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT errors)

Wrong drug administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to 1 of the above 
listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or SoC medication in open label 
studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
The investigator is responsible for recording data pertaining to Serious Adverse Events 
(SAEs) and Adverse Events (AEs) according to the outcome of the review and assessment in 
line with standard safety reporting processes.


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Appendix C
Abbreviations
Abbreviation or special 
term
Explanation
AE
Adverse Event
ACE
Angiotensin-converting enzyme
ACS
Acute coronary syndromes
ARB
Angiotensin receptor blockers
AZ
AstraZeneca
β-hCG
Beta human chorionic gonadotropin
BMI
Body Mass Index
BP
Blood pressure
CABG
Coronary artery bypass grafting
CCS
Canadian Cardiovascular Society
CEC
Clinical Endpoint Committee
CI
Confidence interval
CKD
Chronic kidney disease
COVID-19
Coronavirus Disease of 2019
CRF
Case report form
CRO
Contract Research Organisation
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical study report
CT
Clinical trial
cTn
Cardiac troponin
CV
Cardiovascular
DBL
Data base lock
DBP
Diastolic blood pressure
DKA
Diabetic ketoacidosis
DMC
Data Monitoring Committee
EASD
European Association for the Study of Diabetes
EC
Executive Committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EQ-5D-3L
EuroQol five-dimensional three-level questionnaire
EQ-5D-5L
EuroQol five-dimensional five-level questionnaire
ESC
European Society of Cardiology
FAS
Full Analysis Set


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Abbreviation or special 
term
Explanation
GCP
Good Clinical Practice
HbA1c
Glycosylated haemoglobin
HF
Heart Failure
HFrEF
Heart Failure and reduced Ejection Fraction
HHF
Hospitalisation for Heart Failure
HR
Hazard ratio
I/E
Inclusion/Exclusion
IB
Investigator’s Brochure
ICD
Implantable cardioverter defibrillator
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
Intention to treat
IUS
Intrauterine hormone-releasing system
LBBB
Left bundle branch block 
LVEF
Left ventricular ejection fraction
MACE
Major adverse cardiovascular event
MI
Myocardial infarction
MINAP
The UK-based Myocardial Ischaemia National Audit Project
MRA
Mineralcorticoid receptor antagonist
MRI
Magnetic Resonance Imaging
NHS
National Health Service
NICOR
The National Institute for Cardiovascular Outcomes Research
Non-ST
non-ST segment elevation myocardial infarction
NSTEMI
non-ST segment elevation myocardial infarction
NYHA
New York Heart Association
PACD
Primary analysis censoring date
PCI
Percutaneous coronary intervention
PCSK-9
Proproteins convertase subtilisin/kexin type 9
PSSR
Project Specific Safety Requirements
PTDV
Premature treatment discontinuation visit


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Abbreviation or special 
term
Explanation
QD
Once daily
RISK-HIA
The national registry of acute cardiac care 
R-RCT
Registry-based randomised controlled trial
RRR
Relative Risk Reduction
SAE
Serious adverse event 
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SCV
Study Closure Visit
SEPHIA
The national registry of secondary prevention
SGLT2
Sodium glucose co-transporter 2
s-LDL
serum low-density lipoprotein
SoA
Schedule of Activities
SoC
Standard of Care
ST
STEMI - elevation myocardial infarction
STEMI
ST segment elevation myocardial infarction
s-TG
serum triglycerides
SWEDEHEART
Swedish Web-system for Enhancement and Development of Evidence-based 
care in Heart disease Evaluated According to Recommended Therapies
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
UCR
Uppsala Clinical Research Center
UK
United Kingdom
URL
Upper reference limit


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Appendix D
EQ-5D-5L Health Questionnaire
English verison for the UK
Under each heading, please tick the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about

I have slight problems in walking about

I have moderate problems in walking about

I have severe problems in walking about

I am unable to walk about

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. UK 
(English) v1.1




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Appendix E
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1 25-May-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 Union.
Overall Rationale for the Amendment:
The amendment extends the randomisation window to allow randomisation of patients within 
10 days after MI and includes additional information on awareness of ketoacidosis. The 
amendment also contains information on an additional option for study drug delivery to 
patients due to the COVID-19 pandemic.  At the same time minor clarifications and editorial 
changes have been made.
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Figure 1
Study Design
Extending 
randomisation 
window. 
Extending randomisation 
window to 10 days, if 
earlier randomisation is 
not feasible. 
Substantial
Table 1
Schedule of Activities
Extending 
randomisation 
window. 
Extending randomisation 
window to 10 days, if 
earlier randomisation is 
not feasible. 
Substantial
Table 1
Schedule of Activities
Removal of ‘coronary 
angiography’.
EQ-5D-5L 
questionnaire 
completion 
clarification.
Additional clarification 
statements. 
Non-substantial
Table 2
Risk Assessment
Clarification of 
inclusion criterion 4. 
To clarify the emphasis 
is on symptoms of 
hypotension, not single 
blood pressure readings.
Substantial
Section 5.1
Inclusion Criteria
Addition to inclusion 
criterion 2. 
Extending randomisation 
window to 10 days, to 
allow patients with MI to 
be randomised within 10 
days. 
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 5.1
Inclusion Criteria
Clarification of 
inclusion criterion 4. 
To clarify the emphasis 
is on symptoms of 
hypotension, not single 
blood pressure readings.
Substantial
Section 5.2
Exclusion Criteria
Addition to exclusion 
criterion 1. 
To include information 
on awareness of 
ketoacidosis.
Substantial
Section 6.2
Preparation/Handling/Storage 
of Interventions
Additional option of
study drug delivery to 
patient due to the 
COVID-19 pandemic.
To include information 
about option of study 
drug delivery to patient's 
home during COVID-19 
pandemic.
Non-substantial
Section 6.3.1 
Emergency Unblinding
Clarification. 
Clarification that 
individual treatment 
codes, indicating the 
treatment allocation for 
each randomised patient, 
will be available from the 
IRT to the Investigator(s) 
only.  
Non-substantial
Section 6.5.2 
Background Medication
Clarification.
Clarification statement.
Non-substantial
Section 6.5.5
Invasive Cardiac Procedures
Removal of ‘coronary 
angiography’.
Clarification statement.
Non-substantial
Section 7.1
Discontinuation of Study 
Intervention
Clarification of 
discontinuation option 
if a patient develops 
T1DM during the 
trial.
To clarify patients with 
T1D should permanently 
discontinue study drug.
Non-substantial
Section 7.1.5 
Ketoacidosis in patients with 
type 2 diabetes mellitus
Additional Section 
with information 
regarding 
ketoacidosis in 
patients with type 2 
diabetes mellitus.
To include information 
on awareness of 
ketoacidosis.
Substantial
Section 7.2 
Participant Withdrawal from 
the Study
Removal of wording 
related to withdrawal 
from registry. 
Statement not applicable. 
Non-substantial
Section 8.3.10.1
Maternal Exposure
Revised wording 
related to congenital 
anomalies 
Change to align with 
regulatory requirements. 
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
(“congenital 
anomaly” instead of 
“congenital 
abnormality”).
Section 8.9.2
Visit 1: Screening and 
Randomisation (Day 1)
Adding clarification 
that the first IP dose is 
intended to be taken 
on the randomization 
day.
Clarification statement.
Non-substantial
Section 8.9.3
Visit 2: Early Follow-visit, 
Week 8 (±14)
Removal of ‘coronary 
angiography’.
Clarification statement.
Non-substantial
Section 8.9.4
Visit 3: The Second Follow-
up Visit, Year 1 (±1 month)
Correction of visit 
window. 
Removal of ‘coronary 
angiography’.
Clarification.
Clarification statement.
Non-substantial
Section 8.9.5
Visit 4, 5, 6 etc: Study-
specific Visit(s), Month 22 
(±1 month) and Thereafter 
Occurring Every 10th Month 
Until Study Closure Visit
Correction of visit 
window. 
Removal of ‘coronary 
angiography’.
Clarification.
Clarification statement.
Non-substantial
Section 8.9.6 
Premature Treatment 
Discontinuation Visit
Removal of ‘coronary 
angiography’.
Clarification statement.
Non-substantial
Section 8.9.7 
Study Closure Visit
Removal of ‘coronary 
angiography’.
Clarification statement.
Non-substantial
Appendix A 3 
Informed Consent Process
Removal of 
rescreening 
information. 
To align with study 
design. 
Non-substantial
Appendix A 5
Dissemination of Clinical 
Study Data
Clarification on 
website address. 
Clarification.
Non-substantial
Appendix B 2
Definitions of Serious 
Adverse Event
Revised wording 
related to congenital 
anomalies 
(“congenital 
anomaly” instead of 
“congenital 
abnormality”).
Change to align with 
regulatory requirements. 
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Throughout
Minor editorial and 
document formatting 
revisions
Minor, therefore have not 
been summarised
Non-substantial
Amendment 2 14-Dec-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 Union.
Overall Rationale for the Amendment:
The amendment provides changes in inclusion criteria to broaden the study population to also 
include patients with impaired regional or global LV systolic function without numerical cut-
off LVEF <50%. At the same time minor clarifications have been made.
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
1.1 Synopsis 
Addition of sentence 
that the sample size, 
duration of recruitment 
period, and total study 
duration may change 
depending on the 
recruitment rate and 
event rate of the 
primary endpoint.
The recruitment at the 
beginning of the study was 
slower than expected, 
therefore it is possible that 
recruitment period and 
study duration might be 
extended.
Non-substantial
1.2 Study Design
Change in the study 
scheme to replace  
“Reduced LVEF or Q-
wave” into “Impaired 
LV systolic function or 
Q-wave”.
Due to the change in 
inclusion criterion 3 
(inclusion of the patients 
with impaired regional or 
global LV systolic function 
at any timepoint without 
cut-off LVEF <50%).
Non-substantial
4.6.2.1 Scope
Clarification on 
MINAP registry in 
Scotland.
The country of Scotland 
has started participating in 
the study.
Non-substantial
Section 5 Study population
and Section 5.1
Inclusion Criteria
Inclusion of patients 
with impaired regional 
or global LV systolic 
function at any 
timepoint without cut-
off LVEF <50%.
The experience in the study 
is that echocardiography 
reports frequently 
quantifies the measured 
ejection fraction in 
intervals (eg. 45-50% or 
50-55%) although there are 
findings of impaired 
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
regional wall motion. The 
cut off EF <50% was a risk 
enrichment strategy but 
seems to exclude a 
population of patients with 
impaired regional LV 
systolic function that could 
also benefit from the 
treatment. It has also been 
clarified that the 
investigation showing 
evidence of impaired 
regional or global LV 
systolic function can be 
performed at any timepoint 
during the MI related 
hospitalisation.
Section 5.2
Exclusion Criteria
Removal of word 
‘serum’ from 
description of the 
pregnancy testing type.
Clarification that 
pregnancy testing is not 
restricted to serum testing 
only.
Non-substantial
6.3 Measures to minimise 
bias
Removal of 
information on 30% 
capping from each 
country.
The addition of the country 
of Scotland to Wales and 
England representing the 
UK makes the capping of 
at least 30% from each 
country not possible due to 
imbalance in the study 
population basis.
Non-substantial
8.2. Safety assessments
Clarification on 
information that deaths 
in UK are captured by 
linkage with MINAP 
data, rather than by 
automatic transfer. 
To correct information on 
deaths transferring to 
MINAP in UK, as it differs 
from the automatic data 
transfer to SWEDEHEART
in Sweden. 
Non-substantial
9.2 Sample size 
determination
Addition of sentence 
that the sample size, 
duration of recruitment 
period, and total study 
duration may change 
depending on the 
recruitment rate and 
The recruitment at the 
beginning of the study was 
slower than expected, 
therefore it is possible that 
recruitment period and 
study duration might be 
extended.
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
event rate of the 
primary endpoint.


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11
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SIGNATURE PAGE
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Document Name: d169dc00001-csp-v4
Document Title:
D169DC00001 Clinical Study Protocol version 4
Document ID:
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Server Date
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SAP_005.pdf: 
Statistical Analysis Plan 
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Statistical Analysis Plan
Study Code
D169DC00001
Edition Number
4.0
Date
19 June 2023
DAPA-MI
A Registry-based, Randomised, Double-blind, Placebo-Controlled 
Cardiovascular Outcomes Trial to Evaluate the Effect of Dapagliflozin 
on Cardiometabolic Outcomes in Patients without Diabetes with Acute 
Myocardial Infarction at Increased Risk for Subsequent Development of 
Heart Failure


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 4
AMENDMENT HISTORY................................................................................................... 6
1
STUDY DETAILS ........................................................................................... 14
1.1
Study objectives................................................................................................ 14
1.2
Definitions........................................................................................................ 17
1.2.1
Start of close-out period.................................................................................... 17
1.2.2
Withdrawal of consent ...................................................................................... 17
1.2.3
Discontinuation from study drug....................................................................... 17
1.2.4
Vital status........................................................................................................ 17
1.2.5
Lost to follow-up .............................................................................................. 18
1.3
Study design ..................................................................................................... 18
1.4
Number of patients ........................................................................................... 19
2
ANALYSIS SETS ............................................................................................ 20
2.1
Definition of analysis sets ................................................................................. 20
2.2
Violations and deviations.................................................................................. 21
3
PRIMARY AND SECONDARY VARIABLES ............................................... 21
4
ANALYSIS METHODS................................................................................... 27
4.1
General principles............................................................................................. 27
4.1.1
Estimand for primary and secondary outcomes ................................................. 28
4.1.2
Hypotheses ....................................................................................................... 29
4.1.3
Confirmatory testing procedure......................................................................... 29
4.1.4
Presentation of win-ratio analysis...................................................................... 29
4.1.5
Presentation of time-to-event analyses .............................................................. 30
4.1.6
Vital status and follow-up of endpoints............................................................. 30
4.1.7
Cox Proportional Hazards Model ...................................................................... 31
4.1.8
Analysis of repeated measures........................................................................... 31
4.1.9
Analysis of proportions ..................................................................................... 32
4.2
Analysis methods.............................................................................................. 32
4.2.1
Patient disposition, demographics and baseline characteristics .......................... 32
4.2.2
Concomitant and baseline medication ............................................................... 33
4.2.3
Analysis of the primary efficacy variable and the key secondary endpoint ........ 33
4.2.4
Analysis of the composite of HHF or CV death................................................ 34
4.2.5
Subgroup analysis............................................................................................. 35
4.2.6
Sensitivity analysis ........................................................................................... 36
4.2.7
Analysis of other secondary efficacy variables.................................................. 38
4.2.8
Analysis of exploratory time to event variables................................................. 39
4.2.9
Analysis of recurrent HF events and CV death.................................................. 39
4.2.10
Analysis of change from baseline...................................................................... 40


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4.2.11
Analysis of proportions..................................................................................... 40
4.2.12
Analysis of safety variables............................................................................... 41
4.2.12.1
Adverse events.................................................................................................. 41
4.2.12.2
Serious adverse events ...................................................................................... 41
4.2.12.3
Adverse events leading to discontinuation, interruption or dose reduction......... 42
4.2.12.4
Adverse events of special interest ..................................................................... 42
4.2.12.5
Laboratory Evaluation and vital signs ............................................................... 42
4.2.12.6
Marked laboratory abnormalities....................................................................... 42
4.2.12.7
AEs related to COVID-19................................................................................. 42
4.2.13
EQ-5D-5L ........................................................................................................ 43
4.2.14
Unify app.......................................................................................................... 43
4.2.15
Clever Cap........................................................................................................ 43
5
INTERIM ANALYSES.................................................................................... 43
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 43
7
REFERENCES................................................................................................. 44
8
APPENDIX ...................................................................................................... 44
LIST OF TABLES
Table 1
Characteristics and categories for subgroup analysis................................. 36


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
AE
Adverse Event
AF
Atrial Fibrillation
ACE
Angiotensin Converting Enzyme
ARB
Angiotensin Receptor Blocker
BMI
Body Mass Index
CCS
Canadian Cardiovascular Society
CEC
Clinical Endpoint Committee
CI
Confidence Interval
COVID-19
Coronavirus Disease of 2019
CSP
Clinical Study Protocol
CV
Cardiovascular
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
FAS
Full Analysis Set
HbA1c
Glycosylated haemoglobin
HHF
Hospitalisation for Heart Failure
HF
Heart Failure
HR
Hazard Ratio
I/E
Inclusion/Exclusion  
IP
Investigational Product
ITT
Intention To Treat
IxRS
Interactive Voice/Web Response System
KM
Kaplan-Meier
LTFU
Lost To Follow Up
LVEF
Left Ventricular Ejection Fraction
MACE (3-P MACE)
Major Adverse Cardiovascular Events
MI
Myocardial Infarction
NA
Not Applicable
NSTEMI
Non-ST segment Elevation Myocardial Infarction
NYHA
New York Heart Association


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Abbreviation or special 
term
Explanation
PD
Protocol Deviation
PT
Preferred Term
Q1
First Quarter
Q3
Third Quarter
QD
Once Daily
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SGLT2
Sodium-glucose co-transporter-2
SoC
Standard of Care
SOC
System Organ Class
ST
Sinus Tachycardia
STEMI
ST segment Elevation Myocardial Infarction
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
UK
United Kingdom
WoC
Withdrawal of Consent


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AMENDMENT HISTORY
Category:
Change refers to
Version
Description of change
In line with the 
CSP?
Rationale
Other
1.0
First version published.
N/A 
When first version of the SAP was 
published.
Other
2.0
Section 1.3. Updated 
Figure 1 Study Design.
Y(version 3.0)
To align with the study protocol.
Primary endpoint
2.0
Section 1.4. Added 
clarification regarding 
the sample size
Y(version 3.0)
To align with the study protocol.
Data presentations
2.0
Section 2.2. Added a few 
additional important 
protocol deviations.
N/A
To align with updated AstraZeneca 
SAP template.
Data presentations 
2.0
Section 2.2. Information 
about COVID-19 related 
protocol deviations 
added
Y(version 3.0)
To summarise the effect of 
COVID-19 on the study protocol.
Secondary endpoint
2.0
Section 3. More 
specified description of 
the incidence of new 
onset T2DM (Time to 
the first occurrence). 
Y(version 3.0)
To clarify what patients will be in 
the denominator.
Data presentations
2.0
Section 4.1. Clarified 
baseline definition for 
weight and HbA1c. 
Added minimum and 
maximum for how 
Clever Cap will be 
summarised.
N/A
To clarify what the baseline is for 
these variables and clarify how 
Clever cap will be analysed. 


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Other
2.0
Section 4.1.8, 4.2.7 T-
test being replaced with a 
linear regression model 
containing treatment and 
country.
N/A
To align with the planned 
analysis/output
Primary and secondary endpoints
2.0
Section 4.1.4. Changed 
presentation of KM% 
from 2 year to 1 year. 
Applicable for all time to 
event analyses. 
N/A
The median time in study has 
decreased due to the study delay. 
Data presentations
2.0
Section 4.1.9. Clarified 
how the analysis of 
proportions is conducted 
and what will be 
presented from it.
N/A
To clarify how the analysis is 
carried out and what the output will 
be from it.
Other
2.0
Section 4.2.2. Added 
more detailed 
information about 
prohibited concomitant 
medication 
Y(version 3.0)
To align with the study protocol 
Primary and secondary endpoints
2.0
Section 4.2.3. Changed 
from score statistics to 
Wald statistics when 
evaluating p-values from 
Cox model. Thus p-
values and 95% 
confidence intervals for 
the HR will be based on 
the Wald statistic.
N/A
To clarify how p-values and 95% 
confidence intervals for the HR will 
be calculated.
Other
2.0
Section 4.2.3. Removed 
text explaining about 
non-proportionality.
N/A
Pre-empt a possible interpretation 
of non-proportionality in absence of 
data.


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Primary and secondary endpoints
2.0
Section 4.2.3.1. Table 1: 
Subgroups “Insulin, Oral 
Glucose lowering agent” 
merged to one subgroup 
“Anti-hyperglycemic 
agents”. Renamed 
subgroup “Oral
Antiplatelets” to 
“Thienopyridine/Ticagrel
or” Subgroup Removed 
subgroup “Diuretics” and 
“Angiotensin II receptor 
blocker” since not 
collected in UK at 
baseline. Added category 
LVEF 30-50 into the 
current LVEF subgroup.
N/A
Scientific interest
Primary and secondary endpoints
2.0
Section 4.2.3.1. Table 1: 
“Previous Hypertension 
,Yes/No” inserted as a 
new subgroup 
characteristic in the 
table.
N/A
Scientific interest
Secondary endpoints
2.0
Section 4.2.3.1, 4.2.4. 
Subgroup analysis will 
also be conducted for the 
secondary endpoint “new 
onset of T2DM”.
N/A
Scientific interest
Primary endpoint
2.0
Section 4.2.3.2. 
Sensitivity analysis 
added regarding 
investigated reported 
primary events. 
N/A
To assess the robustness of 
adjudication for the primary 
endpoint.


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Primary endpoint
2.0
Section 4.2.3.2. 
Sensitivity analysis 
added regarding COVID-
19.
N/A
To assess the robustness of the 
primary analysis in relation to 
COVID-19 related events.
Primary endpoint
2.0
Section 4.2.3.2. 
Sensitivity analysis 
added regarding the 
modified Hicks criteria 
for the primary endpoint. 
N/A
To assess the robustness of 
modified Hicks criteria for the 
primary endpoint.
Primary endpoint
2.0
Section 4.2.3.2. Added 
text around a possible
sensitivity analyse to 
investigate the influence 
and magnitude of 
incomplete dates.
N/A
Feedback from authorities
Data presentations
2.0
Section 4.2.6. Clarified 
how the components in 
the composite recurrent 
HF hospitalisation or CV 
death will be analysed.
N/A
To clarify how the LWYY analysis 
will be carried out. 
Data presentations
2.0
Section 4.2.9.2. Section 
renamed to “Serious 
adverse events”. Added 
information how SAE 
will be collected in 
Sweden and UK.
Y(version 3.0)
To clarify how SAE will be 
collected in each country. 
Data presentations
2.0
Section 4.2.9.3. Added 
reason why adverse 
event leading to 
discontinuation , 
interruption or dose 
Y(version 3.0)
To align with study protocol.


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reduction is not collected 
in study. 
Data presentations
2.0
Section 4.2.9.5. 
Excluded S-Creatinine 
and eGFR since they are 
only collected at 
baseline. Added HbA1c, 
Body weight and BMI to 
be presented.
Y(version 3.0)
To clarify which parameters will be 
presented in laboratory and vital 
signs evaluation.
Data presentations
2.0
Added section 4.2.9.7 
added summary of 
COVID-19 related AEs.
N/A
To investigate the influence of 
COVID-19 on AEs.
Data presentations
2.0
Section 4.2.10. Modified 
section text regarding 
EQ-5D-5L
N/A
Clarification about what output will 
be produced added.
Data presentations
2.0
Section 4.2.11. Modified 
section text regarding 
Unify app
N/A
Clarification about what output will 
be produced added.
Data presentations
2.0
Section 4.2.12. Modified 
section text regarding 
Clever Cap
N/A
Clarification about what output will 
be produced added.
Other 
2.0
Section 1.3, 2.1, 3, 4.1, 
4.1.1, 4.1.5-4.1.9, 4.2.1, 
4.2.3, 4.2.7, 4.2.9, 7. 
Several minor 
classification, 
abbreviations added and 
removed, corrections and 
typos. 
N/A
To help readability
Study title
3.0
Updated title
Yes (version 4.0)
To align with study protocol 
version 4.0


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Study objectives (section 1.1)
3.0
Updated objectives and 
endpoints
Yes (version 4.0)
To align with study protocol 
version 4.0
Start of close-out period (former 
known as PACD) (section 1.2.1)
3.0
PACD was removed 
from study design and as 
a consequence the start 
of close-out period was 
re-defined
Yes (version 4.0)
To align with study protocol 
version 4.0
Vital status (section 1.2.4)
3.0
PACD was removed 
from study design and as 
a consequence the vital 
status at study end was 
re-defined
Yes (version 4.0)
To align with study protocol 
version 4.0
Study design (section 1.3)
3.0
The key study 
assumptions were 
updated
Yes (version 4.0)
To align with study protocol 
version 4.0
Number of patients (section 1.4)
3.0
The sample size 
calculation was updated 
as a consequence of 
changed study design
Yes (version 4.0)
To align with study protocol 
version 4.0
Primary and secondary variables 
(section 3)
3.0
The primary and 
secondary variables were 
updated and rearranged
Yes (version 4.0)
To align with study protocol 
version 4.0
Baseline for lab, physical 
examination and vital signs (section 
4.1)
3.0
Baseline was re-defined
Yes (version 4.0)
To align with study set-up
Hypothesis (section 4.1.2)
3.0
Efficacy interim analysis 
was removed, and 
hypothesis endpoint was 
updated from HR to 
Win-Ratio
Yes (version 4.0)
To align with study protocol 
version 4.0


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Confirmatory testing procedure 
(section 4.1.3)
3.0
Win-ratio endpoints were 
placed first and 
secondary endpoints 
were re-ordered
Yes (version 4.0)
To align with study protocol 
version 4.0
Presentation of win-ratio analysis 
(section 4.1.4)
3.0
New section added to 
describe the win-ratio 
analysis
Yes (version 4.0)
To align with study protocol 
version 4.0
Vital status and follow-up of 
endpoints (section 4.1.6)
3.0
PACD was removed 
from study design and as 
a consequence the close-
out period was re-defined
Yes (version 4.0)
To align with study protocol 
version 4.0
Analysis of last assessment for 
continuous variables (section 4.1.8)
3.0
Section removed as no 
such analyses will be 
performed
Yes (version 4.0)
To align with study protocol 
version 4.0
Analysis of the primary efficacy 
variable and the key secondary 
endpoint (section 4.2.3)
3.0
New section added to 
describe analysis method 
for win-ratio endpoints
Yes (version 4.0)
To align with study protocol 
version 4.0
Subgroup analysis (section 4.2.4.1)
3.0
Subgroups updated and 
endpoints for which 
subgroup analysis will be 
performed for updated
Yes (version 4.0)
To align with study protocol 
version 4.0
Analysis of other secondary 
endpoints (section 4.2.5)
3.0
Update of other 
secondary endpoints
Yes (version 4.0)
To align with study protocol 
version 4.0
Analysis of exploratory time to 
event variables (section 4.2.6)
3.0
Update of exploratory 
endpoints
Yes (version 4.0)
To align with study protocol 
version 4.0
Analysis of change from baseline 
(section 4.2.8)
3.0
Update for which 
variables this analysis 
will be performed for
Yes (version 4.0)
To align with study protocol 
version 4.0
Interim analysis (section 5)
3.0
Interim analysis removed
Yes (version 4.0)
To align with study protocol 
version 4.0


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References (section 7)
3.0
List of references 
updated
Yes (version 4.0)
To align with study protocol 
version 4.0
All sections
3.0
Several minor updates, 
corrections and typos
Yes (version 4.0)
To align with study protocol 
version 4.0
Endpoints
4.0
Added the secondary 
composite endpoint of 
CV death, HHF and MI
No
Of scientific interest
Win-ratio method
4.0
Added analysis details
No
To make the analysis method 
clearer


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1
STUDY DETAILS
1.1
Study objectives
Objectives
Endpoints
Primary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM, symptoms of HF as measured 
by NYHA class, as well as reduced Body weight, in 
relation to placebo.
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
7.
Body weight decrease of at least 5% at last 
visit
Secondary
To determine whether the clinical benefit of 
dapagliflozin 10 mg once daily (QD) is superior in 
relation to placebo when added to SoC in patients 
without diabetes with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation. Clinical benefit is reduced 
risk of Death, Heart Failure, non-fatal MI, AF/flutter, 
new onset of T2DM and symptoms of HF as 
measured by NYHA class, in relation to placebo.
The hierarchical composite endpoint of:
1.
Death (first CV death, followed by non-CV 
death)
2.
Hospitalisation due to heart failure (first 
adjudicated, followed by investigator 
reported)
3.
Non-fatal MI
4.
AF/flutter event
5.
New onset of T2DM
6.
NYHA class at last visit
To demonstrate the superiority of dapagliflozin 
10 mg once daily (QD) versus dapagliflozin 10 mg 
placebo to match in reducing the incidence of CV 
death or HHF when added to SoC in non-diabetic 
patients with myocardial infarction and impaired left 
ventricular systolic function during the index MI 
hospitalisation.
Time to the first occurrence of any of the components 
of this composite:
•
HHF
•
CV death
To demonstrate the superiority of dapagliflozin 
10 mg once daily (QD) versus dapagliflozin 10 mg 
placebo to match in reducing the incidence of CV 
Time to the first occurrence of any of the components 
of this composite:
•
HHF


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Objectives
Endpoints
death, HHF or MI when added to SoC in non-
diabetic patients with myocardial infarction and 
impaired left ventricular systolic function during the 
index MI hospitalisation*
•
CV death
•
MI
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing MI, stroke or CV 
Death (MACE) when added to SoC
Time to the first occurrence of any of the components 
of this composite:
•
MI
•
Stroke (incl. ischaemic, haemorrhagic and 
undetermined stroke)
•
CV death
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of CV 
Death when added to SoC
Time to CV Death
To investigate whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of fatal 
or non-fatal MI when added to SoC
Time to the first occurrence of a fatal or a non-fatal 
MI
To determine whether dapagliflozin 10 mg QD, 
compared with placebo, reduces the incidence of new 
onset T2DM in MI patients when added to SoC
Time to new onset of T2DM
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing Body Weight when 
added to SoC
Change from baseline in Body weight
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of 
hospitalisation for any cause when added to SoC
Time to hospitalisation for any cause
To determine whether dapagliflozin 10 mg QD is 
superior to placebo in reducing the incidence of all-
cause mortality when added to SoC
Time to death of any cause
Tertiary/Exploratory
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety
To evaluate the safety of dapagliflozin 10 mg QD in 
clinically stable patients with ST segment elevation 
myocardial infarction (ST)- or non-ST elevation 
myocardial infarction initiated on post-MI therapies 
and without an established diagnosis of type 1 
diabetes mellitus (T1DM) or T2DM
Adverse events defined as events that lead to:
•
death; or 
•
hospitalisation
CCI
CCI


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*The objective/composite endpoint of CV death, HHF or MI has not been specified in the protocol and is 
included here for the purpose of being included in the confirmatory testing (section 4.1.3).
1.2
Definitions
1.2.1
Start of close-out period
The executive committee and AstraZeneca will monitor the accrual of patients and when 
appropriate define a certain date at which time the close-out period will start, and the study 
sites should commence with the study close-out visits.
The analyses of the primary endpoint will include all data collected during the study up until, 
and including, each patient’s individual closing visit. 
1.2.2
Withdrawal of consent
Withdrawal of consent (WoC) means withdrawal from study and should only occur if the 
patient does not agree to any kind of further assessment at all. No data after date of WoC 
should be collected, with the exception for vital status (dead or alive) at the end of the study 
collected from public sources, which will be included in the analysis of death from any cause 
as a sole outcome and in patient disposition summaries. Data collected on or prior to date of 
WoC will be included in analyses.
1.2.3
Discontinuation from study drug
Discontinuation from study drug does not mean WoC. Optimally, patients who discontinue
from study drug should continue study visits according to plan until study closure. 
Alternatively, if the patient does not agree to this approach, modified follow-up should be 
arranged. Data from patients who did not withdraw consent will be included in the intention to 
treat (ITT) analyses irrespective of whether events occur before or following discontinuation 
of study drug.
1.2.4
Vital status
The vital status at the end of the study is considered to be known if a patient is dead or alive at 
their individual closing visit. If not possible to determine if a patient is dead or alive at their 
individual closing visit, the vital status for such patients will be considered to be unknown. 
For patients who have withdrawn consent, the investigator will attempt to collect vital status 


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from publicly available sources at study closure in compliance with local privacy 
laws/practices.
1.2.5
Lost to follow-up
The term lost to follow-up (LTFU) will be limited to patients with unknown vital status at the 
end of the study as defined in Section 1.2.4. Other measures will be used to describe 
incomplete follow-up (Section 4.1.6).
1.3
Study design
This is a multicentre, parallel group, registry-based randomised controlled trial (R-RCT), 
double-blind, placebo-controlled phase 3 study in patients without diabetes presenting with 
myocardial infarction (MI) (STEMI or NSTEMI) and impaired regional or global LV systolic 
function or definite evidence of Q wave MI on ECG. The study is conducted in Sweden and in 
the United Kingdom (UK) and will randomise approximately 4000 patients. In the study the 
effect of dapagliflozin 10 mg versus placebo, given once daily in addition to standard of care 
(SoC) therapy will be evaluated for clinical benefit. 
The anticipated duration of the study is approximately 30 months.  The study closure 
procedures will be initiated when approximately 4000 patients have been randomised. 
Patients will be randomised 1:1 to either dapagliflozin 10 mg or placebo. 
Randomisation will be performed in balanced blocks of fixed size, stratified by country. The 
randomisation codes will be computer generated and loaded into the IxRS (Interactive 
Voice/Web Response System) database.


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1.4
Number of patients
The primary objective of the study is to determine if the clinical benefit of dapagliflozin is 
superior in relation to placebo and this objective will be assessed with a hierarchical 
composite endpoint and analysed using the win-ratio method. With a study duration of 
approximately 30 months and a minimum follow-up of 3 months, assuming a true win-ratio of 
1.20 between dapagliflozin and placebo, 4000 patients will provide a statistical power of 80%, 
based on simulations, for the test of the primary composite endpoint, using a two-sided with 
type I error of 5%. This is based on an overall 1:1 allocation between dapagliflozin and 
placebo. The assumed win-ratio of 1.20 is considered as clinically relevant (if the observed 
win-ratio is 1.20 then the likelihood for a better outcome with Dapagliflozin is 20% higher 
compared to Placebo).
The assumptions for the simulations are described below. Assumed effect sizes are based on 
historical data for related subgroups in Dapagliflozin outcome studies DECLARE, DAPA-HF, 
DAPA-CKD and DELIVER.
1. All-cause mortality: around 55 patients with event and an 
assumed risk ratio Dapagliflozin versus Placebo around 0.89
2. Heart failure events: around 70 patients with event and an 
assumed risk ratio Dapagliflozin versus Placebo around 0.74


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3. Non-fatal MI: around 50 patients with event and an assumed 
risk ratio Dapagliflozin versus Placebo around 0.84
4. Atrial fibrillation/flutter event: around 35 patients with event 
and an assumed risk ratio Dapagliflozin versus Placebo around 
0.86
5. New onset of T2DM: around 70 patients with event and an 
assumed risk ratio Dapagliflozin versus Placebo around 0.75
6. NYHA class at last visit: all patients will participate in the 
analysis (if no event for the first 5 endpoints in the hierarchy)
and the assumption is that patients in the Dapagliflozin arm will 
have a 12% lower risk of developing worse symptoms of HF as 
measured by NYHA class as compared with patients in the 
Placebo arm.
7. Body weight loss at least 5% at last visit: around 725 patients 
and an assumed risk ratio Dapagliflozin versus Placebo around 
1.13
2
ANALYSIS SETS
2.1
Definition of analysis sets
Patients could by error have been randomised more than once. Such patients will be analysed 
according to their first randomisation assignment. Serious adverse events (SAEs), study 
medication and endpoints will be consolidated and re-entered at the discretion of the 
Investigator under the patient identifier used in the first randomisation. The redundant records 
associated with the same patients will be stored in a separate dataset for future references.
Full analysis dataset
All patients who have been randomised to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study. 
Patients will be analysed according to their randomised investigational product (IP) 
assignment, irrespective of the treatment actually received. The FAS will be considered the 
primary analysis set for the primary and secondary efficacy variables and for the exploratory 
efficacy variables.
Safety analysis dataset


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All randomised patients who received at least 1 dose of study treatment will be included in the 
safety population. Patients will be analysed according to the treatment actually received. For 
any patients given incorrect treatment, i.e. randomised to one of the treatment groups but 
actually given the other treatment, the treatment group will be allocated as follows: Patients 
who got both incorrect and correct treatment will be analysed according to their randomised 
treatment. Patients who got only the incorrect treatment will be analysed according to that 
treatment.
2.2
Violations and deviations
The important protocol deviations listed below will be summarised by randomised treatment 
group

Patients who were randomised but did not meet inclusion and exclusion criteria

Patients who received the wrong study treatment at any time during the study

Patients who received prohibited concomitant medication

Written informed consent not obtained prior to mandatory study specific procedures, 
sampling, and analyses

Those who developed discontinuation of protocol specified therapy criteria during the 
study, but remained on protocol specified therapy

Site procedure for unblinding the subject is not compliant with CSP
Patients meeting criteria for important protocol deviations will be identified prior to 
unblinding. As the primary analysis is intention-to-treat analysis, important protocol deviation 
will not imply exclusion from the primary analysis.
All protocol deviations (PDs) related to COVID-19 will also be summarised. In order to allow 
easy filtering and reporting of COVID-19 related PDs (Important PD and Non-Important PD) 
issues must start with “COVID19” prefix recorded in CTMS in description field, followed by 
regular description of occurred case.
3
PRIMARY AND SECONDARY VARIABLES
Adjudication
Adjudication will only be performed for CV death and HHF. Potential events and event dates 
will be adjudicated by an independent clinical event adjudication committee (CEC). The 
committee members will not have access to the treatment codes for any patient. The CEC 
procedures and event definitions will be described in the CEC charter.


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Time to event analyses
For analysis of time to first event, data will be expressed as two variables:
•
A binary variable indicating whether the event in question occurred, or the patient was 
censored.
•
An integer variable for the number of days from randomisation to the first occurrence of 
an event (start date of the event – randomisation date + 1), or for event free patients, from 
randomisation to censoring (censoring date – randomisation date + 1).
Clinical event assessment
Last clinical event assessment is defined as the last date when a patient was assessed for any 
potential events. It is expected that patients alive and under study follow-up will have a 
clinical event assessment at their individual study closure visit.
Primary variable

The hierarchical composite of death, heart failure events, non-fatal MI, atrial 
fibrillation/flutter event, new onset of T2DM, NYHA class at last visit and body 
weight decrease at least 5% at last visit, based on the hierarchical order of clinical 
importance.
Each patient will be represented by its most severe event, according to the below ordering. In 
general, an event will lose compared with no event and an earlier event will lose compared 
with a later event (within the same category). For each pair-wise comparison, only events 
occurring within the shared follow-up time will be considered, i.e., the minimum follow-up 
time within each pair, resulting in censoring at the shared follow-up time for the patient with 
the longest follow-up time as it is unknown what would happen to the patient with shorter 
follow-up time after that timepoint. The follow-up time for each patient will be defined as 
time from randomisation to the following dates in the following order, if present:
1. Date of withdrawn consent
2. Date of death
3. Date of last clinical event assessment


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4. Date of individual close-out visit
Death: Adjudicated cause of death will be used. CV death will lose compared with non-CV 
death.

CV death < non-CV death < alive (time to event will differentiate if comparing two 
patients with event within the same category)
HHF: Investigator reported hospitalisation for heart failure defined as primary cause or 
contributing factor for hospitalisation, as assessed by investigator. Adjudicated HHF will lose 
compared with investigator reported HHF.

Adjudicated HHF < investigator reported HHF < no HHF (time to event will 
differentiate if comparing two patients with event within the same category)
Non-fatal MI: Investigator reported MIs in CIEVENT CRF form.

Event < no event (time to event will differentiate if comparing two patients with event)
AF/Flutter event: SAE leading to hospitalisation with a preferred term of atrial fibrillation or 
atrial flutter regardless of medical history at baseline will be included.

Event < no event (time to event will differentiate if comparing two patients with event)
New onset of T2DM: Investigator reported cases with new diagnosis of type 2 diabetes 
reported on the DMDIAG CRF form after the index hospitalisation will be included.

Event < no event (time to event will differentiate if comparing two patients with event)
NYHA class at last visit: NYHA class 0 and I will be in the same category as hard to 
differentiate. Last visit is defined as the last visit with NYHA measurement available, within 
each pair-wise comparison. Only measurements after the index hospitalisation will be
considered. A pair-wise comparison including missing data at this level will result in a tie.

Class IV < class III < class II < class 0/I
Body weight decrease (vs. baseline) of at least 5% at last visit: Last visit is defined as the last 
visit with body weight measurement available, within each pair-wise comparison. Only 
measurements after the index hospitalisation will be considered. A pair-wise comparison 
including missing data at this level will result in a tie.

No decrease at least 5% < decrease at least 5%


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Key secondary variable

The hierarchical composite of death, heart failure events, non-fatal MI, atrial 
fibrillation/flutter event, new onset of T2DM and NYHA class at last visit, based on 
the hierarchical order of clinical importance.
Other secondary variables
•
The incidence of HHF or CV death (Time to the first occurrence of any of the 
components)
All adjudicated events from randomisation until WoC or each patient’s individual closing 
visit (whatever occurs first) will be included. Patients without events will be censored at 
the earliest of date of WoC or non-CV death, and otherwise at the date of last clinical 
event assessment.
•
The incidence of CV death, HHF or MI (Time to the first occurrence of any of the 
components)
All events from randomisation until WoC or each patient’s individual closing visit 
(whatever occurs first) will be included. Patients without events will be censored at the 
earliest of date of WoC or death, and otherwise at the date of last clinical event 
assessment.
•
The incidence of hospitalisation for any cause (Time to the first occurrence of any of the 
components) (SAEs that requires or prolongs hospitalisation as collected at the SERAE 
CRF form)
All events from randomisation until WoC or each patient’s individual closing visit 
(whatever occurs first) will be included. Patients without events will be censored at the 
earliest of date of WoC or death, and otherwise at the date of last clinical event 
assessment.
•
The incidence of new onset type 2 diabetes mellitus (T2DM) (Time to the first 
occurrence)
Defined as reporting of new onset T2DM after discharge from the index hospitalisation as 
reported by investigators in the dedicated CRF form (DMDIAG). 
All events from randomisation until WoC or each patient’s individual closing visit 
(whatever occurs first) will be included. Patients without events will be censored at the 


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earliest of date of WoC or death, and otherwise at the date of last clinical event 
assessment.
•
The incidence of MACE (CV death, MI and stroke) (Time to the first occurrence of any 
of the components)
MI will include investigator reported non-fatal and fatal MI. Stroke will include 
investigator reported non-fatal and fatal stroke. All events from randomisation until WoC 
or each patient’s individual closing visit (whatever occurs first) will be included. Patients 
without events will be censored at the earliest of date of WoC or non-CV death, and 
otherwise at the date of last clinical event assessment. 
•
The change from baseline to last visit in body weight
All data after the index hospitalisation until WoC or each patient’s individual closing visit 
(whatever occurs first) will be considered. These analyses will be done for the on-
treatment period and will include measurements on or after first dose of randomised study 
drug and on or before 30 days after last dose of study drug.
•
The incidence of fatal or non-fatal MI (Time to the first occurrence)
All investigator reported events from randomisation until WoC or each patient’s 
individual closing visit (whatever occurs first) will be included. Patients without events 
will be censored at the earliest of date of WoC or death, and otherwise at the date of last 
clinical event assessment.
•
The incidence of CV death (Time to occurrence)
CV death will include CV deaths and deaths with undetermined cause of death, as 
adjudicated by the CEC. All events from randomisation until WoC or each patient’s 
individual closing visit (whatever occurs first) will be included. Patients without events 
will be censored at the earliest of date of WoC or non-CV death, and otherwise at the date 
of last clinical event assessment.
•
The incidence of all-cause mortality (Time to occurrence)
All events from randomisation until each patient’s individual closing visit, including 
deaths after WoC, will be included. Patients without events will be censored at the date 
last known alive.


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Causes of deaths
The causes of deaths, as adjudicated by the CEC, will include CV cause, non-CV cause, and 
undetermined cause. Analyses of CV death, either as a component of a composite or on its 
own, will include deaths adjudicated as CV cause as well as deaths adjudicated as 
undetermined cause.
Potential death cases found in publicly available sources after withdrawal of consent will not 
be adjudicated. 
Non-fatal MI and non-fatal stroke
MI is defined as fatal if patient dies due to CV cause (according to CEC adjudication) within 
30 days after onset of AE. Non-fatal MIs are all investigator reported MI that are not fatal.
Stroke is defined as fatal if patient dies due to CV cause (according to CEC adjudication) 
within 30 days after onset of AE. Non-fatal strokes are all investigator reported stroke that are 
not fatal.
Safety variables and collection of safety data
The safety variables are adverse events (AEs) leading to death or hospitalisation (Summary 
statistics)
The safety events will be collected from randomisation until and including the patient’s last 
visit.
CEC will adjudicate deaths and HHF. If not adjudicated as HHF the event will be considered 
as an AE. All deaths will be considered as endpoints. For MI and Stroke, the investigator will 
decide if it is an endpoint. No events that are considered to be endpoints will be reported to 
health authorities to avoid unnecessary unblinding of efficacy endpoints.


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4
ANALYSIS METHODS
All statistical analyses will be performed using the SAS® statistical analysis system (SAS 
Institute Inc., Cary, NC) and, where appropriate, additional validated software.
4.1
General principles
95% confidence intervals for the point estimates will be provided, without multiplicity 
adjustment as they will be interpreted descriptively and used as a measure of precision. All p-
values will be unadjusted. P-values for variables not included in the confirmatory testing 
sequence or following a non-significant test in the sequence will be regarded as nominal. All 
p-values will be presented as 2-sided.
Incomplete dates
All efforts should be made to obtain complete dates of clinical assessments and events. For 
analyses requiring complete dates, partially missing dates will be imputed based on available 
corroborating information. Absence of any additional corroborating information, partially 
missing dates will be imputed as follows: if only the year part of a date is available (YY), then 
the date will be set to YY0701. If only the year and month is available (YYMM), then the date 
will be set to YYMM15. Additional imputation rules will be defined as appropriate to ensure 
that for example dates will not be imputed as prior to randomisation, after death, after WoC or 
end date before start date.
Special cases for date of death:
•
For a patient that died with the date of death imputed, the maximum of the imputed date 
and last date the patient was known to be alive will be used as date of death.
•
If adjudicated date of death is completely missing, the site-reported date of death will be 
used.


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•
For a patient that died that has a completely missing date of death, the last date the patient 
was known to be alive will be imputed and used as date of death.
Baseline for laboratory and physical examination/vital signs parameters
Baseline is defined as the last value on or before the date of randomisation. If no value is 
available, the last value on or before the day of discharge from the index hospitalisation will 
be used. Baseline values should be obtained during the index hospitalisation, with HbA1c as 
the only exception for which the measurements before the index hospitalisation but within 30 
days prior to the randomisation are allowed.
Descriptive statistics
Numerical variables will be summarised using standard summary statistics including the 
number of patients, mean, standard deviation (SD), median, Q1, Q3 and range (i.e., minimum,
and maximum) as appropriate.  For categorical data, proportions will be presented in a 
frequency table format.  
Study drug compliance
It will not be possible to calculate study drug compliance in this study due to no pill count. 
Instead, the number of times during the study that each patient opens (on or after date of 
randomisation and on or before the date of each patient’s individual closing visit) the Clever 
Cap, will be summarized, including mean, median, maximum, minimum, quartiles and 5% 
and 95% percentiles will be calculated for each treatment arm for comparison.
4.1.1
Estimand for primary and secondary outcomes
It is important to distinguish between non-adherence with, or withdrawal from, randomised 
treatment and discontinuation from the trial. A randomised patient can withdraw from the 
study but not from the analysis, and according to the intention to treat principle, all data will 
be included. The potential impact of intercurrent events (events that occur after treatment 
initiation and either preclude observation of the variable or affect its interpretation (e.g., 
discontinuation of treatment, switching treatment, terminal events such as death, lost to 
follow-up or withdrawn consent)) is anticipated to be low and with even distribution between 
the treatment arms. The primary and secondary objectives will be evaluated under the 
treatment policy estimand to reflect the effect of the initially assigned randomised study drug, 


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irrespective of adherence to randomised study treatment. Specifically, the analyses will be 
performed for the full analysis set including all data collected on or prior to each patient’s 
individual closing visit, including data following premature discontinuation of study drug.
4.1.2
Hypotheses 
For the primary and key secondary endpoints, the following null hypothesis will be tested at 
the 5% two-sided significance level
H0: Win-Ratio [dapagliflozin:placebo] =1 
versus the alternative hypothesis
H1: Win-Ratio [dapagliflozin:placebo] ≠ 1
For the secondary time-to-event endpoints, the hypotheses will be in reference to hazard ratio 
rather than win ratio. 
For the secondary endpoint of change in body weight, the hypotheses will be in reference to 
difference in mean absolute change from baseline.
4.1.3
Confirmatory testing procedure 
The primary and secondary endpoints will be tested in the same order as listed in the 
objectives/endpoints table in section 1.1. In each step, the endpoint will be tested at full alpha, 
two-sided level of 0.05, and if meeting statistical significance, testing will continue to the next 
endpoint in order.
The secondary all-cause mortality endpoint will be tested outside the multiple testing 
procedure at a two-sided alpha level of 0.05, in consideration of the principles around testing 
of ‘hard’ endpoints as outlined O’Neill. (Robert T. O’Neill, PhD 1997)
4.1.4
Presentation of win-ratio analysis 
For estimation of clinical benefit, the win-ratio and corresponding 95% confidence interval 
and p-value for confirmatory testing will be reported. Win-ratio is calculated as the ratio of the 
number of “winner” pairs to the number of “loser” pairs for the dapagliflozin arm.


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The statistic represents the ratio of having a more favorable outcome versus a less favorable 
outcome when comparing the dapagliflozin group with the placebo group. If the estimated 
win-ratio is greater than 1 then the treatment effect is estimated to be in favors of 
dapagliflozin. The variance will be calculated by the method described by Yu et al, which is 
approximately the same as asymptotic normal U statistic approach. (Pocock et al 2012) (Yu et 
al 2022)
The results of the win-ratio analysis of the hierarchical composite endpoints will be tabulated
and depicted. The contribution of the individual components will be described.
4.1.5
Presentation of time-to-event analyses
In general, summary tables of time-to-event analyses will include the number and percent of 
patients with event per treatment group, the 1-year KM rate, hazard ratio with 95% confidence 
interval and p-value.
Kaplan-Meier (KM) estimates of the cumulative proportion of patients with events will be 
calculated and plotted per treatment group, with the number of patients at risk indicated below 
the plot at specific time points. The KM plots will be presented for all time to event analyses, 
including the individual components of the composite endpoints. (Kaplan EL and Meier P 
1958). One year will be considered to be 360 days and one month will be considered to be 30 
days. Specific time points for KM estimates will be the visit at week 8, the visit at 1 year, and 
the following visits at every 10 months.
A patient may have one or more events. For composite endpoints, the time to first event 
within the composite list will be used. For each component of a composite, the time to first 
component event will be used, regardless of other events occurring earlier (e.g., if a stroke 
precedes an MI in a patient, then the stroke counts in the composite MACE as the first event, 
but the MI counts in the time to first MI analysis).
4.1.6
Vital status and follow-up of endpoints
Potential endpoints will be collected from randomisation throughout the study until and 
including the patient’s last visit. The investigator will attempt to collect vital status (dead or 
alive) at the end of the study for all patients, including vital status from publicly available 
sources for patients who have withdrawn consent, in compliance with local privacy 
laws/practices.
Known vital status at the end of the study will be defined when the patient is dead or is known
to be alive at close-out visit (derived from the eCRF final status form). In patient disposition 
the number of patients who are dead, alive or with unknown vital status will be reported. The 


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term lost to follow-up (LTFU) will be limited to only patients with unknown vital status, who 
did not withdraw consent.
Follow-up of efficacy endpoints will be defined in terms of completion of the event 
assessment. Thus, a patient that is not LTFU, i.e., with known vital status, may have 
incomplete follow-up of endpoints.
Complete follow up of the composite of HHF or CV death will be defined as the patient had a 
HHF or CV death event or had complete event assessment on the individual closing visit.
In addition to the number and percent of patients with complete follow-up, the proportion of 
total patient time with complete follow-up will be reported per treatment group.
Patient time with complete follow-up will be defined as time from randomisation until the 
earliest of first primary endpoint event, WoC, censoring due to incomplete event assessment 
(in cases where last complete event assessment is prior to their individual closing visit) or 
their individual closing visit. The denominator, representing maximum complete follow-up, 
will be the time to first HHF or CV death event or patient’s individual closing visit. 
The Executive Committee will monitor the accrual of patients and when the required number 
of patients are predicted to have been recruited, upon confirmation from the Sponsor, will 
instruct all sites that to perform all individual study closure visits by a certain defined date.
4.1.7
Cox Proportional Hazards Model
Cox proportional hazards model will be used to analyse the time-to-events variables.  The 
model will be stratified by country, with treatment as a model term.
With respect to randomised treatment, hazard ratio estimates and 2-sided 95% confidence 
intervals (CIs) will be presented.  No hazard ratio estimates will be given for subgroups with 
less than 15 events in total, both arms combined. P-values will be presented from the Wald’s 
test.
4.1.8
Analysis of repeated measures 
Repeated measure analysis (using PROC MIXED model in SAS) will be used to analyse 
change from baseline to each relevant time point.  The model contains terms for randomised 
treatment group, baseline measurement, time (each relevant visit) and time by randomised 
treatment group interaction, and country. 


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The MIXED model will present least squares (LS) mean estimates and 2-sided 95% 
confidence intervals (CIs) for treatment difference as well as change from baseline within 
treatments.
To model the covariance structure, the within patients unstructured covariance structure will 
be used. The MIXED model is computationally intensive, if the algorithm does not converge, 
the Toeplitz first-order autoregressive or compound symmetric covariance structure will be 
used.
4.1.9
Analysis of proportions 
Proportions of patients may be analysed using the Cochran-Mantel-Haenszel test, stratified by 
country. p-value of the test of general association will be presented. Mantel-Haenszel common 
risk difference will be obtained along with 95% confidence intervals, based on the Sato 
variance estimator. 
4.2
Analysis methods
4.2.1
Patient disposition, demographics and baseline characteristics
The number and percent of patients who completed the study, discontinued from the study 
will be summarized by treatment group and overall, for all randomised patients. Listings of 
patients who prematurely discontinued from the study will be provided. 
The number and percent of patients who discontinued randomised treatment and reasons for 
discontinuation of treatment will be summarized by treatment group and overall, for all 
randomised patients. Listings of patients who prematurely and permanently discontinued 
treatment will be provided. 
Demographic and baseline (as defined in Section 4.1 General principles) characteristics, 
including medical/disease history, will be summarized, using frequency distributions and 
summary statistics based on the FAS data set, for each treatment group as well as for all 
patients combined.  No statistical test will be performed for comparison of any baseline 
measurement among treatment groups.
All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentage will be calculated out of the total number of patients 
with non-missing observations, overall and by treatment group.


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4.2.2
Concomitant and baseline medication 
Baseline medications are defined at the index MI hospitalisation discharge visit.
Concomitant medication is defined as medications taken post the index MI event 
hospitalisation, irrespective of study drug, but will be limited to relevant concomitant 
cardiovascular medication and treatment for T2DM.
The frequency of baseline and concomitant medications will be presented for the FAS per 
treatment group.
Summaries of prohibited medication will be presented. In this study prohibited concomitant 
medication is limited to open label SGLT2 inhibitors taken at any time during the study, at the 
same time as study drug.
4.2.3
Analysis of the primary efficacy variable and the key secondary 
endpoint
The objective of the study is to assess clinical benefit. The clinical benefit will be assessed 
using a hierarchical composite endpoint (HCE) and analysed with the win-ratio method 
(Pocock et al 2012). The hierarchical assessment will consist of the following endpoints in the 
following order: death, heart failure events, non-fatal MI, atrial fibrillation/flutter event, new 
onset of T2DM, NYHA class at last visit and body weight loss at least 5% at last visit. Each 
patient will be represented by their most severe event within each pair-wise comparison. The 
pair-wise comparisons will be restricted to the shared follow-up time within each individual 
pair.
•
Compares each patient in the treatment group with each patient in the control group 
to determine the winner/loser/tie within each pair across the multiple outcomes
•
Each paired comparison starts with the most important outcome, and moves to 
lower priority outcomes only if higher priority outcomes result in a tie
•
The win-ratio is the number of wins in the treatment group divided by the number of 
wins in the control group
CV death will be considered as most severe, followed by non-CV death. If two patients within 
the same category (for example CV death) are compared, then the patient with shortest time to 


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event will be considered as more severe. For death and heart failure, adjudicated events will 
be considered first, followed by investigator reported events (for heart failure). If a patient 
experienced a heart failure event this patient will be represented by this event, if the patient is 
not already represented by a death event. Adjudicated heart failure is considered as more 
severe as compared to Investigator reported. If two patients within the same heart failure 
category are compared, then shortest time to first event will be considered as more severe. 
Next step is non-fatal MI. If a patient experienced a non-fatal MI this patient will be 
represented by this event, if the patient is not already represented by a death event or a heart 
failure event. Next step is atrial fibrillation/flutter followed by new onset of T2DM. The 
shortest time to event will be considered also for non-fatal MI, AF/Flutter and T2DM in the 
same manner as described for death and heart failure. The following step is NYHA at last 
measurement and at this step all patients will participate (if no event for the first 5 endpoints 
in the hierarchy). For NYHA class, a significant number of ties are expected, as most patients 
will have 0 or I which can be considered as the reference, and predominantly patients with 
NYHA class II, III and IV will affect the analysis. For ties in the NYHA comparison, body 
weight loss at least 5% at last measurement will be used to break the ties. Note that the first 5 
endpoints included in the hierarchical assessment is severe events and that a higher NYHA 
class is worse than a lower NYHA class (class 0 and I will be combined), while body weight 
loss at least 5% is beneficial and a patient with at least 5% body weight loss will win against a 
patient without the loss, in that comparison, if patients have tie for NYHA class and no event 
for the first 5 endpoints in the hierarchy.
4.2.4
Analysis of the composite of HHF or CV death
This secondary variable is the time to first event included in the composite endpoint. The 
analysis will be based on the ITT principle using the FAS, including events with onset on or 
prior to each patient’s individual closing visit, adjudicated and confirmed by the CEC 
committee.
In the analysis of this composite endpoint, treatments (dapagliflozin versus placebo) will be 
compared using a Cox proportional hazards model with a factor for treatment group, stratified 
by country using the Efron method for ties.  P-values and 95% confidence intervals for the HR 
will be based on the Wald statistic. The KM rates, p-value, HR, and 95% confidence interval 
will be reported.
The contribution of each component of this composite endpoint to the overall treatment effect 
will be examined.  In the analysis of the components, all first event of the given type will be 
included irrespective of any preceding non-fatal composite event of a different type. 
Consequently, the sum of the number of patients with events in the component analysis will 
be larger than the number of patients with composite events. Methods similar to those 


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described for this analysis will be used to separately analyse the time from randomisation to 
the first occurrence of each of the components.
Kaplan-Meier estimates of the cumulative proportion of patients with event will be calculated 
and plotted, for the composite endpoint and for the individual components.
HRs and CIs for overall analysis will be presented with forest plots.
The assumption of proportional hazards for the factor for treatment groups will be assessed 
visually using log-cumulative hazard plots. The effect of any departures from proportional 
hazards will be discussed as part of the presentation of results of the analyses. 
4.2.5
Subgroup analysis
Exploratory subgroup analyses for the primary composite endpoint as well as for the key 
secondary endpoint and the composite endpoint of CV death or HHF will be performed for the 
variables listed in Table 1. 
Win-ratio endpoints:
Descriptive statistics will be presented stratified by each subgroup categories including sample 
size, win ratio with 95% confidence interval, the interaction p-value between treatment effect 
and subgroup. The interaction p-values are obtained from the hypothesis testing for different 
treatment benefit across different strata of subgroup variables based on the point estimate and 
standard error of the natural logarithm of the win ratio. The p-values for interaction will not be 
adjusted for multiple comparison as the tests are exploratory and will be interpreted 
descriptively.
The composite of HHF or CV death:
A test of interaction between randomised treatment group and the subgroup variable will be 
performed in each Cox model, including the relevant subgroup variable and the interaction 
between treatment and the subgroup variable.  In addition to the number and percent of 
patients with event, KM rate estimate and HR with 95% confidence interval for each 
subgroup, the interaction p-value will be presented. HRs with confidence interval will be 
presented in a forest plot, also including the KM rate and interaction p-value. The p-values for 
interaction will not be adjusted for multiple comparisons as the tests are exploratory and will 
be interpreted descriptively.


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No hazard ratio estimates with confidence interval and p-values will be given for subgroups 
with less than 15 events in total, both treatment groups combined.
Table 1
Characteristics and categories for subgroup analysis
Characteristic
Categories
Country
Sweden/UK (and subcategorised by 
Scotland and Wales)
Age (years)
<= 65, >65
Sex
Male, Female
Race
White, Black, or African American, Asian, 
Other
Medications at baseline (Acetylsalicylic 
Acid, Statins, ACE Inhibitor/ARB, 
Thienopyridine/Ticagrelor, Oral 
Anticoagulants, Beta blockers, Anti-
hyperglycemic agents, Aldosterone receptor 
blocker, Any Antiplatelets)
Yes, No
Baseline Body weight (kg)
<90, ≥90
Baseline BMI (kg/m2)
<30, ≥30
Baseline eGFR by CKD-EPI 
(ml/min/1.73m2)
<60, ≥60
<90, ≥90
Baseline DBP and SBP (mmHg)
<80, ≥80 for DBP
<130, ≥130 for SBP
Baseline LVEF
<30, 30-49, ≥50
MI index event
STEMI, NSTEMI
Smoking
Yes, No
Previous MI
Yes, No
Previous hypertension
Yes, No
Previous PCI
Yes, No
Previous CABG
Yes, No
Previous Stroke
Yes, No
Previous HF
Yes, No
Baseline HbA1c, Troponin, Creatinine, 
Glucose
<Median, ≥Median
4.2.6
Sensitivity analysis


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Win-ratio endpoints:
A supplementary analysis not taking shared follow-up time into account and excluding pair-
wise comparisons where at least one patient has missing data on NYHA class (and no 
previous events in the hierarchy) and excluding pair-wise comparisons having tie for NYHA 
class and where at least one patient has missing data on body weight (and no previous events 
in the hierarchy) may be performed.
The composite of HHF and CV death:
Undetermined cause of death
A sensitivity analysis where deaths adjudicated as ‘undetermined’ cause are not included as 
endpoint events, but treated as censoring events, will be performed.
Missing data and informative censoring
The time-to-event analysis using the Cox regression depends on the assumption of non-
informative or ignorable censoring, corresponding to the missing-at-random assumption.  The 
missing data in this context are patients who are prematurely censored due to WoC, LTFU or 
otherwise incomplete follow-up of endpoints. The amount of missing data may be described 
e.g., in terms of the number of patients and patient time with incomplete follow-up as 
described in Section 4.1.6.
Patient retention and follow-up are at the forefront of study planning and conduct, and the 
amount of incomplete follow-up is expected to be small.  To assess the impact of missing data 
and the robustness of the results with regard to the assumption of non-informative censoring, 
sensitivity analysis will be planned based on the evaluation of the missing follow-up and 
discussed in relation to the observed efficacy signal. This may include analysis where data for 
patients with incomplete information related to this endpoint will be imputed using data from 
patients with complete information.
Incomplete dates
The number of patients with incomplete dates, and the type of incompleteness, will be 
investigated by randomised treatment arm. If the proportions and degrees of missing are 
substantially different between treatment arms, the following sensitivity analyses will be 
considered: 1) Exclude patients who do not have adjudicated date of events and 2) Use 
multiple imputation to impute dates to account for more uncertainty. For example, for patients 
who have the year information but not the month and date, randomly select multiple imputed 
dates in the year interval and average all estimates across imputed datasets.


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Investigator reported events
A sensitivity analysis using investigator reported events instead of adjudicated events will be 
performed.
COVID-19
A sensitivity analysis censoring all patients at any COVID-19-related AEs (defined as any
COVID-19-related MedDRA terms) or PDs. The associated estimand strategy regarding 
intercurrent events will be Hypothetical Strategy (censoring at COVID-19-related AEs or 
PDs) combined with Treatment Policy (other intercurrent events will be ignored).
Modified Hicks-criteria
The primary approach for HHF adjudication is that it needs to fulfil at least four out of five 
Hicks-criteria with 1, 2 and 5 being mandatory:
1
The patient is admitted to the hospital with a primary diagnosis of HF.
2
The patient’s length-of-stay in hospital extends for at least 24 hours.
3
The patient exhibits documented new or worsening symptoms due to HF.
4
The patient has objective evidence of new or worsening Hf, consisting of at least two
physical examination findings or one physical examination finding and at least one
laboratory criterion.
5
The patient receives initiation or intensification of treatment specifically for HF.
To assess the robustness of the Hicks-criteria a sensitivity analysis including HHF events 
fulfilling all five Hicks-criteria instead of the current at least four out of five will be 
performed.
4.2.7
Analysis of other secondary efficacy variables 
The other secondary time-to-event variables will be analysed in a similar manner as for the 
composite of CV death or HHF. Censoring is described in Section 3. Using MI, stroke, T2DM 
and hospitalisation for any cause as reported by the investigators and HHF and CV death as 
adjudicated and confirmed by the CEC.
The change from baseline to last visit (last visit with body weight measurement available after 
the index hospitalisation) in body weight will be analysed by a repeated measures method 


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following the method in Section 8. The model will be used to derive a least-squares estimate 
of the treatment difference with 95% confidence interval and corresponding two-sided 
nominal p-value. Further, two-sided 95% confidence intervals for the mean change within 
each treatment group will be calculated. Missing data will not be imputed. Summaries by visit 
be presented.
4.2.8
 
 
 
 
 
 
 
4.2.9
Analysis of recurrent HF events and CV death 
The composite outcome of recurrent HF hospitalisations or CV death will be analysed by the 
semi-parametric proportional rates model (Lin et al 2000) known as the LWYY (Lin-Wei-
Yang-Ying) method, to test the treatment effect and to quantify the treatment difference in 
terms of the rate ratio with 95% confidence interval and p-value. Recurrent HF 
hospitalisations, CV death and censoring processes all have continuous distributions so that 
HF hospitalisation and death cannot happen at the same time. If a HF hospitalisation and CV 
death occurred at the same day, then only CV death will be counted. Moreover, CV death is a 
terminating event which, unlike censoring, prevents the occurrence of new HF 
hospitalisations.
CCI


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In addition, the two components in the composite endpoint (total HF hospitalisations and CV 
death) will be analysed separately to quantify the respective treatment effects and check the 
consistency between the composite and the components. Total HF hospitalisation will be 
analysed from the LWYY model and CV death as an individual component from the Cox 
proportional hazard model Section 4.1.7. For the analysis of total HF hospitalisations 
component, occurrence of CV death can be regarded as semi-competing risk (informative 
censoring) and may introduce a bias in the treatment effect estimate for HF hospitalisations 
(dilution of effect size if the drug has a positive effect on both components). 
4.2.10
Analysis of change from baseline
These analyses will be done for the on-treatment period and will include measurements on or 
after first dose of randomised study drug and on or before 30 days after last dose of study 
drug. 
Change from baseline for HbA1c, diastolic blood pressure (DBP), systolic blood pressure 
(SBP) and BMI will be analysed by a repeated measures method following the method in 
Section 4.1.8. The model will be used to derive a least-squares estimate of the treatment 
difference with 95% confidence interval and corresponding two-sided nominal p-value. 
Further, two-sided 95% confidence intervals for the mean change within each treatment group 
will be calculated. Missing data will not be imputed. Summaries by visit be presented.
4.2.11
Analysis of proportions 
Preventing symptoms of HF as measured by New York Heart association (NYHA) functional 
class will be analysed as proportion (of patients having class II or worse at last assessment) as 
described in Section 4.1.9.
Preventing symptoms of angina as measured by Canadian Cardiovascular Society (CCS) 
Angina class will be analysed as proportion (of patients having class II or worse at last 
assessment) as described in Section 4.1.9.
Change in body weight will be analysed as proportion (of patients having at least 5% decrease
from baseline to last assessment) as described in Section 4.1.9.


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These analyses will include all subjects and all data, and regardless of treatment 
discontinuation.
4.2.12
Analysis of safety variables 
Analysis set
For safety analyses, all summaries will be based on the safety analysis set.
Exposure
The total exposure to study drug will be defined as the length of period on study drug, 
calculated for each patient as date of last dose – date of first dose +1.
Exposure will be presented descriptively. 
Treatment periods
The summaries for the on-treatment period will include events with an onset date on or after 
first dose of randomised study drug and on or before 30 days after last dose of study drug. 
Additional presentations will include all events with onset on or after first dose of study drug 
regardless of whether patients are on or off study treatment at the time of the event (the ‘on 
+off ‘ treatment period).
All summaries of reportable Aes will be presented for the on-treatment period and the on+off 
treatment period. The on-treatment period will be the primary analysis approach for all SAEs.
4.2.12.1
Adverse events
See section below
4.2.12.2
Serious adverse events
In Sweden only Aes leading to hospitalisation or death will be collected. In UK all SAEs will 
be collected.


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Collected Aes will be presented as described below both on treatment and on+off treatment.
The number and percent of patients with SAEs will be presented by system organ class 
(SOC), preferred term (PT) and treatment group. The most common SAEs will also be 
presented by PT and treatment group only.
SAEs with outcome of death will be presented separately by SOC and PT.
4.2.12.3
Adverse events leading to discontinuation, interruption or dose reduction
Not collected according to CSP.
4.2.12.4
Adverse events of special interest
NA
4.2.12.5
Laboratory Evaluation and vital signs
Summaries of HbA1c, DBP, SBP, Body weight and BMI will be presented in SI units. 
The result and the change from baseline will be summarized by treatment group at each 
scheduled visit using descriptive statistics, including n, mean, SD, median and quartiles.
4.2.12.6
Marked laboratory abnormalities
NA
4.2.12.7
Aes related to COVID-19


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All Aes related to COVID-19 will be summarised by randomised treatment group. These Aes 
will be identified using MedDRA terms.
4.2.13
EQ-5D-5L
To collect utilities assessed by the Euro Quality of Life-5 Dimensions questionnaire (EQ-5D) 
to support health technology assessment and health economic modelling. A descriptive 
summary will be presented in the study report. Only data on or after date of randomisation and 
on or before the date of each patient’s individual closing visit will be considered. Further 
assessments will be analysed and reported separately from the study report. EQ-5D is 
collected via the Unify app.
4.2.14
Unify app
Assessments of the Unify app will be analysed and reported separately from the study report.
4.2.15
Clever Cap
The number of times during the study that each patient opens (on or after date of 
randomisation and on or before the date of each patient’s individual closing visit) the Clever 
Cap, will be summarized and presented in the study report. Further assessments will be 
analysed and reported separately from the study report.
5
INTERIM ANALYSES
Not Applicable
6
CHANGES OF ANALYSIS FROM PROTOCOL
Added the objective/secondary composite endpoint of CV death, HHF or MI.


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7
REFERENCES
Kaplan EL and Meier P 1958
Kaplan EL and Meier P. Nonparametric Estimation From Incomplete Observations.  Journal 
of the American Statistical Association 1958;53:457-481.
Robert T. O’Neill, PhD 1997
Secondary Endpoints Cannot Be Validly Analyzed if the Primary Endpoint Does Not 
Demonstrate Clear Statistical Significance
Controlled Clinical Trials 18:550-556 (1997)
Lin et al 2000
Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate functions
of recurrent events. Journal of the Royal Statistical Society: Series B (Statistical
Methodology) 2000; 62(4):711–730.
Pocock et al 2012
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012 
Jan;33(2):176-82. doi: 10.1093/eurheartj/ehr352. Epub 2011 Sep 6. PMID: 21900289.
Yu et al 2022
Yu RX, Ganju J. Sample size formula for a win ratio endpoint. Stat Med. 2022 Mar 
15;41(6):950-963. doi: 10.1002/sim.9297. Epub 2022 Jan 27. PMID: 35084052.
8
APPENDIX


SIGNATURE PAGE
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Document Name: d169dc00001-sap-ed-4
Document Title:
Statistical Analysis Plan Edition 4
Document ID:
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