Clinical trial NCT03619213
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: AstraZeneca
Start date: 2018-08-27; Completion date: 2022-03-27
Enrollment: 6263 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind, placebo-controlled study in HFpEF patients, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death or heart failure events.

Detailed description:
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind study in patients with HFpEF, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death and heart failure events (hospitalisations for HF or urgent HF visits). Adult patients aged ≥40 years with HFpEF (LVEF \>40% and evidence of structural heart disease) and New York Heart Association (NYHA) class II-IV who are eligible according to the inclusion/exclusion criteria will be randomised in a 1:1 ratio to receive either dapagliflozin 10 mg or placebo. Both out-patients and in-patients hospitalised for heart failure and off intravenous heart failure-therapy for 24 hours can be randomised. It is estimated that approximately 11000 patients at approximately 400-500 sites in 20-25 countries will need to be enrolled to reach the target of approximately 6100 randomised patients.

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: 10 mg tablets given once daily, per oral use. intervention 2: Placebo matching dapagliflozin 10 mg

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Drug Substance
Dapagliflozin
Study Code
D169CC00001
Version
4.0
Date
12th November 2020
An International, Double-blind, Randomised, Placebo-Controlled Phase III 
Study to Evaluate the Effect of Dapagliflozin on Reducing CV Death or 
Worsening Heart Failure in Patients with Heart Failure with Preserved Ejection 
Fraction (HFpEF)
DELIVER - Dapagliflozin Evaluation to Improve the LIVEs of Patients 
with PReserved Ejection Fraction Heart Failure
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
Eudra CT number: 2018-000802-46








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6.
8. Study 
Assessments and 
Procedures
It was clarified that during Visit 1, the investigator assesses patient’s 
eligibility criteria and reviews concomitant medications, and relevant 
medications will be recorded.
COVID-19 testing was added to Safety events assessment during Visits: 
3,4,5,6,7 and onwards, as well as Premature Treatment Discontinuation 
Visit and Study Closure Visit.
It was clarified that starting from Visit 6, vital signs (BP, pulse), and 
weight assessment as well as blood samples collection for creatinine (for 
calculation of eGFR) will be repeated every 12 months - on Visit 6, Visit 
9 and Visit 12.
7.
8.3 Efficacy 
Assessments
An alternative phone collection mode solution was implemented for the 
administration of electronic PROs in settings that are affected by COVID-
19 pandemic.
8.
8.4 Safety 
Assessments
COVID-19 testing results recording was added into Other safety 
assessments.
9. 8.5 Collection of 
adverse events
The process of Adjudication of potential DKA events by an independent 
DKA Committee was implemented (section 8.5.1.2.2.)
Requirements for capturing of Major hypoglycaemic events were added as 
section 8.5.1.4.
10. 9.2 Sample size 
determination
Section updated to reflect the dual primary hypothesis, changed multiple 
testing procedure and increased event target.
11. 9.3 Populations 
for analysis
A subset of the full analysis set consisting of patients with baseline LVEF 
of <60% (or LVEF <60% subpopulation) will be analysed separately as part 
of the confirmatory statistical testing procedure added to full analysis set.
12.
9.4 Statistical 
Analyses
Analysis of the primary variable updated with dual primary analysis.
Analysis of the secondary variables updated with regard to analysis of 
recurrent HF events and CV death for the LVEF < 60 subpopulation, and 
addition of time to CV death as a secondary endpoint.
Methods for multiplicity control updated according to the dual primary 
hypotheses and updated testing procedure.
13.
9.5 Interim 
Analyses
Clarification added that the interim analysis testing will be done in the full 
study population. Futility analysis was removed.
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.


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TABLE OF CONTENTS
TITLE PAGE............................................................................................................................................ 1
VERSION HISTORY............................................................................................................................. 2
TABLE OF CONTENTS....................................................................................................................... 6
1.
PROTOCOL SUMMARY .................................................................................................. 11
1.1
Schedule of Activities (SoA) .............................................................................................. 12
1.2
Synopsis ................................................................................................................................ 15
1.3
Schema .................................................................................................................................. 19
2.
INTRODUCTION .............................................................................................................. 20
2.1
Study rationale ..................................................................................................................... 20
2.2
Background........................................................................................................................... 21
2.3
Benefit/risk assessment...................................................................................................... 21
2.3.1
Potential risks to patients................................................................................................... 22
2.3.1.1
Protection against risks ...................................................................................................... 22
2.3.2
Potential benefits to patients............................................................................................. 23
2.3.4
Conclusion............................................................................................................................ 23
3.
OBJECTIVES AND ENDPOINTS................................................................................. 24
4.
STUDY DESIGN................................................................................................................ 26
4.1
Overall design...................................................................................................................... 26
4.2
Scientific rationale for study design................................................................................ 27
4.3
Justification for dose........................................................................................................... 28
4.4
End of study definition....................................................................................................... 29
5.
STUDY POPULATION.................................................................................................... 29
5.1
Inclusion criteria.................................................................................................................. 31
5.2
Exclusion criteria................................................................................................................. 32
5.3
Lifestyle restrictions (not applicable) ............................................................................. 33
5.4
Screen failures...................................................................................................................... 33
5.5
Procedures for handling of randomized not eligible patients..................................... 34
6.
STUDY TREATMENTS .................................................................................................. 35
6.1
Treatments administered.................................................................................................... 35
6.2
Preparation/handling/storage/accountability ................................................................. 35
6.3
Measures to minimise bias: randomisation and blinding............................................ 36
6.3.1
Stratification and capping.................................................................................................. 37
6.3.1.1
Stratification......................................................................................................................... 37
6.3.1.2
Capping ................................................................................................................................. 37


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6.4
Treatment compliance........................................................................................................ 37
6.5
Concomitant therapy .......................................................................................................... 38
6.5.1
Prohibited medication ........................................................................................................ 38
6.5.2
Recording of concomitant treatment............................................................................... 38
6.5.3
Heart failure background standard of care..................................................................... 38
6.5.4
Anti-diabetes treatment...................................................................................................... 38
6.5.4.1
Background........................................................................................................................... 38
6.5.4.2
Treatment of patients with established diagnosis of type 2 diabetes........................ 38
6.5.5
Other concomitant treatment ............................................................................................ 39
6.6
Dose modification (not applicable) ................................................................................. 39
6.7
Treatment after the end of the study................................................................................ 39
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL... 39
7.1
Discontinuation of study treatment ................................................................................. 39
7.1.1
Temporary discontinuation ............................................................................................... 39
7.1.1.1
Unexpected acute declines in eGFR................................................................................ 40
7.1.1.2
Volume depletion/hypotension......................................................................................... 40
7.1.1.3
Patients at risk of volume depletion ................................................................................ 40
7.1.2
Procedures for discontinuation of study treatment....................................................... 40
7.2
Lost to follow-up................................................................................................................. 41
7.3
Withdrawal from the study................................................................................................ 41
8.
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 42
8.1
Enrolment Period................................................................................................................. 42
8.1.1
Visit 1, Enrolment (Day -21 to Day -1).......................................................................... 42
8.2
Treatment period ................................................................................................................. 43
8.2.1
Visit 2, Randomisation (Day 1)........................................................................................ 43
8.2.2
Visit 3 (Day 30; ±7 days): ................................................................................................. 44
8.2.3
Visit 4 (Day 120 ±7 days): ................................................................................................ 44
8.2.4
Visit 5 (Day 240 ±7 days) ................................................................................................. 45
8.2.5
Visit 6 (Day 360 ±7 days) ................................................................................................. 45
8.2.6
Visit 7 and onwards (Day 480 and every 120 days ±14 days)................................... 46
8.2.7
Premature Treatment Discontinuation Visit .................................................................. 46
8.2.8
Study Closure Visit............................................................................................................. 47
8.2.9
Unscheduled visits .............................................................................................................. 47
8.3
Efficacy assessments .......................................................................................................... 48
8.3.1
Efficacy event capture........................................................................................................ 48
8.3.2
Efficacy event adjudication............................................................................................... 48
8.3.3
Clinical Outcome Assessments (COA) .......................................................................... 48
8.3.3.1
KCCQ .................................................................................................................................... 48
8.3.3.2
Patient Global Impression of Severity (PGIS).............................................................. 49
8.3.3.3
EuroQoL five-dimensional five-level questionnaire (EQ-5D-5L)............................ 49
8.3.3.4
Administration of electronic PROs ................................................................................. 50
8.4
Safety assessment................................................................................................................ 50
8.4.1
Physical examinations........................................................................................................ 51


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8.4.2
Vital Signs ............................................................................................................................ 51
8.4.3
Electrocardiogram............................................................................................................... 51
8.4.4
Safety laboratory assessments .......................................................................................... 51
8.4.5
Other safety assessments ................................................................................................... 51
8.4.6
Other clinical assessments................................................................................................. 51
8.4.6.1
Body weight and height ..................................................................................................... 51
8.5
Collection of adverse events ............................................................................................. 52
8.5.1
Method of detecting AEs and SAEs................................................................................ 52
8.5.1.1
Adverse events (AEs) leading to amputation and potential risk factor AEs for
amputations affecting lower limbs (“preceding events”) ........................................... 52
8.5.1.2
Capture of DKA events...................................................................................................... 52
8.5.1.2.1 DKA definition...................................................................................................53
8.5.1.2.2 Diabetic Ketoacidosis Adjudication Committee T2D..........................................53
8.5.1.3
Capture of cardiac ischaemic events and stroke ..................................................53
8.5.1.4 
Capture of Major hypoglycaemic events.............................................................53
8.5.1.5
Capture of additional laboratory values.......................................................................... 54
8.5.2
Time period and frequency for collecting AE and SAE information....................... 54
8.5.3
Follow-up of AEs and SAEs............................................................................................. 54
8.5.4
Adverse event data collection........................................................................................... 54
8.5.5
Causality collection............................................................................................................. 55
8.5.6
Adverse events based on signs and symptoms.............................................................. 55
8.5.7
Adverse events based on examinations and tests ......................................................... 55
8.5.8
Disease-under study (DUS) (not applicable)................................................................. 56
8.5.9
Disease progression (not applicable) .............................................................................. 56
8.6
Safety reporting and medical management.................................................................... 56
8.6.1
Reporting of serious adverse events................................................................................ 56
8.6.1.1
Reporting of SAEs considered to be potential endpoints ........................................... 56
8.6.2
Pregnancy.............................................................................................................................. 57
8.6.2.1
Maternal exposure............................................................................................................... 57
8.6.3
Overdose ............................................................................................................................... 57
8.7
Pharmacokinetics (not applicable)................................................................................... 58
8.8
Pharmacodynamics (not applicable) ............................................................................... 58
8.9
Optional exploratory genetics........................................................................................... 58
8.10
Biomarkers (not applicable).............................................................................................. 58
8.11
Health Economics (not applicable).................................................................................. 58
9.
STATISTICAL CONSIDERATIONS ........................................................................... 58
9.1
Statistical hypotheses ......................................................................................................... 58
9.2
Sample size determination................................................................................................. 58
9.3
Populations for analyses .................................................................................................... 60
9.4
Statistical analyses .............................................................................................................. 60
9.4.1
Efficacy analyses................................................................................................................. 60
9.4.1.1
Analysis of the primary variable...................................................................................... 60


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9.4.1.2
Analysis of the secondary variables ................................................................................ 61
9.4.1.3
Subgroup analysis ............................................................................................................... 61
9.4.1.4
Sensitivity analysis.............................................................................................................. 62
9.4.2
Safety analyses..................................................................................................................... 62
9.4.3
Methods for multiplicity control...................................................................................... 62
9.5
Interim analyses................................................................................................................... 62
9.5.1
Data monitoring committee (DMC)................................................................................ 63
10.
REFERENCES .................................................................................................................... 64
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS......................................................................................................... 69
LIST OF TABLES
Table 1
Study of Assessments..........................................................................................12
Table 2
Objectives and Endpoints...................................................................................16
Table 3
Study objectives ...................................................................................................24
Table 4
Study Treatments .................................................................................................35
Table 5
Population for analysis........................................................................................60
LIST OF FIGURES
Figure 1
Study design.......................................................................................... 19
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations...............................69
Appendix B
Adverse event definitions and additional safety information .....................72
Appendix C
Cardiovascular related events............................................................................76
Appendix D
Genetics..................................................................................................................79
Appendix E
Handling of Human Biological Samples.........................................................82
Appendix F
Actions required in cases of increases in liver biochemistry and
evaluation of Hy’s Law (not applicable) ........................................................84
Appendix G
Medical device incidents: definition and procedures for recording,
evaluating, follow-up, and reporting (not applicable)..................................84
Appendix H
Abbreviations........................................................................................................85
Appendix I
New York Heart Association (NYHA) Functional Classification.............86


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Appendix J
The KC Cardiomyopathy Questionnaire.........................................................86
Appendix K
EQ-5D-5L Questionnaire ...................................................................................91
Appendix L
Patient Global Impression of Severity for Heart Failure Symptoms.........95


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1.
PROTOCOL SUMMARY
1.1 Schedule of Activities (SoA)


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Table 1
Study of Assessments
Visit
1
Enrolment
2
Randomisation
3
4
5
6
7 –
onwards
Premature
Treatment
Discontinuation
Visit
Study
Closure
Visit
For details
see Section:
Day/Month
Day -21 to
Day -1
Day 1
Day 30
(±7)
Day 120
(±7)
Day 240
(±7)
Day 360
(±7)
Day 480 -
onwards
(every 120
days ±14
days)
≤ 6 weeks
after
PACD
Informed consent
X6
5.1, A 3
Inclusion/exclusion
criteria
X
X
5.1, 5.2
Demographics
X
5.1
Medical history
X
X
5.1
Concomitant
medication
X
X
X
X
X
X
X
X
X
6.5
Cardiac and HF
related procedures
X
X
X
X
X
X
X
8.5.1.3
Physical exam
X
X
X
8.4.1
Systolic and
diastolic BP
X
X
X
X3
X3
X
X
5.2, 8.4.2
Pulse
X
X
X
X3
X3
X
X
5.2, 8.4.2
Weight
X
X3
X3
X
X
8.4.6.1
Height
X
8.4.6.1
NYHA classification
X
X
X
X
X
X
X
5.1,
Appendix I
12-lead ECG
X
8.4.3


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Visit
1
Enrolment
2
Randomisation
3
4
5
6
7 –
onwards
Premature
Treatment
Discontinuation
Visit
Study
Closure
Visit
For details
see Section:
Day/Month
Day -21 to
Day -1
Day 1
Day 30
(±7)
Day 120
(±7)
Day 240
(±7)
Day 360
(±7)
Day 480 -
onwards
(every 120
days ±14
days)
≤ 6 weeks
after
PACD
C-lab NT-proBNP
X
5.1
C-lab eGFR
(creatinine)
X
X
X
X3
X3
5.2, 8.4.4
C-lab HbA1c
X
6.3.1.1
Sample for genetic
research, if
applicable5
X
Appendix D
KCCQ
X4
X4
X4
X4
X4
X4
8.3.3.1
PGIS
X4
X4
X4
X4
X4
X4
8.3.3.2
EQ-5D-5L
X
4
X4
X4
X4
8.3.3.3
Local pregnancy test
(female patients with
childbearing
potential only)
X
5.1
Randomisation
X
8.2.1
Dispense
investigational
product (IP)
X
X
X
X
X
6
Collect unused IP;
check IP compliance
X
X
X
X
X
X
6


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Visit
1
Enrolment
2
Randomisation
3
4
5
6
7 –
onwards
Premature
Treatment
Discontinuation
Visit
Study
Closure
Visit
For details
see Section:
Day/Month
Day -21 to
Day -1
Day 1
Day 30
(±7)
Day 120
(±7)
Day 240
(±7)
Day 360
(±7)
Day 480 -
onwards
(every 120
days ±14
days)
≤ 6 weeks
after
PACD
Efficacy events
(death and
worsening heart
failure) 1
X1
X
X
X
X
X
X
X
8.3
Safety events2,7
X
X
X
X
X
X
X
X
X
8.4
AEs Adverse events; DAEs Adverse events leading to discontinuation of investigational product; PACD Primary Analysis Censoring Date; SAEs 
Serious adverse events; C-lab Central laboratory
1 Efficacy events are considered as endpoints from time of randomisation and throughout the study. Prior to randomisation, these events are considered as SAEs.
2 SAEs will be recorded from the time of informed consent. DAEs and Amputations, adverse events (AEs) leading to amputation and potential risk factor AEs 
for amputations affecting lower limbs will be recorded from Visit 2 onwards.
3Assessments to be repeated every 12 months (Visit 6, Visit 9, Visit 12).
4Will be administered using a site-based electronic device. It is preferred that PRO questionnaires are completed prior to any other study procedures and 
before discussion of disease progression to avoid biasing the patient’s responses to the questions
5Blood sample for future genetic research is optional. The genetic sampling is subject to separate consent by the patient.
6The Patient signs the ICF. Patients who agree to the optional sampling of blood for genetic research will provide their consent.
7Including recording of COVID-19 testing results from Visit 2 onwards. 




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Table 2
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To determine whether dapagliflozin is superior 
to placebo, when added to standard of care, in 
reducing the composite of CV death and HF 
events (hospitalisation for HF or urgent HF visit) 
in patients with HF and preserved systolic 
function in

full study population 

subpopulation with LVEF <60%
Time to the first occurrence of any of the 
components of this composite: 
1.
CV death
2.
Hospitalisation for HF
3.
Urgent HF visit (e.g., emergency 
department or outpatients visit)
Secondary objective:
Endpoint/variable:
To determine whether dapagliflozin is superior 
to placebo in reducing the total number of HF 
events (hospitalisation for HF or urgent HF visit) 
and CV death in 

full study population

subpopulation with LVEF <60%
Total number of HF events (first and 
recurrent) and CV death
To determine whether dapagliflozin is superior 
to placebo in improving Patient Reported 
Outcomes measured by KCCQ
Change from baseline in the total symptom 
score (TSS) of the KCCQ at 8 months
To determine whether dapagliflozin is superior 
to placebo in reducing CV death
Time to the occurrence of CV death 
To determine whether dapagliflozin is superior 
to placebo in reducing all-cause mortality
Time to the occurrence of death from any 
cause
Safety objective:
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients 
with HFpEF
Serious adverse events (SAEs), adverse 
events leading to treatment discontinuation 
(DAEs), amputations, adverse events (AEs) 
leading to amputation and potential risk 
factor AEs for amputations affecting lower 
limbs
Exploratory Objective:
To determine whether dapagliflozin is superior 
to placebo in reducing all-cause hospitalisation
Time to the first occurrence of hospitalisation 
from any cause


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To determine whether dapagliflozin is superior 
to placebo in reducing the proportion of patients 
with worsened NYHA class
Proportion of patients with worsened NYHA 
class from baseline to 8 months
To describe health status assessed by EuroQol 
five-dimensional five-level questionnaire (EQ-
5D-5L) to support health economic analysis and 
health technology assessment
Results will be reported separately in a health 
economic report
To determine whether dapagliflozin compared 
with placebo will have an effect on systolic BP
Change in systolic BP from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on body 
weight
Change in body weight from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on eGFR.
Change in eGFR from baseline
To explore whether dapagliflozin compared to 
placebo improves KCCQ summary scores, 
subscores of TSS (Symptom frequency and 
symptom burden) and domains
Change in Clinical summary score, TSS 
subscores, Overall summary score, QoL score
To collect and store blood samples for future 
exploratory genetic research
Not applicable. Results will be reported separately
BP Blood pressure; CV Cardiovascular; EQ-5D-5L EuroQol five-dimensional five-level questionnaire
HF Heart failure; HFrEF Heart failure with reduced ejection fraction; KCCQ Kansas City Cardiomyopathy 
Questionnaire NYHA New York Heart Association
Overall design:
This is an international, multicentre, parallel-group, event-driven, randomised, double- blind study 
in patients with HFpEF, evaluating the effect of dapagliflozin 10 mg versus placebo, given once 
daily in addition to background regional standard of care therapy, including treatments to control 
co- morbidities, in reducing the composite of CV death and heart failure events (hospitalisations 
for HF or urgent HF visits). Adult patients aged ≥40 years with HFpEF (LVEF >40% and evidence 
of structural heart disease) and New York Heart Association (NYHA) class II-IV who are eligible 
according to the inclusion/exclusion criteria will be randomised in a 1:1 ratio to receive either 
dapagliflozin 10 mg or placebo. Both out-patients and in-patients hospitalised for heart failure and 
off intravenous heart failure-therapy for 24 hours can be randomised. It is estimated that 
approximately 11000 patients at approximately 400-500 sites in 20-25 countries will need to be 
enrolled to reach approximately 6100 randomised patients.
Study Period:
Estimated date of first patient enrolled: Q3 2018
Estimated date of last patient completed: Q4 2021
Number of randomised Subjects: approximately 6100 patients


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Treatments and treatment duration:
Patients will be randomised in a 1:1 ratio to receive either dapagliflozin 10 mg or placebo once 
daily. The original anticipated average treatment duration was 24 months (range 15 to 33  months). 
With updated sample size and increased target number of events, the maximum treatment duration 
is expected to be approximately 39 months.
Data Monitoring Committee:
An independent Data Monitoring Committee (DMC) will review accumulating trial data by 
treatment group in order to monitor patient safety and efficacy, ensure the validity and integrity of 
the trial, and make benefit-risk assessment.
Statistical methods
This study is event-driven with a target of 1117 patients with a primary endpoint event. The primary 
objective of the study is to determine the superiority of dapagliflozin versus placebo, when added to 
standard of care, in reducing the composite of CV death and HF events (hospitalisation for HF or urgent 
HF visit). Two hypotheses will be tested simultaneously (i.e, dual primary analyses) for this primary 
objective: (1) in the full population and in (2) an LVEF <60% subpopulation, with alpha allocated to 
each test. The final alpha split will be defined in the SAP prior to the interim analysis. It is anticipated 
that at least 70% of the events (i.e. approximately 780 events) will be available for the LVEF <60% 
subpopulation. To illustrate, assuming a true hazard ratio (HR) of 0.80 between dapagliflozin and 
placebo, a two-sided alpha of 1.5% would yield a power of 90% for the full population and a two-sided 
alpha of 2.4% would yield a power of 80% for the LVEF <60% subpopulation. 
Based on above assumption and ongoing blinded monitoring of events accrual, approximately 6100 
patients are estimated to provide the required number of primary events in the full population during 
an anticipated recruitment period up to 29 months and followed until the pre-specified number of 
primary events has occurred. Randomisation will be stratified by presence or absence of Type 2 
Diabetes (T2D).
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. 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 occurring on or prior 
to the primary analysis censoring date (PACD), 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, stratified 
by type 2 diabetes (T2D) status at randomisation. The p-value, hazard ratio and 95% confidence 
interval will be reported.
Interim analysis is planned to be performed including approximately 67% of target number of 
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2.
INTRODUCTION
2.1
Study rationale
The prevalence of chronic HF continues to increase globally. An estimated 38 million people are 
affected worldwide (Braunwald 2015), with over 1 million hospitalisations annually in both the 
United States and Europe (Ambrosy et al 2014). The annual global economic burden in 2012 was 
estimated to be $108 billion, (Cook et al 2014); this will increase dramatically as the population 
ages.
Heart failure is a complex syndrome caused by structural and/or functional abnormalities. It is 
characterised by dyspnoea, fatigue, and pulmonary congestion and/or peripheral oedema due to 
fluid retention. Patients with signs and symptoms of HF are categorised, based on measurement of 
left-ventricular ejection fraction (LVEF), as having HF with reduced LVEF (HFrEF) or HF with 
preserved LVEF (HFpEF).
Approximately half of all heart failure patients have HFpEF (Oktay et al 2013). Risk of death for 
HFpEF patients is high, with annualised mortality rate up to 15% in community settings ( Lam et 
al 2011). In controlled clinical trials, patients with HFpEF tend to be older and have a higher
prevalence of hypertension as compared to patients with HFrEF, although major clinical outcomes 
are similarly dominated by CV death and HF hospitalisation, the yearly event rates appear to be 
lower than in HFrEF (Solomon et al 2005). However, patients with HFpEF have a particularly 
significant unmet medical need given that outcome studies hitherto performed have not resulted in 
any approved pharmacotherapy specifically for this condition. Conversely, outcome studies have 
provided evidence for treatments for HFrEF that hence can improve symptoms and 
haemodynamics as well as reduce hospitalisations for heart failure and mortality. These treatments 
include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, 
angiotensin II receptor blocker neprilysin inhibitors, mineralocorticoid receptor antagonists, and 
beta-blockers (Iwaz et al 2016).
Recent data from cardiovascular (CV) outcome trials of SGLT2 inhibitors (empagliflozin and 
canagliflozin) indicate that treatment with SGLT2 inhibitors can reduce the risk of CV death and 
hospitalisation due to HF in patients with T2D overall, and in patients with T2D and concomitant 
HF (Zinman et al 2015; Fitchett et al 2016; Neal et al 2017; Rådholm et al 2018).
Results from real-world observational studies are broadly consistent with the randomised clinical 
trials in supporting the benefits of SGLT2 inhibitors in reducing risk of HF hospitalisation and CV 
death. The CVD-REAL study, consisting of more than 300000 patients with T2D, both with and 
without established CV disease, across 6 countries found that patients treated with SGLT2 
inhibitors compared to patients treated with other glucose lowering drugs was associated with a 
relative risk reduction in hospitalisation due to HF (39%), all-cause death (51%), and the composite 
of hospitalisation due to HF or CV death (46%) (Kosiborod et al 2017a).
Limitations associated with the randomised clinical trials as well as the observational studies are 
that only patients with T2D were studied, and that the proportion of patients with HFrEF and 
HFpEF, respectively, is unknown.


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This study will simultaneously test the two hypotheses that dapagliflozin is superior to placebo in 
reducing the composite of CV death and HF events (hospitalisation for HF or urgent HF visit) in 
patients with HF and preserved systolic function (LVEF >40%), with or without T2D, in (1) the 
full population and in (2) an LVEF <60% subpopulation.
2.2
Background
Dapagliflozin is a potent, highly selective and orally active inhibitor of human renal SGLT2. A 
detailed description of the chemistry, pharmacology, efficacy, and safety of dapagliflozin is 
provided in the Investigator’s Brochure. Supporting the hypothesis that dapagliflozin may reduce 
CV Death and HF events in HF patients, irrespective of diabetes status, are observations from the 
overall dapagliflozin clinical development programme. Dapagliflozin lowers HbA1c with a low 
risk of inducing hypoglycaemia. In addition, dapagliflozin treatment has also been shown to reduce 
weight and systolic blood pressure, and to have favourable effect on increased blood uric acid, 
albuminuria, and arterial elasticity, conditions which are associated with increased CV and renal 
risk (Shigiyama et al 2017). Dapagliflozin is believed be nephroprotective through non-glycaemic 
mechanisms (Wanner et al 2016).
The identified blood pressure lowering effects, may reduce the primary outcome in a study 
population with high prevalence of hypertension, similarly, the observed effects on body weight, 
may be beneficial to the large part of the study population with obesity. The findings from EMPA-
REG, with a similar SGLT2 inhibitor compound, suggests that kidney function is preserved, or 
improved in this diabetic study population. Furthermore, HFpEF patients are characterized by 
fluid retention and a change in cardiac metabolism favouring glucose as substrate, both of which 
has been hypothesised to be positively impacted by SGLT2 inhibitor treatment. Moreover, arterial 
stiffness, and abnormal ventriculo-arterial coupling, are common in patients with HFpEF, and may 
be modified by SGLT2 inhibitor treatments.
The clinical studies in healthy subjects at high multiple doses also show that, due to the mechanism 
of action, dapagliflozin does not induce hypoglycemia in nondiabetic subjects; however, 
pharmacodynamic effects on glucose, sodium, and urinary volume are observed. Therefore, the 
changes in these diabetes-independent mechanisms and intrarenal physiology are expected to be 
similar regardless of underlying disease.
This study is an international, multicentre, parallel-group, event-driven, randomised, double-blind, 
placebo-controlled study in HFpEF patients, evaluating the effect of dapagliflozin 10 mg, given 
once daily in addition to background regional standard of care therapy, including treatments to 
control co-morbidities, in reducing the composite of CV death and heart failure events 
(hospitalisations for HF or urgent HF visits).
2.3
Benefit/risk assessment
Dapagliflozin has global marketing approval in approximately 90 countries with the most recent 
estimate of cumulative post-marketing experience totalling over 1.6 million patient-years. Detailed 
information about the known and expected benefits and risks and reasonably expected adverse 
events of dapagliflozin appears in the Investigator’s Brochure. The following is a summary of 
benefit-risk considerations relevant to the HFpEF target population.
2.3.1
Potential risks to patients


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Dapagliflozin reduces blood volume and blood pressure from its diuretic effect, which could be a 
concern in patients with HFpEF, but also be important mechanisms of a potential treatment effect. 
However, in the dapagliflozin type 2 diabetes mellitus (T2D) program, the rate of events related to 
volume depletion and impaired renal function have been similar between dapagliflozin and placebo. 
Loop-diuretics are widely used in the target patient population and are also allowed in this study. A 
pooled analysis of patients with T2D and HF in the dapagliflozin development program, showed no 
increase of volume depletion events but increase in renal events, mainly creatinine increases, in patients 
treated with dapagliflozin (n=171) compared with placebo treated patients (n=149). About half of the 
patients were on loop diuretics (Kosiborod et al 2017b).
An increase in amputations, mostly affecting toes, was observed in a clinical trial (Neal et al 2017) 
with another SGLT2 inhibitor. There is no indication from the clinical development program that 
dapagliflozin is associated with an increased risk of amputation (see Section 8.5.1.1 for the 
detection and capture of amputation events).
Dapagliflozin has not been shown to induce hypoglycaemia in non-diabetes patients. In clinical 
pharmacology studies, healthy subjects have been treated with single oral doses up to 500 mg and 
multiple oral doses of 100 mg up to 14 days without any hypoglycaemic events.
There have been post-marketing reports of ketoacidosis, including diabetic ketoacidosis, in patients 
with T2D taking dapagliflozin and other SGLT2 inhibitors, although a causal relationship has not 
been established.
Patients treated with dapagliflozin 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 interruption of dapagliflozin treatment should be considered and the 
patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (e.g., T1D, history of pancreatitis, or pancreatic surgery), insulin dose 
reduction, reduced caloric intake, or increased insulin requirements due to infections, illness or 
surgery and alcohol abuse. Dapagliflozin should be used with caution in patients in these 
circumstances. Dapagliflozin is currently not indicated for the treatment of patients with T1D; these 
patients are excluded from this study.
2.3.1.1
Protection against risks
This study has been designed with appropriate measures in place to monitor and minimise any 
potential risks to participating patients. Data regarding amputations and adverse events 
potentially placing the patient at risk for a lower limb amputation will be collected (see Section 
8.5.1.1). To ensure the safety of all patients participating in AstraZeneca sponsored studies, 
reviews of all safety information from all ongoing clinical dapagliflozin studies are conducted as 
they become available. In addition, an independent Data Monitoring Committee (DMC) will be 
responsible for safeguarding the interests of the patients by reviewing safety data throughout the 
study (see Section 9.5.1).
2.3.2
Potential benefits to patients


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All patients in the study are expected to be optimally treated according to regional standard of care 
therapy, including treatments to control co-morbidities, and dapagliflozin or placebo will be 
administered on top of this treatment.
All patients participating in clinical trials irrespective of whether treated with active treatment or 
not, generally receive closer medical attention than those in ordinary clinical practice which may 
be to their advantage.
2.3.3
Conclusion
Considering the non-clinical and clinical experience with dapagliflozin and the precautions 
included in the study protocol, participation in this study should present a minimal and thus 
acceptable risk to eligible patients. Although hypothesis-generating data suggest beneficial effects 
of SGLT2 inhibitors in patients with T2D with heart failure, at the time of writing of this clinical 
study protocol, no available SGLT2 inhibitor has a treatment indication for patients with HFpEF. 
The proposed clinical study will test the hypothesis that dapagliflozin reduces the risk of CV death 
and HF events in patients with HFpEF, with or without T2D, in a rigorous fashion. The results 
could potentially offer substantial benefit to patients with HFpEF, a patient population with a large 
medical need for effective treatments.


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3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/variable:
To determine whether dapagliflozin is superior 
to placebo, when added to standard of care, in 
reducing the composite of CV death and HF 
events (hospitalisation for HF or urgent HF visit) 
in patients with HF and preserved systolic 
function in

full study population

subpopulation with LVEF <60% 
Time to the first occurrence of any of the 
components of this composite: 
4.
CV death
5.
Hospitalisation for HF
6.
Urgent HF visit (e.g., emergency 
department or outpatients visit)
Secondary objective:
Endpoint/variable:
To determine whether dapagliflozin is superior 
to placebo in reducing the total number of HF 
events (hospitalisation for HF or urgent HF visit) 
and CV death in 

full study population

subpopulation with LVEF <60%
Total number of HF events (first and 
recurrent) and CV death
To determine whether dapagliflozin is superior 
to placebo in improving Patient Reported 
Outcomes measured by KCCQ
Change from baseline in the total symptom 
score (TSS) of the KCCQ at 8 months
To determine whether dapagliflozin is superior 
to placebo in reducing CV death
Time to the occurrence of CV death 
To determine whether dapagliflozin is superior 
to placebo in reducing all-cause mortality
Time to the occurrence of death from any 
cause
Safety objective:
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients 
with HFpEF
Serious adverse events (SAEs), adverse 
events leading to treatment discontinuation 
(DAEs), amputations, adverse events (AEs) 
leading to amputation and potential risk 
factor AEs for amputations affecting lower 
limbs
Exploratory Objective:
To determine whether dapagliflozin is superior 
to placebo in reducing all-cause hospitalisation
Time to the first occurrence of hospitalisation 
from any cause


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To determine whether dapagliflozin is superior 
to placebo in reducing the proportion of patients 
with worsened NYHA class
Proportion of patients with worsened NYHA 
class from baseline to 8 months
To describe health status assessed by EuroQol 
five-dimensional five-level questionnaire (EQ-
5D-5L) to support health economic analysis and 
health technology assessment
Results will be reported separately in a health 
economic report
To determine whether dapagliflozin compared 
with placebo will have an effect on systolic BP
Change in systolic BP from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on body 
weight
Change in body weight from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on eGFR.
Change in eGFR from baseline
To explore whether dapagliflozin compared to 
placebo improves KCCQ summary scores, 
subscores of TSS (Symptom frequency and 
symptom burden) and domains
Change in Clinical summary score, TSS 
subscores, Overall summary score, QoL score
To collect and store blood samples for future 
exploratory genetic research
Not applicable. Results will be reported separately
BP Blood pressure; CV Cardiovascular; EQ-5D-5L EuroQol five-dimensional five-level questionnaire
HF Heart failure; HFrEF Heart failure with reduced ejection fraction; KCCQ Kansas City Cardiomyopathy 
Questionnaire NYHA New York Heart Association


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4.
STUDY DESIGN
4.1
Overall design
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind, placebo-
controlled study in HFpEF patients, evaluating the effect of dapagliflozin 10 mg versus placebo, given 
once daily in addition to background regional standard of care therapy, including treatments to control 
co-morbidities, in reducing the composite of CV death or heart failure events.
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1.
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.
Adult patients with HFpEF (defined for the purposes of this study as LVEF >40% and evidence of 
structural heart disease) aged ≥40 years and with NYHA class II- IV who meet the inclusion 
criteria, and none of the exclusion criteria, will be randomised in a 1:1 ratio to receive either 
dapagliflozin 10 mg or placebo. Randomised treatment should be started as soon as possible and 
within 24 hours after randomisation. It is estimated that approximately 11000 patients at 
approximately 400-500 sites in 20-25 countries will be enrolled to reach approximately 6100 
randomised patients (see Section 9.2).
Study closure procedures will be initiated when the predetermined number of primary endpoints 
are predicted to have occurred (n=1117), i.e. the Primary Analysis Censoring Date (PACD). 
Patients should be scheduled for a Study Closure Visit (SCV) within 6 weeks of the PACD, which 
can be extended if decided by Global Study Team. The anticipated total study duration is 
approximately 39 months dependent on randomisation rate and event rate. The study duration, and 
the number of patients, may be changed if the randomisation rate or the event rate is different than 
anticipated. The study may be terminated early if a clear harmful effect of the study treatment is 
detected during the DMC review, or due to DMC recommendations following pre-specified interim 
analyses (see Section 9.5).
Data on baseline characteristics, endpoints and AEs will be collected through a validated electronic 
data capture (EDC) system with electronic case report forms (eCRFs).


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4.2
Scientific rationale for study design
This is a randomised, multi-centre, double-blind, parallel-group study. Randomisation and double-
blinding will minimise potential bias. The target population includes adult (aged ≥ 40 years) male 
and female patients with HFpEF, which is defined in this study as individuals with an established 
diagnosis of heart failure and a LVEF >40% and structural heart disease who meet natriuretic 
peptide thresholds. The requirement of demonstrated structural heart disease (i.e. left ventricular
hypertrophy or left atrial enlargement1) and elevated natriuretic peptides aims to support the 
diagnosis of heart failure, since other common co-morbidities may cause overlapping symptoms. 
Most randomised patients will be out-patients. However, to address a specific need in a period with 
high risk for events, a proportion of patients will be enrolled and randomised during hospitalisation 
for heart failure or within 30 days of discharge from hospitalisation for heart failure (subacute 
subgroup).
The study population will include patients both with and without T2D, as the beneficial 
haemodynamic effects of dapagliflozin appear to be independent of the glycaemic effect, and can 
therefore be expected in both groups. Enrolment in the study may be capped based on the 
proportion of patients with/without T2D, in certain LVEF categories, in each NYHA class, 
with/without atrial fibrillation, randomised during or early after HF hospitalisation (subacute 
subgroup), and geographic region.
The control group will receive placebo; there are no approved pharmacological treatments for 
HFpEF that could be utilised as a comparator. All patients will be treated according to local 
guidelines on standard of care treatment for patients with HFpEF, focusing on treatment of HF 
symptoms (e.g. diuretics) and comorbidities (including treatment for high blood pressure, 
ischaemic heart disease, atrial fibrillation).
The study population will include patients with eGFR ≥ 25 ml/min/1.73m2. Patients with reduced 
renal function have a clinical picture with increased intra-glomerular pressure, hypertension, 
proteinuria and fluid/sodium overload and SGLT2 inhibition can improve all these abnormalities 
through metabolic-independent mechanisms. Thus, patients with heart failure and reduced renal 
function could be expected to benefit from treatment with dapagliflozin.
The primary efficacy endpoints of the study are adjudicated CV death and HF events 
(hospitalisation for HF or urgent HF visit). The rationale for selecting CV death over all-cause 
death is the expectation that HF treatment will decrease CV death and not all potential causes of 
death (Zannad et al 2014). Heart failure events include both HF hospitalisations and unplanned HF 
visits requiring urgent treatment independently of whether the exacerbation of HF results in 
hospitalisation (according to CDISC definitions; Hicks et al 2014; Hicks et al 2018). These are the
same endpoint definitions currently employed in the Sponsor’s HFrEF outcome study (Dapa-HF; 
Study D1699C00001).
1 Left Atrial Enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length 
≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m
2 Left Ventricular Hypertrophy defined by septal thickness or posterior wall thickness ≥1.1 cm


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The rationale for including outpatient HF events, in addition to hospital admissions, is that it is the 
occurrence of worsening of the patient’s condition necessitating treatment, and not the place of 
treatment, that is important. As stated in EMA Guidance 2016, ‘…patient are often managed for 
episodes of transient decompensation or worsening HF in outpatient settings (eg, emergency 
departments, observation units, other outpatient settings). The capture of events of worsening HF 
without hospitalisation may be warranted as an additional endpoint.’ Including only hospital 
admissions is likely to overlook a modest but significant proportion of episodes of worsening HF 
(Skali et al 2014, Okumura et al 2016, Greene et al 2018).
While CV death and HF hospitalisations are clearly important to patients and health-care systems, 
the impact of HF on patients’ symptoms and physical/social functioning is also important. In order 
to evaluate the treatment effects on these aspects of the impact of HF, we will use the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), a disease-specific patient reported outcomes (PRO) 
measure developed for patients with chronic HF. The KCCQ has shown to be a valid, reliable and 
responsive measure for patients with HF (Greene et al 2018, Spertus et al 2005).
There has been a gradual accumulation of data that HF patients with mildly abnormal (or “mid-
range”) ejection fraction (LVEF 40-50%), although traditionally classified as HFpEF, may 
potentially benefit from therapies that have been shown to improve outcomes in HFrEF (Nauta et 
al 2017). During the course of the DELIVER trial, the PARAGON-HF trial was completed, 
randomizing patients with HFpEF to sacubitril/valsartan or valsartan alone. While the study failed 
to meet its primary objective (Solomon et al 2019), there appeared to be a differential treatment 
effect by LVEF with benefit largely seen in patients with LVEF 45-60% (Solomon et al 2020). 
This new data suggests that HFpEF with a high-normal LVEF may constitute different clinical 
entities than heart failure with low-normal or mildly reduced LVEF (Lam et al 2020). To account 
for this emerging information in DELIVER, it was decided to formally investigate the treatment 
effect in both the subset of patients with LVEF<60% and in the full study population.
4.3
Justification for dose
The 10 mg dose of dapagliflozin has a well-characterised efficacy and safety profile in the T2D 
clinical development program and is the recommended dose in the majority of countries 
worldwide.
From a pharmacokinetic perspective, the currently approved dapagliflozin dose of 10 mg once 
daily is appropriate for use in patients with HFpEF. Slightly higher systemic exposure to 
dapagliflozin is expected in HFpEF patients when symptomatic, based on the dual renal and hepatic 
metabolism of dapagliflozin and the lower perfusion of these organs in this patient group. However, 
the increase in systemic exposure of 10 mg dapagliflozin is not anticipated to warrant dose 
adjustment in HF patients. Moreover, the anticipated slightly higher systemic exposure to 
dapagliflozin is likely to be beneficial in HF patients, by compensating for the reduced renal 
perfusion and consequently lower renal glucose and sodium filtered loads in these patients. Doses 
lower than 10 mg are therefore unlikely to provide as much benefit to patients with HF as the 10-
mg dose. Lastly, no changes in dose of concomitant medications in the HFpEF population are 


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needed due to a lack of clinically meaningful drug-drug interactions for dapagliflozin with current 
medications used for treatment of patients with HFpEF, including standard of care medications 
used to control co-morbidities in this patient group.
In the dapagliflozin clinical program, there are no dose-related SAEs that preclude the use of 10 
mg as a preferred dose. Additionally, in a post-hoc analysis of data from 320 patients with a 
documented history of HF and concomitant T2D in placebo-controlled clinical trials, dapagliflozin 
10 mg was found to be well tolerated in this population (Kosiborod et al 2017b).
There are mechanistic reasons for choosing the 10-mg dose as well. One hypothesis of underlying 
pathophysiology in HFpEF is abnormal pressure coupling between the left ventricle and aorta, and 
drugs that reduce aortic stiffness may have beneficial effects in patients with HFpEF (Borlaug and 
Paulus 2011). Studies examining the highest approved dose for empagliflozin have reported
improvements in aortic elasticity (Chilton et al 2015,Cherney et al 2014); similar studies are 
ongoing with dapagliflozin. In a completed placebo-controlled study, treatment with dapagliflozin 
10 mg resulted in improvements in parameters associated with arterial remodelling in addition to 
lowering blood pressure in patients with T2D (Ott et al 2017). This prior work suggests that 
selecting the 10-mg dose of dapagliflozin is reasonable from a mechanistic perspective to 
demonstrate a clinical effect.
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if no patients are recruited. Patients from terminated sites will 
have the opportunity to be transferred to another site to continue the study. AstraZeneca may also 
terminate the entire study prematurely if concerns for safety arise within this study or in any other 
study with dapagliflozin, or due to recommendation by the DMC. Regardless of the reason for
termination, all data required by the protocol at the time of discontinuation of follow-up will be 
collected. In terminating the study, the Sponsor will ensure that adequate consideration is given to 
the protection of the patients’ interests.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
In this protocol, ‘enrolled’ patients are defined as those who sign the informed consent form (ICF) 
and received E-Code. The ICF process is described in Appendix A 3. ‘Randomised’ patients are 
defined as those who undergo randomisation and receive a randomisation code.


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Patients are eligible to be randomised in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply. Enrolled patients who for any reason are not randomised are 
considered screen failures (see Section 5.4).


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5.1
Inclusion criteria
Subjects are eligible to be randomised in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
1. Provision of signed informed consent prior to any study specific procedures.
2. Male or female patients age ≥40 years.
3. Documented diagnosis of symptomatic heart failure (NYHA class II-IV) at enrolment, 
and a medical history of typical symptoms/signs2 of heart failure ≥6 weeks before 
enrolment with at least intermittent need for diuretic treatment.
4. Left Ventricular Ejection Fraction (LVEF) >40% and evidence of structural heart 
disease (i.e. left ventricular hypertrophy or left atrial enlargement3) documented by the 
most recent echocardiogram, and/or cardiac MR within the last 12 months prior to 
enrolment. For patients with prior acute cardiac events or procedures that may reduce 
LVEF, e.g. as defined in exclusion criterion 6, qualifying cardiac imaging assessment 
at least 12 weeks following the procedure/event is required.
5. NT-pro BNP ≥300 pg/ml at Visit 1 for patients without ongoing atrial fibrillation/flutter. 
If ongoing atrial fibrillation/flutter at Visit 1, NT-pro BNP must be ≥600 pg/mL.
6. Patients may be ambulatory, or hospitalized; patients must be off intravenous heart 
failure therapy (including diuretics) for at least 12 hours prior to enrolment and 24 hours 
prior to randomisation.
2 Typical symptoms associated with heart failure: breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, 
reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling;
Signs associated with Heart Failure:
More specific: elevated jugular venous pressure, hepatojugular reflex, third heart sound (gallop rhythm), laterally 
displaced apical impulse
Less specific: weight gain (>2 kg/week), weight loss (in advanced HF), tissue wasting (cachexia), cardiac murmur, 
peripheral oedema (ankle, sacral, scrotal), pulmonary crepitations, reduced air entry and dullness to percussion at lung 
bases (pleural effusion), tachycardia, irregular pulse, tachypnoea, cheyne stokes respiration, hepatomegaly, ascites, 
cold extremities, oliguria, narrow pulse pressure
3 Left Atrial Enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm 
or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m2. Left Ventricular Hypertrophy defined by 
septal thickness or posterior wall thickness ≥1.1 cm


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5.2
Exclusion criteria
1.
Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomisation or 
previous intolerance to an SGLT2 inhibitor.
2.
Type 1 diabetes mellitus (T1D).
3.
eGFR <25 mL/min/1.73 m2 (CKD-EPI formula) at Visit 1.
4. Systolic blood pressure (BP) <95 mmHg on 2 consecutive measurements at 5-minute 
intervals, at Visit 1 or at Visit 2.
5. Systolic BP≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications 
or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements at 5-minute 
intervals, at Visit 1 or at Visit 2.
6. MI, unstable angina, coronary revascularization (percutaneous coronary intervention (PCI) 
or coronary artery bypass grafting (CABG)), ablation of atrial flutter/fibrillation, valve 
repair/replacement within 12 weeks prior to enrolment. Before enrolment, these patients 
must have their qualifying echocardiography and/or cardiac MRI examination at least 12 
weeks after the event.
7. Planned coronary revascularization, ablation of atrial flutter/fibrillation and valve 
repair/replacement.
8. Stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment.
9. Probable alternative or concomitant diagnoses which in the opinion of the investigator 
could account for the patient's HF symptoms and signs (e.g. anaemia, hypothyroidism).
10. Body mass index >50 kg/m2.
11. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease 
including COPD (i.e., requiring home oxygen, chronic nebulizer therapy or chronic oral 
steroid therapy, or hospitalisation for exacerbation of COPD requiring ventilatory assist 
within 12 months prior to enrolment).
12. Previous cardiac transplantation, or complex congenital heart disease. Planned cardiac 
resynchronisation therapy.
13. HF due to any of the following: known infiltrative cardiomyopathy (e.g. amyloid, sarcoid, 
lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac 
tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic 
cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 
or uncorrected primary valvular disease.


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14. A life expectancy of less than 2 years due to any non-cardiovascular condition, based on 
investigator's clinical judgement.
15. Inability of the patient, in the opinion of the investigator, to understand and/or comply with 
study medications, procedures and/or follow-up OR any conditions that, in the opinion of 
the investigator, may render the patient unable to complete the study.
16. Active malignancy requiring treatment (with the exception of basal cell or squamous cell 
carcinomas of the skin).
17. Acute or chronic liver disease with severe impairment of liver function (e.g., ascites, 
oesophageal varices, coagulopathy).
18. Women of child-bearing potential (i.e. those who are not chemically or surgically sterilised 
or post-menopausal) not willing to use a medically accepted method of contraception 
considered reliable in the judgment of the investigator OR who have a positive pregnancy 
test at randomisation OR who are breast-feeding.
19. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
personnel and/or personnel at the study site).
20. Previous randomisation in the present study.
21. Participation in another clinical study with an IP or device during the last month prior to 
enrolment.
5.3
Lifestyle restrictions (not applicable)
5.4
Screen failures
Enrolled patients who are found not eligible (i.e. not meeting all the inclusion criteria or fulfilling 
any of the exclusion criteria) must not be randomised or initiated on treatment.
Screen failures are defined as patients who signed the informed consent form to participate in the 
study but are not subsequently randomised. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, eligibility criteria (reason for screen 
failure), and any serious adverse event (SAE).
Screen failures may be re-enrolled one time during the study if the Investigator considers that the 
patient may be eligible for participation in this study at another time point. Re-enrolled patients 
should be assigned the same enrolment code as for the initial enrolment. All enrolment assessments 
and procedures, including signing the informed consent form, should be performed again.


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5.5
Procedures for handling of randomized not eligible patients
If a patient is randomised and later found not eligible, the Investigator should immediately inform 
the AstraZeneca representative, who will report the protocol deviation to the AstraZeneca Study 
Physician.
Study treatment must be discontinued in all cases where continued treatment is deemed to pose a safety 
risk to the patient. Regardless of whether study treatment is discontinued or not, the patient should 
continue his/her participation in the study for follow- up of endpoints and other protocol-defined study 
procedures until the end of the study. Consistent with the intention-to-treat principle, all randomised 
patients are included in the efficacy analysis according to randomised treatment assignment. The 
AstraZeneca Study Physician must ensure that the protocol deviation and the rationale for the decision 
to discontinue or continue study treatment are appropriately documented.


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6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to dapagliflozin or matching 
placebo.
6.1
Treatments administered
Table 4
Study Treatments
Dapagliflozin
Placebo
Investigational Product name
Dapagliflozin 10 mg
Matching placebo 10 mg
Dosage formulation
Green, diamond shaped,
film coated tablets 10 mg
Green, diamond shaped, film 
coated tablets 10 mg
placebo
Route of administration
Oral
Oral
Dosing instructions
Once daily
Once daily
Packaging and labeling 
Investigational Product will 
be provided in bottles. Each 
bottle will be labelled in 
accordance with Good 
Manufacturing Practice 
Annex 13 and per country 
regulatory requirements
Investigational Product will 
be provided in bottles. Each 
bottle will be labelled in 
accordance with Good 
Manufacturing Practice 
Annex 13 and per country 
regulatory requirements
Provider
AstraZeneca
AstraZeneca
The tablets contain lactose, in quantities not likely to cause discomfort in lactose-intolerant 
individuals.
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.


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All investigational product (IP) should be kept in a secure place under appropriate storage 
conditions. The label on the IP bottle specifies the appropriate storage.
Only patients randomised in the study may receive IP and only authorised site staff may supply or 
administer IP. The administration of all investigational products should be recorded in the 
appropriate sections of the eCRF.
The Investigator is responsible for IP accountability, reconciliation, and record maintenance (i.e.
receipt, reconciliation, and final disposition records).
The investigator will retain the returned IP until the AZ representative or delegate collects it, along 
with any IP not dispensed. The AZ representative or delegate is responsible for confirming the 
investigator or delegate has recorded the quantities of returned and unused tablets at a patient level 
before IP is destroyed. The AZ representative or delegate will advise on the appropriate method 
for destruction of unused IP.
6.3
Measures to minimise bias: randomisation and blinding
All patients will be centrally assigned to randomised IP using an interactive voice/web response 
system (IxRS). Randomisation to IP will be performed in balanced blocks to ensure approximate 
balance between the treatment groups (1:1). The randomisation codes will be computer generated 
and loaded into the IxRS database. Before the study is initiated, the telephone number and call-in 
directions for the IxRS and/or the log-in information and directions for the IxRS will be provided 
to each site.
If a randomised patient withdraws from the study, then his/her enrolment/randomisation code 
cannot be reused. Withdrawn randomised patients will be included in the intention to treat analysis.
The IxRS will provide the Investigator with the kit identification number to be allocated to the 
patient at each dispensing visit. At all visits where IP is dispensed, site personnel will do a kit 
verification in IxRS before providing the IP bottle to the patient. Routines for this will be described 
in the IxRS user manual that will be provided to each centre.
The blinding of treatment is ensured by using a double-blind technique. Individual treatment codes, 
indicating the randomised treatment for each patient, will be available to the investigator(s) or 
pharmacists from the IxRS. Instructions for code breaking/unblinding will be described in the IxRS 
user manual that will be provided to each site.
The randomisation code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The Investigator is 
to document and report the action to AstraZeneca, without revealing the treatment given to the 
patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected to 
be causally related to an investigational product and that potentially require expedited reporting to 
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until all decisions on the evaluability of the data from each individual patient have been made and 
documented.
6.3.1
Stratification and capping
The recruitment will be continuously monitored in order to achieve adequate proportions of patient 
sub-populations.
6.3.1.1
Stratification
Randomisation will be stratified in IxRS based on patients with and without T2D at the time of 
randomisation in order to ensure approximate balance between treatment groups within each sub-
population. Stratification on T2D at the time of randomisation is based on:

Established diagnosis of T2D
OR

HbA1c ≥6.5% (48 mmol/mol) shown at central laboratory test at enrolment (Visit 1)
6.3.1.2
Capping
The intent is to enrol a typical cross-section of patients with HFpEF and to include representative 
proportions of diabetic and non-diabetic patients. The number of randomised patients with and 
without T2D will be monitored in order to ensure a minimum of 30% in each sub-population. 
Randomisation may be capped (i.e., no more patients can be randomised in a specific sub-
population) if the pre-determined limit is reached.
Randomisation of patients based on geographic region will be monitored to ensure global 
representation. LVEF value, NYHA class, subacute subgroup (i.e. randomised in- hospital or 
within 30 days from discharge) and atrial fibrillation status at Visit 1 may be capped in IxRS to 
avoid over- or under-representation of these patient subgroups.
6.4
Treatment compliance
The administration of all IP should be recorded in the appropriate sections of the eCRF. Any change 
from the dosing schedule should be recorded in the eCRF.
Patients will be asked to return all unused IP and empty packages to the clinic at the site visit except 
Visit 3. At each visit, any patient found to be non-compliant will be counselled on the importance 
of taking their IP as prescribed. The investigator or delegate will enter the number of returned 
tablets in the eCRF.
The Investigational Product Storage Manager is responsible for managing IP from receipt by the 
study site until the destruction or return of all unused IP. The Investigator(s) is responsible for 
ensuring that the patient has returned all unused IP.


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6.5
Concomitant therapy
All patients should be treated according to regional standard of care of HFpEF and existing 
comorbidities (including treatment of hypertension, ischemic heart disease, atrial fibrillation, 
diabetes, hyperlipidaemia). Background medications should be part of clinical practice and will 
not be provided by the Sponsor.
6.5.1
Prohibited medication
Concomitant treatment (i.e., treatment in combination with IP) with open label SGLT2 inhibitors 
e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin and luseogliflozin and
fix dose combinations containing these drugs should not be used. 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. If treatment with an SGLT2 inhibitor alone or in 
combination is deemed essential, IP must be discontinued before that treatment is started.
6.5.2
Recording of concomitant treatment
Recording of relevant concomitant medications in the eCRF will be made according to the schedule 
of activities (Table 1). These include medications for cardiovascular conditions as well as diabetes 
mellitus.
6.5.3
Heart failure background standard of care
The patients should be on background standard of care therapies for patients with HFpEF according 
to local guidelines, including diuretics when needed to control symptoms and volume overload and 
adequate treatment of co-morbidities such as hypertension and ischaemic heart disease.
6.5.4
Anti-diabetes treatment
6.5.4.1
Background
More than 40% of patients with established HF are estimated to have T2D (Kristensen et al 2016). 
Therefore, it is expected that a large proportion of patients will have an established T2D diagnosis 
when included in this study and that some patients will develop T2D during the course of the study. 
Treatment of diabetes should follow established guidelines, such as according to glycaemic goals 
as recommended by the American Diabetes Association (ADA) and European Association for the 
Study of Diabetes (EASD) in their joint Position Statement (Inzucchi et al 2012, Inzucchi et al 
2015).
6.5.4.2
Treatment of patients with established diagnosis of type 2 diabetes
Diabetes medications at baseline and during the study will be recorded in the eCRF. Patients with 
T2D at randomisation will continue their T2D treatment. SGLT2-inhibitors should be avoided (see 
Section 6.5.1). Patients treated with insulin or insulin secretagogues have a higher risk of 
experiencing hypoglycaemic events compared with those treated with other antidiabetic agents. If 
needed, T2D treatments may be adjusted at the discretion of the Investigator or diabetes health care 
provider.


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6.5.5
Other concomitant treatment
Medications other than described above, which is considered necessary for the patient’s safety 
and wellbeing, may be given at the discretion of the Investigator.
6.6
Dose modification (not applicable)
6.7
Treatment after the end of the study
The patients will stop taking IP at the study closure visit (SCV). Remaining IP will be collected at 
that time. Post-study treatment will not be provided by the Sponsor. Patients should receive 
standard of care therapy after the SCV, at the discretion of the Investigator.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL
7.1
Discontinuation of study treatment
Discontinuation from study treatment is NOT the same thing as a withdrawal from the study. If the 
patient temporarily or permanently discontinues IP, the patient should remain in the study and it is 
important that the scheduled study visits and data collection continue according to the study 
protocol until study closure.
Patients may be discontinued from IP in the following situations:

Contraindication to further dosing with IP, in the opinion of the Investigator, such as 
Adverse event or other safety reasons.

Severe non-compliance with the study protocol.

Diabetic ketoacidosis (DKA). Consider temporarily interrupting IP if DKA is suspected. 
If DKA is confirmed, IP should be discontinued permanently.

Positive pregnancy test (discontinue IP and notify Sponsor representative).

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.
See the Table 1 for data to be collected at the time of treatment discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.1.1
Temporary discontinuation
Every attempt should be made to maintain patients on IP during the course of the study. If IP has 
been interrupted, it should be re-introduced as soon as, in the opinion of the Investigator, the 
patient’s condition is stable.


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7.1.1.1
Unexpected acute declines in eGFR
If an unexpected, acute decline in kidney function is observed, the patient should be evaluated and 
temporary interruption of IP should be considered. 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 (NSAID) 
and certain antibiotics such as trimethoprim. If any drug is suspected of causing or contributing to 
worsening kidney function, their use should be re-considered.
7.1.1.2
Volume depletion/hypotension
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should in addition to considering temporary interruption of IP have their regular 
medication reviewed, and consideration given to reducing the dose of, or stopping concomitant
medications, as assessed on an individual basis, including diuretics and drugs that lower blood 
pressure. The need for conventional diuretics (or the dose of diuretic used) should be re-evaluated 
in light of the patient’s symptoms and signs.
7.1.1.3
Patients at risk of volume depletion
Temporary interruption of IP may be considered in patients thought to be at risk of volume 
depletion/hypotension, such as patients with an acute medical illness potentially causing volume 
depletion because of inadequate fluid intake or fluid/blood loss (e.g. gastroenteritis, gastrointestinal 
haemorrhage), or those undergoing major surgery.
7.1.2
Procedures for discontinuation of study treatment
Investigators should instruct their patients to contact the site before or at the time IP is stopped. A 
patient that decides to discontinue IP will always be asked about the reason(s) and the presence of 
any AEs. Generally, AEs, SAEs, and potential endpoint events should not lead to IP 
discontinuation, unless there is a clear clinical rationale to do so.
The date of last intake of IP should be documented in the eCRF. All IP should be returned by the 
patient at their next on-site study visit or unscheduled visit. Patients permanently discontinuing IP 
should be given locally available standard of care therapy, at the discretion of the Investigator.
Discontinuation of IP, for any reason, does not impact on the patient´s participation in the study. 
The patient should continue attending subsequent study visits and data collection should continue 
according to the study protocol. If the patient 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 patient, a contact with a relative or treating physician, 
or information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn from the 
study.


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Restart of randomised IP is always encouraged. Even if a premature treatment discontinuation visit 
(PTDV) was completed due to discontinuation of IP, this should not prevent the patient to return 
to randomised IP if deemed appropriate.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and it is not possible for the site to get contact with the patient. To optimise the chance of 
getting in contact with the patient during the study, Investigators should record as much contact 
information as possible at the start of the study including home phone, mobile phone, holiday home 
phone, family member phone numbers, email address, and social media contact details.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed potentially lost to follow up, the Investigator or designee must 
make every effort to regain contact with the patient or next of kin by, e.g. repeat telephone 
calls, certified letter to the patient´s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the patient’s medical record.

Efforts to reach the patient should continue until the end of the study. Information regarding 
vital status should always be collected if possible.
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments), without prejudice to 
further treatment. Withdrawal of consent should only occur if the patient has received appropriate 
information about and does not agree to any kind of further assessments or contact, including 
modified follow up options (see Section 7.1.2). Discontinuation of IP in itself is not considered 
withdrawal of consent.
Withdrawal of consent must be ascertained and documented in writing by the Investigator who 
must inform the AZ representative and document the withdrawal of consent in the eCRF and 
medical records.
A patient who withdraws from the study will always be asked about the reason(s) and the presence 
of any AE. The Investigator will follow up AEs reported outside of the clinical study.
If a patient withdraws from participation in the study, then his/her enrolment and randomisation 
codes cannot be reused. Withdrawn patients will not be replaced. If the patient withdraws consent 
for disclosure of future information, the sponsor may retain and continue to use any data collected 
before such a withdrawal of consent.


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To ensure validity of study data, it is very important to collect as much data as possible throughout 
the study and especially vital status (dead or alive) at study closure (also for patients who have 
withdrawn their informed consent). The Investigator will therefore attempt to collect information 
on all patients’ vital status from publicly available sources at study closure, even if informed 
consent has been withdrawn, in compliance with local privacy laws/practices.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (see Section 1.1).
An Electronic Data Capture (EDC) system will be used for data collection and query handling. The 
Investigator will ensure that data are recorded in the eCRFs as specified in the study protocol and 
in accordance with the eCRF instructions provided.
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site.
All screening evaluations must be completed and reviewed to confirm that potential patients meet 
all eligibility criteria. The Investigator will maintain a screening log to record details of all patients 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (e.g. LVEF assessment) 
and obtained before signing of the ICF may be utilised for screening or baseline purposes provided 
the procedures met the protocol-specified criteria.
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct.
8.1
Enrolment Period
8.1.1
Visit 1, Enrolment (Day -21 to Day -1)
Enrolment of hospitalized patients is allowed.
At enrolment the following assessments and procedures will be completed:

The patient signs the ICF
- Patients who agree to the optional sampling of blood for genetic research will 
provide their consent

The investigator assesses patient’s eligibility criteria and reviews concomitant 
medications, relevant medications will be recorded in the eCRF 


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!
The patient will be enrolled and assigned an E-code in IxRS assuming 
inclusion/exclusion criteria are met
!
Demography and relevant medical history (including prior cardiac imaging 
assessments) will be recorded
!
A physical examination will be conducted
!
NYHA Functional Classification will be evaluated and recorded
!
12-lead ECG will be recorded
!
Vital signs (BP, pulse), height and weight will be assessed and recorded

Blood samples will be taken for NT-proBNP, creatinine (for calculation of eGFR) and 
HbA1c assessment (central laboratory)
8.2
Treatment period
8.2.1
Visit 2, Randomisation (Day 1)
Prior to Visit 2, the investigator will assess eligibility based on the central laboratory assessments 
from Visit 1. Patients not eligible will be considered screen failures and should not continue to 
Visit 2.
Randomisation of hospitalized patients is allowed.
At randomisation, the following assessments and procedures will be completed:
!
Medical history (including cardiac imaging assessments) will be re-assessed
!
A physical examination will be conducted
!
A pregnancy test for women of child-bearing potential will be done locally with a 
dipstick provided by central laboratory with result recorded in the medical record
!
Vital signs (BP, pulse) will be assessed and recorded
!
NYHA Functional Classification will be evaluated and recorded
!
The investigator will re-assess the inclusion and exclusion criteria
!
KCCQ, PGIS and EQ-5D-5L questionnaires will be completed
!
Review of concomitant medication and recording of relevant medications
!
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
Randomisation 1:1 ratio to IP (either dapagliflozin at 10 mg or placebo) will be done in 
IxRS

IP will be dispensed via IxRS to the patient. The patient will be instructed to take the IP 
in accordance with protocol without interruptions, and to bring all dispensed bottles to 
all study visits

Patients who have consented to sampling for genetic research, will provide a blood 
sample
8.2.2
Visit 3 (Day 30; ±7 days):
At Visit 3, the following assessments and procedures will be conducted:

KCCQ and PGIS questionnaires will be completed

NYHA Functional Classification will be evaluated and recorded

Vital signs (BP, pulse) will be assessed and recorded

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or amputations, 
adverse events (AEs) leading to amputation and potential risk factor AEs for amputations 
affecting lower limbs since the last visit, this will be recorded in the eCRF

Blood samples will be taken for creatinine (for calculation of eGFR) assessment 
(central laboratory)
8.2.3
Visit 4 (Day 120 ±7 days):
At Visit 4, the following assessments and procedures will be conducted:

KCCQ and PGIS questionnaires will be completed

NYHA Functional Classification will be evaluated and recorded

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results


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
If the patient has experienced any potential endpoints, SAEs, DAEs and/or amputations, 
adverse events (AEs) leading to amputation and potential risk factor AEs for amputations 
affecting lower limbs since the last visit, this will be recorded in the eCRF.

Blood samples will be taken for creatinine (for calculation of eGFR) assessment 
(central laboratory)

IP will be dispensed via IxRS to the patient. Drug accountability of the returned IP will 
be checked. The patient will be instructed to take the IP in accordance with protocol and 
without interruptions
8.2.4
Visit 5 (Day 240 ±7 days)
At Visit 5, the following assessments and procedures will be conducted:

KCCQ, PGIS and EQ-5D-5L questionnaires will be completed

NYHA Functional Classification will be evaluated and recorded

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or amputations, 
adverse events (AEs) leading to amputation and potential risk factor AEs for amputations 
affecting lower limbs since the last visit, this will be recorded in the eCRF.

IP will be dispensed via IxRS to the patient. Drug accountability of the returned IP will 
be checked. The patient will be instructed to take the IP in accordance with protocol and 
without interruptions.
8.2.5
Visit 6 (Day 360 ±7 days)
At Visit 6, the following assessments and procedures will be conducted:

Vital signs (BP, pulse), and weight will be assessed and recorded

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or 
amputations, adverse events (AEs) leading to amputation and potential risk factor AEs 
for amputations affecting lower limbs since the last visit, this will be recorded in the 
eCRF.


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
IP will be dispensed via IxRS to the patient. Drug accountability of the returned IP will 
be checked. The patient will be instructed to take the IP in accordance with protocol and 
without interruptions.

Blood samples will be taken for creatinine (for calculation of eGFR) assessment 
(central laboratory)
8.2.6
Visit 7 and onwards (Day 480 and every 120 days ±14 days)
At visit 7 and subsequent visits, the following assessments and procedures will be conducted:

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or 
amputations, adverse events (AEs) leading to amputation and potential risk factor AEs 
for amputations affecting lower limbs since the last visit, this will be recorded in the 
eCRF.

IP will be dispensed via IxRS to the patient. Drug accountability of the returned IP will 
be checked. The patient will be instructed to take the IP in accordance with protocol and 
without interruptions.

Starting from Visit 6, vital signs (BP, pulse), and weight assessment as well as blood 
samples collection for creatinine (for calculation of eGFR) will be repeated every 12 
months - on Visit 6, Visit 9 and Visit 12.
8.2.7
Premature Treatment Discontinuation Visit
Patients who prematurely and permanently discontinue treatment with IP should return for a 
premature treatment discontinuation visit (PTDV), which will be done as soon as possible after last 
dose of IP. The following assessments and procedures will be conducted:

KCCQ, PGIS and EQ-5D-5L questionnaire will be completed

NYHA Functional Classification will be evaluated

Vital signs (BP, pulse) and weight will be assessed and recorded

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures


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
Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or amputations, 
adverse events (AEs) leading to amputation and potential risk factor AEs for amputations 
affecting lower limbs since the last visit, this will be recorded in the eCRF

Drug accountability of the returned IP will be checked
Patients who discontinue treatment prematurely should attend all study visits according to plan, 
including the study closure visit (SCV). Patients may re-start treatments if assessed as appropriate 
by the Investigator. For further details regarding discontinuations from IP, please see Section 7.1.
8.2.8
Study Closure Visit
A primary analysis censoring date (PACD) will be declared based on the rate of accrued endpoints. A 
study closure visit (SCV) will be scheduled within 6 weeks of the PACD. All patients (including any 
patients who have discontinued treatment with IP) should return for this visit.
The patient will stop taking IP at the SCV. Remaining IP will be collected at that time and drug 
accountability will be checked. The following assessments and procedures will be conducted:

KCCQ, PGIS and EQ-5D-5L questionnaire will be completed

NYHA Functional Classification will be evaluated

A physical examination will be conducted

Vital signs (BP, pulse) and weight will be assessed and recorded.

Review and updating of concomitant medication and recording of relevant medications

Review and recording of any cardiac and HF related procedures

Review of potential efficacy and safety events including COVID-19 testing results

If the patient has experienced any potential endpoints, SAEs, DAEs and/or amputations, 
adverse events (AEs) leading to amputation and potential risk factor AEs for amputations 
affecting lower limbs since the last visit, this will be recorded in the eCRF

Drug accountability of the returned IP will be checked
8.2.9
Unscheduled visits
An unscheduled on-site or telephone visit may occur in-between scheduled on-site visits (for 
example assessment of potential endpoint events or safety events).


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8.3
Efficacy assessments
8.3.1
Efficacy event capture
Efficacy events (i.e. death, hospitalisation or urgent visits for HF) will be collected by site 
personnel according to the study visit schedule. All potential efficacy events should be recorded as 
an AE and on additional event modules in the eCRF. If the potential efficacy event fulfils SAE 
criteria (see Appendix B 2) the site is to record and report these events to the sponsor or designee 
within timelines described in Section 8.6.
NYHA classification will be done by the Investigators and recorded in the eCRF. PROs will be 
collected for all patients throughout the study period via a hand-held electronic device. All-cause 
hospitalisations will be derived from SAE reports.
8.3.2
Efficacy event adjudication
A Clinical Events Adjudication (CEA) Committee will be established for this trial and adjudicate 
primary efficacy events in accordance with adjudication criteria detailed in the CEA charter.
Events to be adjudicated include components of the primary efficacy endpoint: deaths, 
hospitalisation for HF, and urgent HF visits. All deaths will be adjudicated to determine if they are 
CV or non-CV deaths. All adjudication will be done on an ongoing basis throughout the trial.
8.3.3
Clinical Outcome Assessments (COA)
A COA is any assessment that may be influenced by human choices, judgement, or motivation and 
may support either direct or indirect evidence of treatment benefit. Patient Reported Outcomes 
(PROs) is one of the types of COAs. A PRO is any report of the status of a patient’s health condition 
that comes directly from the patient, without interpretation of anyone else. PROs have become a 
significant endpoint when evaluating benefit/risk of treatments in clinical trials. The following 
PROs will be collected: KCCQ, PGIS and EQ-5D-5L (see Appendix I, Appendix K, Appendix L).
PROs will be collected for all patients throughout the study period via a hand-held electronic 
device. See study of assessment (See Table1) for the timing of collection. The ePRO devices should 
be administered prior to first dose at visit 2/randomisation. Site staff should stress that the 
information is confidential.
8.3.3.1
KCCQ
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered disease 
specific instrument and has shown to be a valid, reliable and responsive measure for patients with 
HF (Greene et al 2018, Spertus et al 2005). The KCCQ was developed to independently measure 
the patient’s perception of their health status, which includes heart failure-related symptoms 
(frequency, severity and recent change), impact on physical and social function, self- efficacy and 
knowledge, and how their heart failure impacts their quality of life (QOL). Scores are transformed 
to a range of 0-100. Higher scores represent a better outcome.
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KCCQ Symptom Domain quantifies the frequency and burden of clinical symptoms in 
heart failure, including fatigue, shortness of breath, paroxysmal nocturnal dyspnea and 
patients’ edema/swelling. An overall symptom score is generally used in analyses; 
subscale scores for both frequency and severity are also available. The total symptom 
Score incorporates the symptom domains into a single score

KCCQ Physical Function Domain measures the limitations patients experience, due to 
their heart failure symptoms, in performing routine activities. Activities are common, 
gender-neutral, and generalizable across cultures, while also capturing a range of 
exertional requirements

KCCQ Quality of Life Domain is designed to reflect patients’ assessment of their 
quality of life, given the current status of their heart failure

KCCQ Social Limitation Domain quantifies the extent to which heart failure symptoms 
impair patients’ ability to interact in a number of gender-neutral social activities

KCCQ Self-efficacy Domain quantifies patients’ perceptions of how to prevent heart 
failure exacerbations and manage complications when they arise. This scale is not 
included in the summary scores

KCCQ Symptom Stability Domain measures recent changes in patients’ symptoms; their 
shortness of breath, fatigue or swelling. It compares patients frequency of heart failure 
symptoms at the time of completing the KCCQ with their frequency 2 weeks ago. As a 
measure of change, it is most interpretable as a baseline assessment of the stability of 
patients’ symptoms at the start of a study and shortly thereafter, as a measure of the acute 
response to treatment. This domain is not included in the summary scores.

Clinical Summary Score includes total symptom and physical function scores to 
correspond with NYHA Classification

Overall Summary Score includes the total symptom, physical function, social 
limitations and quality of life scores
8.3.3.2
Patient Global Impression of Severity (PGIS)
The PGIS item is included to assess how a patient perceives his/her overall current severity of heart 
failure symptoms. Patients will choose from response options from “no symptoms” to “very 
severe”.
8.3.3.3
EuroQoL five-dimensional five-level questionnaire (EQ-5D-5L)
The EQ-5D-5L is a self-reported questionnaire that is used to derive a standardized measure of 
health status, also referred to as a utility score. EQ-5D-5L utility scores are widely accepted by 
reimbursement authorities and will be used to support health economic evaluations.


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8.3.3.4
Administration of electronic PROs
Each site must allocate the responsibility for the administration of the ePROs to a specific 
individual and, if possible, assign a backup person to cover if that individual is absent. A key aspect 
of study success is to have high PRO compliance. Therefore, it is essential to follow SoA and that 
sites make sure the device is charged and fully functional at all times in order to minimize missing 
data.
It is important that the site staff explains the value and relevance of PRO data: to hear directly from 
patients how they feel. The following best practice guidelines should be followed:

Patient must not receive help from relatives, friends, or site personnel to answer or 
clarify the PRO questionnaires in order to avoid bias. If a patient uses visual aids (e.g., 
spectacles or contact lenses) for reading and does not have them at hand, the patient will 
be exempted from completing the PROs questionnaires on that visit

Before any other study procedures are conducted at a given visit (except the Visit 2: 
eligibility confirmation before the KCCQ)

Before being seen by the investigator

PRO questionnaires must be completed by the patient in private

The appointed site personnel should also stress that the information is confidential. 
Therefore, if the patient has any medical problems, he or she should discuss them with 
the doctor or research nurse separately from the ePRO assessment

The appointed site personnel must show patients how to use the ePRO device, in 
accordance with the instructions provided

The appointed site personnel should remind patients that there are no right or wrong 
answers, and the patient should be given sufficient time to complete the PRO 
questionnaires at his/her own speed
If a site is affected by COVID-19 pandemic and on-site visits are not possible, phone collection of 
ePRO is an alternative solution to maintain continuity of the assessments. The details of the 
procedure will be provided in a separate instruction.
If the patient is unable to read the questionnaire (e.g., is blind or illiterate), the patient will be 
exempted from completing the PRO questionnaires and may still participate in the study. Patients 
exempted in this regard should be flagged appropriately by the site personnel.
8.4
Safety assessment
Planned time points for all safety assessments are provided in the schedule of activities (Table 1).


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8.4.1
Physical examinations
A physical examination will be performed at the time-points specified in Table 1 and include an 
assessment of the following: general appearance, respiratory and cardiovascular systems (including 
oedema) and abdomen.
The assessment dates will be recorded in the eCRF.
8.4.2
Vital Signs

Pulse and BP will be measured twice at all applicable visits, and all measurements will 
be recorded in the eCRF.

The measurements should be done before any blood sampling. The measurements will 
be assessed in a sitting position with a completely automated device. Manual techniques 
will be used only if an automated device is not available.

The measurements should be preceded by at least 5 minutes of rest for the subject in a 
quiet setting without distractions (e.g., television, cell phones).
8.4.3
Electrocardiogram
A 12-lead ECG (standard ECG with a paper speed of 25-50 mm/second covering at least 6 
sequential beats) will be recorded at baseline (Visit 1) after the patient has been lying down to rest 
for at least 5 minutes, to confirm presence or absence of atrial fibrillation/flutter at enrolment. Heart 
rate and heart rhythm will be reported in the eCRF. The baseline ECG should be stored and be 
made available upon request for adjudication purposes
8.4.4
Safety laboratory assessments
Serum creatinine will be collected for calculation of eGFR using CKD-EPI equation (Levey et al 
2009).
8.4.5
Other safety assessments 
If COVID-19 testing was done, the type of test and result (positive/negative) should be recorded 
in the eCRF.
8.4.6
Other clinical assessments
8.4.6.1
Body weight and height
The patient’s body weight will be measured with light clothing and no shoes. If the patient has a 
prosthetic limb, this should be consistently worn during all weight measurements. The patient’s 
height will be measured at Visit 1, with no shoes. The weight and height will be recorded in the 
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8.5
Collection of adverse events
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 patient (or, when appropriate, by a caregiver, surrogate, or the patient's 
legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of a SAEs and DAEs, amputation and events potentially placing the 
patient at risk for a lower limb amputation (preceding events). For information on how to follow-
up AEs see Section 8.5.3.
8.5.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting SAEs or DAEs. Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about AE occurrences.
Safety information on SAEs and DAEs, amputations, adverse events (AEs) leading to amputation 
and potential risk factor AEs for amputations affecting lower limbs will be collected and entered 
into eCRFs by site personnel according to the study visit schedule.
If the potential efficacy event fulfils SAE criteria (see Appendix B 2) the site is to record and report 
these events to the Sponsor or designee within timelines described in Section 8.6.1.
8.5.1.1
Adverse events (AEs) leading to amputation and potential risk factor AEs for 
amputations affecting lower limbs (“preceding events”)
To ensure that data on amputations is systematically collected, amputations and underlying 
conditions relevant to amputation will be recorded on a specific eCRF page. The adverse event 
leading to amputation should be recorded in the eCRF as AE/SAE.
In addition to amputation, non-serious and serious events potentially placing the patient at risk for 
a lower limb amputation (“preceding events”) should also be recorded in the eCRF as AE/SAE 
whether or not an amputation has taken place. The lower limb amputation “preceding events” of 
interest include diabetic foot related conditions, vascular, volume depletion, wounds/injury/trauma, 
infection and neuropathy. If any of these or other potentially relevant events have occurred, relevant 
information must be provided (this will be collected on a dedicated eCRF page - for details see 
eCRF instruction)”.
8.5.1.2
Capture of DKA events
For SAEs or DAEs reported by the Investigator as Diabetic Ketoacidosis (DKA - see definition 
below) additional information will be recorded on specific eCRF pages in addition to the AE/SAE 
form. All potential events of DKA will be submitted to an independent DKA Adjudication 
Committee, see Section 8.5.1.2.2)


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8.5.1.2.1 DKA definition
A diagnosis of Diabetic Ketoacidosis should only be made in a clinical setting consistent with DKA 
(based on patient history, symptoms, and physical exam) and in the absence of more likely 
alternative diagnoses and causes of acidosis (such as lactic acidosis). The following biochemical 
data should support diagnosis:

Ketonaemia ≥3.0 mmol/L and/or significant ketonuria (more than 2+ on standard urine 
sticks)

At least one of the following criteria suggesting high anion gap metabolic acidosis:

Arterial or Venous pH ≤7.3

Serum bicarbonate ≤18 mEq/L

Anion gap [Na – (Cl + HCO3)] >10
8.5.1.2.2 Diabetic Ketoacidosis Adjudication Committee T2D
All potential events of DKA will be submitted to an independent DKA Adjudication Committee. 
The committee will be kept blinded to the treatment codes. A separate DKA Adjudication Manual 
will define and describe the procedures for the collection of DKA information, handling, 
adjudication criteria and reporting of these events.
8.5.1.3
Capture of cardiac ischaemic events and stroke
For myocardial infarctions, unstable angina and stroke additional information will be recorded on 
specific eCRF pages in addition to the AE/SAE form.
The diagnosis of stroke, MI and unstable angina should be made according to standard clinical 
practice and align with the definition for stroke in the standardised definitions for endpoints (Hicks 
et al 2018) described in Appendix C.
8.5.1.4 Capture of Major hypoglycaemic events
A major hypoglycemic event is defined as an event that is characterized by altered mental and/or 
physical status, any symptoms of severe impairment in consciousness or behavior, that require 
external assistance of another person for treatment of hypoglycemia and recovery, to actively 
administer carbohydrates, glucagon, or take other corrective actions.
Plasma glucose concentrations may not be available during a hypoglycaemic event, but 
neurological recovery following the corrective actions is considered sufficient evidence that the 
event was induced by a low plasma glucose concentration. Major hypoglycaemic episodes will be 
recorded in the eCRF as an AE and on an additional eCRF page.


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8.5.1.5 
Capture of additional laboratory values
Any additional safety laboratory assessments during the study period, including creatinine, will be 
obtained per the Investigator’s medical judgment in the course of standard care using local 
laboratories. Laboratory values would be recorded only on SAE eCRFs as part of narrative 
information, per the Investigator’s judgment.
8.5.2
Time period and frequency for collecting AE and SAE information
Non-serious adverse events as defined per protocol will be collected from randomisation (Visit 2), 
throughout the treatment period until and including the patient’s last visit (the study closure visit). 
Serious adverse events are recorded from the time of signing of informed consent form throughout 
the treatment period until and including the patient's last visit.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated in 
Appendix B. The Investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.5.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAE and events of amputation and potential preceding events will 
be followed until resolution, stabilization, the event is otherwise explained, or the patient is lost to 
follow-up.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.5.4
Adverse event data collection
The following variables will be collect for each AE;

AE (verbatim)

The date when the AE started and stopped

Maximum intensity (mild/moderate/severe)

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to IP

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In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s) and/or other medication

Description of AE
8.5.5
Causality collection
The Investigator will assess causal relationship between the IP and each 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?’
For SAEs, causal relationship will 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.
8.5.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: ‘Have you had any health problems since the previous visit/you were last 
asked?’ or revealed by observation will be collected and recorded in the eCRF if they fulfil the 
criteria specified in Section 8.5.2. 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.
8.5.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated vital signs and laboratory values will be 
summarised in the clinical study report. Deterioration as compared with baseline in protocol-
mandated vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the IP. If deterioration in a vital sign is 
associated with clinical signs and symptoms, the sign or symptom will be reported as an AE if they 


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fulfil any of the SAE criteria or are the reason for discontinuation of treatment of IP, and the 
associated vital sign will be considered as additional information.
8.5.8
Disease-under study (DUS) (not applicable)
8.5.9
Disease progression (not applicable)
8.6
Safety reporting and medical management
8.6.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
Investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study Protocol.
8.6.1.1
Reporting of SAEs considered to be potential endpoints
In order to avoid unnecessary unblinding of efficacy endpoint events, certain SAEs which are also 
potential endpoints (i.e., fatal AEs and HF events) will not be reported to health authorities. Clinical 
data for the above mentioned events will be recorded as AEs/SAEs as well as on separate event 
forms in the eCRF. Recording of a suspected endpoint should be done within the same timeframes 
as defined for SAEs (see Section 8.6.1).


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In addition, fatal AEs and potential HF endpoints will be centrally adjudicated by an independent 
CEA committee (see Section 8.3.1 and 8.3.2). If adjudication confirms the endpoint, the SAE will 
not be reported to health authorities. However, if it is determined by the CEA committee that a 
potential endpoint does not meet the endpoint criteria, the event will be reported (according to the 
timelines specified in Section 8.6.1) to AZ patient safety data entry site and if applicable to the 
health authorities (note that the clock starts when the adjudication results are available).
8.6.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study patient has received any IP. If a pregnancy is reported, 
the Investigator should inform the sponsor within 24 hours of learning of the pregnancy. Abnormal
pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs.
8.6.2.1
Maternal exposure
Women of childbearing potential who are not using contraception as defined in Section 5.2; 
exclusion criterion number 18 are not allowed to be included in this study. Should a pregnancy still 
occur, the investigational product should be discontinued immediately and the pregnancy reported 
to AstraZeneca.
Dapagliflozin must not be used in the second and third trimesters of pregnancy. In the time period 
corresponding to second and third trimester of pregnancy with respect to human renal maturation, 
maternal exposure to dapagliflozin in rat studies was associated with increased incidence and/or 
severity of renal pelvic and tubular dilatations in progeny.
There are no adequate and well-controlled studies of dapagliflozin in pregnant women. When 
pregnancy is detected, investigational product(s) should be discontinued.
8.6.3
Overdose
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 T2D. Suspected single intake of more than 50 tablets of 10 mg dapagliflozin tablets 
or repeated intake of more than 10 tablets of 10 mg dapagliflozin tablets should be reported on the 
eCRF overdose module. If an overdose is suspected, monitoring of vital functions as well as 
treatment should be performed as appropriate.
For further information regarding overdose, refer to the IB.

An overdose without associated symptoms is only recorded on the Overdose eCRF 
module

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
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If an overdose on an AstraZeneca IP occurs in the course of the study, then the investigator or other 
site personnel inform appropriate AstraZeneca representatives immediately, or no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.5.2.
For other overdoses, reporting must occur within 30 days.
8.7
Pharmacokinetics (not applicable)
8.8
Pharmacodynamics (not applicable)
8.9
Optional exploratory genetics
Approximately 6 mL blood sample for DNA isolation will be collected from subjects who have 
consented to participate in the genetic analysis component of the study. Participation is optional. 
Subjects who do not wish to participate in the genetic research may still participate in the study.
See Appendix D for Information regarding genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in Appendix D.
8.10
Biomarkers (not applicable)
8.11
Health Economics (not applicable)
9.
STATISTICAL CONSIDERATIONS
9.1
Statistical hypotheses
For the primary and secondary endpoints, the following hypothesis will be tested at the 4.980 % 
2-sided level:
H0: HR [dapagliflozin:placebo] =1
versus
H1: HR [dapagliflozin:placebo] ≠1
9.2
Sample size determination
The primary objective of the study is to determine the superiority of dapagliflozin versus placebo 
added to standard of care in reducing the composite of CV death and heart failure events 
(hospitalisation for HF or urgent HF visit). Two hypotheses will be tested simultaneously (i.e., dual 
primary analyses) for the primary objective: (1) in the full population and in (2) an LVEF <60% 
subpopulation, with alpha allocated to each test. Originally, assuming a true hazard ratio (HR) of 
0.80 between dapagliflozin and placebo, using a two-sided alpha of 5%, 844 primary endpoint 


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events were targeted in order to provide a statistical power of 90% for the test of the primary 
composite endpoint. To allow testing for the dual primary analyses, alpha will be allocated to each 
test to ensure strong control of the overall type I error rate. The target number of patients with a 
primary endpoint has been increased to 1117 in order to provide adequate statistical power for each 
test. It is anticipated that at least 70% of the events (i.e., approximately 780 events) will be available 
for the LVEF <60% subpopulation. To illustrate, assuming a true HR of 0.80, a two-sided alpha of 
2.4% allocated to the LVEF <60% subpopulation will result in a power of 80% to detect a treatment 
difference, whereas an alpha allocation of 1.5% to the full population will result in 90% power. 
The final alpha split for the dual primary analyses will be specified in the SAP prior to the planned 
interim analysis. This is based on an overall 1:1 allocation between dapagliflozin and placebo.
The HR 0.80 was originally chosen as a conservative assumption based on the observed HR 0.72 
(95% confidence interval 0.50-1.04) for the composite of HF hospitalisation and CV death in 
patients with HF at baseline in the EMPA- REG OUTCOME trial (Fitchett et al 2016) and HR 0.61 
(0.46-0.80) for patients with history of HF in the CANVAS program (Rådholm et al 2018) 
considering that these were post-hoc analyses in subgroups with limited documentation of baseline 
HF diagnosis, not characterised by ejection fraction.
The event rate assumptions are based on sub analyses of the TOPCAT and I-PRESERVE studies 
by geographic region, NT-proBNP levels, prior hospitalisation for HF, and T2D status (Pfeffer et 
al 2015, Kristensen et al 2015, Kristensen et al 2017). The original sample size calculation (~ 4700
randomized patients) built on the assumption of an annual event rate of 9% in the placebo group 
for the majority of prevalent HFpEF patients, importantly all with NT -proBNP ≥300 pg/ml by 
inclusion criterion. Additionally, a subgroup of patients due to be discharged or recently discharged 
from a HF hospitalisation (here denoted ‘subacute’ patients) with a higher event rate is planned to 
be included. Assuming 20% of patients from the subacute category with an annual event rate of 
24% during the first year and 9% thereafter for the remainder of the study, the original sample size 
of 4700 patients was estimated to provide the required number of 844 patients with a primary event 
during a recruitment period of 18 months and a minimum follow-up period of 15 months. 
Based on the ongoing blinded monitoring of event accrual (including the percentage of patients 
from the subacute category), the sample size is increased from original 4700 to approximately 6100 
randomised patients. Accordingly, the recruitment period is anticipated to increase from the 
original 18 months to 26 months. Recruitment might be marginally prolonged in a few countries 
to meet local targets. The study is event driven and the number of patients or duration may further 
change.
With the same event rate assumptions as above, assuming 11% of patients from the subacute 
category, approximately 6100 patients are estimated to provide the required number of 1117 
patients with a primary event during an anticipated recruitment period of 26 months and a minimum 
follow-up period of 13.5 months (total study duration 39  months).
In addition, the expected number of patients who will be lost to follow-up is expected to be small; 
hence, these are not considered in the determination of the sample size.


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9.3
Populations for analyses
For purposes of analysis, the following populations are defined:
Table 5
Population for analysis
Population
Description
Enrolled
All patients who sign the ICF
Full Analysis Set (FAS)
All patients who have been randomised to study treatment, irrespective
of their protocol adherence and continued participation in the study.
Patients will be analysed according to their randomised investigational
product assignment, irrespective of the treatment actually received. The
FAS will be considered the primary analysis set for the intention to
treat analysis of primary and secondary variables. A subset of the full 
analysis set consisting of patients with baseline LVEF of <60% (or 
LVEF <60% subpopulation) will be analysed separately as part of the 
confirmatory statistical testing procedure.
Safety analysis set
All patients randomly assigned to Study treatment and who take at
least 1 dose of investigational product. Patients will be analysed
according to the treatment actually received. The Safety analysis set
will be considered the primary analysis set for all safety variables
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock and 
Clinical Study Protocol deviations identified.
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive statistical analysis plan (SAP) will be developed prior to first patient randomised 
and any subsequent amendments will be documented, with final amendments finalised before
database lock. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the clinical study report.
9.4.1
Efficacy analyses
9.4.1.1
Analysis of the primary variable
The primary variable is the time from randomisation to first event included in the primary 
composite endpoint. Two hypotheses will be tested simultaneously (i.e., dual primary endpoint 
analyses): (1) in the full population and (2) in an LVEF <60% subpopulation, with alpha allocated 
to each test. The primary analysis will be based on the ITT principle using the FAS, including 
events occurring on or prior to the PACD, adjudicated by the CEA 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 T2D status at randomisation. The p-value, HR and 95% confidence interval will be reported.


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The contribution of each component of the primary composite endpoint to the overall treatment 
effect will be examined. Methods similar to those described for the primary analysis will be used 
to separately analyse the time from randomisation to the first occurrence of each component of the 
primary composite endpoint. HR and 95% confidence intervals will be reported.
Kaplan-Meier estimates of the cumulative incidence to the first occurrence of any event in the 
primary endpoint will be calculated and plotted, for overall analysis and for the individual 
components.
9.4.1.2
Analysis of the secondary variables
The outcome of all HF events (first and recurring) and CV death will be analysed by the semi-
parametric proportional rates model (Lin et al 2000) to test the treatment effect and to quantify the 
treatment difference. The rate ratio and its 95% confidence interval and corresponding two-sided 
p-value will be presented. This outcome will also be analysed for the LVEF <60% subpopulation 
within the multiple testing procedure as described in Section 9.2.
The analysis of change from baseline for KCCQ total symptom score at 8 months will be further 
detailed in the statistical analysis plan, e.g. with consideration of handling of patients who die. In 
addition to the secondary endpoint, total symptom score, the overall summary score, clinical 
summary score and domain scores will be analysed. A responder analysis will also be performed 
(more details presented in the SAP).
The analysis of the endpoints time from randomisation to CV death and time to all-cause mortality 
will be analysed in the similar manner as the primary variable.
9.4.1.3
Subgroup analysis
Subgroup variables for the primary efficacy endpoint include demography, baseline disease 
characteristics, baseline concomitant medications and others. Cox proportional hazard model
stratified for T2D with factors for treatment group, the subgroup variable and the interaction 
between treatment and subgroup will be used to examine treatment effects within relevant 
subgroups separately. A test of interaction between randomised treatment group and the subgroup 
variable will be performed in each Cox model. The p-values for the subgroup analyses will not be 
adjusted for multiple comparisons as the tests are exploratory and will be interpreted descriptively. 
Treatment differences with 95% confidence intervals will be reported for each subgroup. HRs and 
CIs for overall analysis and subgroups will be presented with forest plots as well. Further details 
of the subgroup analysis, including the list of subgroup variables, will be provided in the SAP.


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9.4.1.4
Sensitivity analysis
Details of the sensitivity analysis for the primary and secondary endpoints will be provided in the 
SAP.
9.4.2
Safety analyses
All safety analyses will be performed on the Safety analysis set. The number and percent of patients 
with SAEs, DAEs, amputations, and potential preceding events for lower limb amputations will be 
summarised by treatment group, and by system organ class and preferred term.
For safety analyses, summaries will be provided using both on treatment observations and using 
all observations regardless of whether patients are on or off study treatment.
9.4.3
Methods for multiplicity control
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilised. The Type I error will be controlled at an overall two-sided 
5% level for multiplicity across primary and secondary endpoints and in consideration of the 
planned interim analysis. With one interim analysis at 67% of events (see Section 9.5) the two-
sided significance level in final analysis, α, will be 4.980%. Statistical significance will be assessed 
in two branches in a pre-specified order of the endpoints and populations which is further described 
in the SAP. The significance level α, will be split for the two primary analyses, denoted α1 and α2. 
If either of the tests of the primary endpoint in the full study population and for LVEF <60% 
subpopulation is significant at respective levels α1 and α2, the next hypothesis in the respective 
branch sequence will be tested at the same significance level. The exact split of alpha will be 
documented in an updated SAP before the interim analysis. If all hypotheses in one arm are 
rejected, the alpha will be recycled to the other branch. 
9.5
Interim analyses
An interim analysis is planned to be performed including approximately 67% of the target number 
of patients with adjudicated primary endpoint events (approximately 748 events). There will in 
principle be one planned interim analysis for efficacy, with the possibility of the DMC to conduct 
subsequent interim analysis if they deem necessary. The significance level for final analysis will 
be determined by the Haybittle-Peto function based on the actual number of interim analyses. The 
interim analysis will assess superiority of dapagliflozin to placebo. The interim analysis will have 
a nominal two-sided alpha level of 0.2%. At the interim analysis, the primary composite endpoint 
will be tested in the full study population at the specified alpha level. If superiority is achieved for 
the primary endpoint, then the superiority of dapagliflozin to placebo on CV deaths will be tested
in the full study population at a two-sided level of 0.2%. If CV death is significant, then an action 
is triggered whereby the DMC will evaluate the totality of the efficacy data and safety data, to 
determine if benefit is unequivocal and overwhelming such that the DMC recommends ending the 
study.
In the initial version of the protocol, there was a planned futility analysis to be performed at the 
time of interim analysis. This futility analysis was removed, since formal testing was updated to 


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include both the LVEF <60% subpopulation and full study population, and that this potentially 
creates complex scenarios related to futility and benefit in one, other or both populations.
9.5.1
Data monitoring committee (DMC)
An independent data monitoring committee (DMC) will be appointed and will report to the 
Executive Committee. 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 study. The DMC will 
have access to the individual treatment codes and be able to merge these with the collected study 
data while the study is ongoing. A charter will be prepared to detail precise roles and 
responsibilities and procedures of the DMC.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
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 Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g. advertisements) must be submitted to an IRB/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 approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
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 


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responsible for providing information on financial interests during the course of the study and for 
1 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 subject or 
his/her legally authorised representative and answer all questions regarding the study.
Subjects must be informed that their participation is voluntary. Subjects or their legally authorised 
representative will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) 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 subject 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.
Subjects 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 subject or the subject’s legally authorised 
representative.
A subject who is rescreened is required to sign another ICF.
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor. Any subject records or data sets 
transferred to the sponsor will contain only the identifier; subject names or any information which 
would make the subject identifiable will not be transferred.
The subject 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 must also be explained to the 
subject.
The subject 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
Committees structure
Executive Committee
Together with AZ, the Executive Committee will be responsible for the final overall study design, 
including the development of the study protocol and eCRF, supervision of the study conduct and 
progress, development of any protocol amendments needed during the study, liaison with the CEA 
committee and DMC committee as needed, development of the statistical analysis plan, 


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interpretation of the final data and reporting (presentations at international congresses and 
publications in peer reviewed journals) of the study.
The Executive Committee will make recommendations to AstraZeneca with regards to early 
stopping or modifications of the study based on the information received from the DMC. The
Executive Committee will be comprised of designated international academic leaders and 
nonvoting members of the Sponsor, and will operate under an Executive Committee charter.
National Lead Investigator (NLI) Committee
The National Lead Investigator (NLI) Committee will be comprised of NLIs from each country 
where the study is conducted and supervised by the Executive Committee. Members of the 
committee will be responsible for providing clinical guidance on study implementation, 
recruitment and study conduct in their respective country.
Data Monitoring Committee (DMC)
An independent DMC will be appointed and will report to the Executive Committee. 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 study, and for reviewing the overall conduct of the study. 
The DMC will have access to the individual treatment codes and be able to merge these with the 
collected study data while the study is ongoing. A 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.
Clinical Event Adjudication (CEA) Committee
The role of the CEA committee is to independently review, interpret and adjudicate potential 
endpoints that are experienced by the patients. Endpoints will be identified preliminary by the 
investigators, and also by AZ personnel or in the CEA process as specified in the CEA charter. The 
CEA committee members will not have access to individual treatment codes for any patient or 
clinical efficacy endpoint and safety event. The precise responsibilities and procedures applicable 
for CEA will be detailed in the CEA charter.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are available. 
The clinical trial and/or summary of main study results may also be available on other websites 
according to the regulations of the countries in which the main study is conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
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The Investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorised site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of subjects are being protected; 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 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF 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.
A 9
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.
Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events


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An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject 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 
(e.g. 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 serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject 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 subject’s death. ‘Life-
threatening’ does not mean that had an AE occurred in a more severe form it might have caused 
death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., 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 
subject was enrolled in the study, provided that it did not deteriorate in an unexpected way during 
the study.
B 5
Important medical event or medical treatment


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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 jeopardize the subject or may require 
medical treatment to prevent one 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 (e.g. neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
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 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 7
A Guide to Interpreting the Causality Question
When assessing 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 subject 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 


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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.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

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 recognized 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 judgment. With limited or insufficient information in the case, it is likely that 
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.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an AstraZeneca investigational product 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


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
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. 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 e.g. tablet dissolved in water when it should be taken as 
a solid tablet

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature

Wrong participant received the medication (excluding IxRS errors)

Wrong drug administered to participant (excluding IxRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IxRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error

Participant accidentally missed drug dose(s) e.g.  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 standard of care 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.
Appendix C
Cardiovascular related events
C 1
Myocardial Infarctions (MI)
MIs are not endpoints in this study but unstable angina and myocardial infarction should be 
recorded as SAEs if serious criteria are met and additional information be collected in specific 
eCRF. The diagnoses of unstable angina and MI should adhere to the standardised definitions for 
endpoints (Hicks et al 2018) described in Appendix C 2


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C 2
Diagnosis of MI and Unstable Angina
Myocardial infarction (MI)
The diagnosis of an MI should be made according to standard clinical practice but is expected to 
align with the criteria from Third Universal Definition of MI, i.e. detection of a rise and/or fall of 
cardiac biomarkers such as troponin and at least one of the following: typical clinical symptoms, 
ischaemic ECG findings, imaging evidence of myocardial injury, or detection of an intracoronary 
thrombus by angiography or autopsy (Thygesen et al 2012).
The diagnosis should be made by, or in consultation with, a cardiologist. The findings supporting 
the diagnosis should be documented in the description of the SAE in the eCRF.
Unstable Angina (UA)
Unstable Angina (UA) is not an endpoint in this study but should be recorded as SAEs (and DAEs 
when appropriate). The diagnosis of an UA should be made according to standard clinical practice 
but is expected to align with the following definition:
The diagnosis of unstable angina will require ischemic chest pain (or equivalent) at rest 10 
minutes in duration considered to be myocardial ischemia upon final diagnosis and prompting 
hospitalisation within 24 hours of the most recent symptoms, and without elevation in cardiac 
biomarkers of necrosis, and the presence of objective evidence of ischemia as defined by at least 1 
of the following criteria:
1.
New or worsening ST or T wave changes in ≥2 anatomically contiguous leads on 
a resting ECG (in the absence of LVH and LBBB):
a) transient (<20 minutes) ST elevation at the J point ≥ 0.2 mV in men (> 0.25 mV in men < 40 
years old) or ≥ 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads, or
b) horizontal or down-sloping ST depression ≥ 0.10 mV, or
c) T-wave inversion ≥ 0.2 mV
2.
Definite evidence of myocardial ischemia on myocardial scintigraphy (clear reversible 
perfusion defect), stress echocardiography (reversible wall motion abnormality), or MRI 
(myocardial perfusion deficit under pharmacologic stress) that is believed to be responsible for the 
myocardial ischemic symptoms/signs.
3.
Angiographic evidence of ≥ 70% lesion and/or thrombus in an epicardial coronary artery 
that is believed to be responsible for the myocardial ischemic symptoms/signs.


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C 3
Stroke
Stroke is not an endpoint in this study but should be recorded as SAEs if serious criteria are met, 
with additional information e.g. classification of stroke type (ischaemic, haemorrhagic, or 
undetermined) collected in a specific eCRF.
The diagnosis of stroke should be made according to standard clinical practice and align with the 
definition for stroke in the standardized definitions for endpoints (Hicks et al 2018) described in 
Appendix C 4 and be differentiated vs Transient Ischaemic Attack (TIA).
C 4
Definition of Stroke and Transient Ischemic Attack
The distinction between an Ischemic Stroke and a Transient Ischemic Attack is the presence of 
infarction. Persistence of symptoms ≥24 hours or until death3 is an acceptable indicator of acute 
infarction in the absence of imaging evidence of infarction.
Transient Ischemic Attack
Transient ischemic attack (TIA) is defined as a transient episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without acute infarction.
Stroke
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal 
cord, or retinal vascular injury as a result of haemorrhage or infarction.
Classification:
A. Ischemic Stroke
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused 
by infarction of central nervous system tissue.
Haemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic 
stroke with haemorrhagic transformation and not a haemorrhagic stroke.
B. Haemorrhagic Stroke
Haemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction 
caused by non-traumatic intraparenchymal, intraventricular, or subarachnoid haemorrhage. NOTE: 
Subdural hematomas are intracranial haemorrhagic events and not strokes.
C. Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global neurological dysfunction caused by 
presumed brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction but with 
insufficient information to allow categorization as either ischemic or haemorrhagic.


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References:
Hicks KA et al. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. J Am Coll 
Cardiol 2018;71:1021–34 https://doi.org/10.1016/j.jacc.2017.12.048
Draft Definitions for CDISC August 20, 2014
Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MSV, George MG, 
Hamdan AD, Higashida RT, Hoh BL, Janis LS, Kase CS, Kleindorfer DO, Lee J-M, Moseley ME, 
Peterson ED, Turan TN, Valderrama AL, Vinters HV; on behalf of the American Heart Association 
Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Council on Cardiovascular 
Radiology and Intervention, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology 
and Prevention, Council on Peripheral Vascular Disease, and Council on Nutrition, Physical Activity 
and Metabolism. An updated definition of stroke for the 21st century: a statement for healthcare 
professionals from the American Heart Association/American Stroke
Association. Stroke. 
2013;44:2064-2089.
Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that impact 
drug absorption, distribution, metabolism, and excretion; mechanism of action of the drug; disease 
aetiology; and/or molecular subtype of the disease being treated. Therefore, where local regulations 
and IRB/IEC allow, a blood sample will be collected for DNA analysis from consenting subjects.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, treatments 
or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e. the entire 
genome.
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on heart failure with preserved ejection fraction 
continues but no longer than 15 years or other period as per local requirements.


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D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and if a 
subject decline to participate there will be no penalty or loss of benefit. The subject will not be
excluded from any aspect of the main study.
Inclusion criteria

For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and Provide informed consent 
for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2. Although DNA 
is stable, early sample collection is preferred to avoid introducing bias through excluding subjects 
who may withdraw due to an adverse event (AE), such subjects would be important to include in 
any genetic analysis. If for any reason the sample is not drawn at Visit 2, it may be taken at any 
visit until the last study visit. Only one sample should be collected per subject for genetics during 
the study. Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality. Samples will be stored for a maximum of 15 years, from the date 
of last subject last visit, after which they will be destroyed. DNA is a finite resource that is used up 
during analyses. Samples will be stored and used until no further analyses are possible or the 
maximum storage time has been reached.


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An additional second code will be assigned to the blood sample either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be identifiable 
only by the second, unique number. This number is used to identify the sample and corresponding 
data at the AstraZeneca genetics laboratories, or at the designated organisation. No personal details 
identifying the individual will be available to any person (AstraZeneca employee or designated 
organisations working with the DNA).
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or designated 
organisations. The link will be used to identify the relevant DNA samples for analysis, facilitate 
correlation of genotypic results with clinical data, allow regulatory audit, and permit tracing of 
samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate in the 
genetic component of the study the subject must sign and date both the consent form for the main 
study and the genetic component of the study. Copies of both signed and dated consent forms must 
be given to the subject and the original filed at the study centre. The Principal Investigator(s) is 
responsible for ensuring that consent is given freely and that the subject understands that they may 
freely withdrawal from the genetic aspect of the study at any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, any 
employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see both 
the genetic data and the personal identifiers of a subject. For example, in the case of a medical 
emergency, an AstraZeneca Physician or an investigator might know a subject’s identity and also 
have access to his or her genetic data. In addition, Regulatory authorities may require access to the 
relevant files, though the subject’s medical information and the genetic files would remain 
physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca and/or
designated organizations to analyse the samples.


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AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can be 
done by placing the results in scientific databases, where they can be combined with the results of 
similar studies to learn even more about health and disease. The researchers can only use this 
information for health-related research purposes. Researchers may see summary results but they 
will not be able to see individual subject data or any personal identifiers.
Some or all of the clinical datasets from the main study may be merged with the genetic data in 
a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.
Appendix E
Handling of Human Biological Samples
E 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring of 
study sites, auditing or process checks, and contractual requirements of external laboratory 
providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be registered 
by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
E 2
Withdrawal of Informed Consent for donated biological samples
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, AstraZeneca 
is not obliged to destroy the results of this research.


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As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples 
is notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
E 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was removed 
from the Dangerous Goods Regulations in the 46th edition (2005). Infectious substances are now 
classified either as Category A, Category B or Exempt. There is no direct relationship between 
Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever virus:

Are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens


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
Clinical trial samples will fall into Category B or exempt under IATA 
regulations

Clinical trial samples will routinely be packed and transported at ambient

Temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.ht m)

Biological samples transported in dry ice require additional dangerous 
goods specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are subject to local regulations 
which require that they are also packed and transported in a safe and appropriate 
way to contain any risk of infection or contamination by using approved couriers 
and packaging/containment materials at all times. The IATA 650 biological 
sample containment standards are encouraged wherever possible when road or 
rail transport is used.
Appendix F
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law (not applicable)
Appendix G
Medical device incidents: definition and procedures for recording, 
evaluating, follow-up, and reporting (not applicable)


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Appendix H
Abbreviations
Abbreviation or
Explanation
special term
AE
Adverse Event
BP
Blood Pressure
CEA
Clinical Event Adjudication
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
              Coronavirus Disease 2019
CSA
Clinical study Agreement
CV
Cardiovascular
DAE
Adverse Event leading to discontinuation of investigational product
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EDC
Electronic Data Capture
EHRs
Electronic Health Records
FAS
Full Analysis Set
GCP
Good Clinical Practice
HF
Heart Failure
HFpEF
Heart Failure with Preserved Ejection Fraction
HR
Hazard Ratio
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
International
If a study is conducted in several countries the International Co-ordinating
Co-ordinating
Investigator is the Investigator co-ordinating the Investigators and/or
Investigator
activities internationally.
IxRS
Interactive Voice/Web Response System
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAE
Left Atrial Enlargement
LSLV
Last Subject Last Visit
LVEF
Left Ventricular Ejection Fraction
MI
Myocardial Infarction


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NYHA
New York Heart Association
PACD
Primary Analysis Censoring Date
PTDV
Premature Treatment Discontinuation Visit
PI
Principal Investigator
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCV
Study Closure Visit
SoA
Schedule of Activities
T2D
Type 2 Diabetes Mellitus
Appendix I   New York Heart Association (NYHA) Functional Classification
Class
Patient symptoms
I
No limitation of physical activity.  Ordinary physical activity does
not cause undue fatigue, palpitation, dyspnoea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary
physical activity results in fatigue, palpitation, dyspnea (shortness of
breath).
III
Marked limitation of physical activity. Comfortable at rest. Less
than ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort.
Symptoms of heart failure at rest. If any physical activity is
undertaken, discomfort increases.
Appendix J
The KC Cardiomyopathy Questionnaire
The KC Cardiomyopathy Questionnaire
The following questions refer to your heart failure and how it may affect your life. Please read and 
complete the following questions. There are no right or wrong answers. Please mark the answer that 
best applies to you.
1. Heart failure affects different people in different ways. Some feel shortness of breath while
others feel fatigue. Please indicate how much you are limited by heart failure (shortness of 
breath or fatigue) in your ability to do the following activities over the past 2 weeks.
Place an X in one box on each line
Not at
Limited for
Extremely Quite a bit
Moderately  Slightly
other reasons
Activity
all
Limited
Limited
Limited
Limited
or did not do
Limited
the activity


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Dressing yourself
❏
❏
❏
❏
❏
❏
Showering/Bathing
❏
❏
❏
❏
❏
❏
Walking 1 block
❏
❏
❏
❏
❏
❏
on level ground
Doing yardwork,
❏
❏
❏
❏
❏
❏
housework or
carrying groceries
Climbing a flight
❏
❏
❏
❏
❏
❏
of stairs without
stopping
Hurrying or
❏
❏
❏
❏
❏
❏
jogging (as if to
catch a bus)
2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, 
fatigue, or ankle swelling) changed?
My symptoms of heart failure have become…
Much
Slightly
Not
Slightly
Much
I’ve had no symptoms
worse
worse
changed
better
better
over the last 2 weeks
❏
❏
❏
❏
❏
❏
3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when 
you woke up in the morning?
3 or more times
Less than once a Never over the
Every morning
a week, but not
1-2 times a week week
past 2 weeks
every day
❏
❏
❏
❏
❏
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
bothersome
swelling


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❏
❏
❏
❏
❏
❏
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what 
you want?
All of the
Several
At least
3 or more times 1-2 times Less than
Never over
time
times per
once a
per week but 
not
per week once a
the past 2
❏
day
day
every day
❏
week
weeks
❏
❏
❏
❏
❏
6. Over the past 2 weeks, how much has your fatigue bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
bothersome
fatigue
❏
❏
❏
❏
❏
❏
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your 
ability to do what you wanted?
All 
of 
the
time
Several 
times 
per 
day
At 
least 
once 
a 
day
3 or 
more 
times 
per week 
but not 
everyday
1 – 2 
times 
per 
week
Less 
than 
once 
a 
week
Never 
over 
the 
past 2 
weeks
❏
❏
❏
❏
❏
         ❏
❏
8. Over the past 2 weeks, how much has your shortness of breath bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
bothersome
shortness of breath
❏
❏
❏
❏
❏
❏


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9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in 
a chair or with at least 3 pillows to prop you up because of shortness of breath?
Every
3 or more times per
1-2 times a
Less than
Never over the
night
week, but not every day week
once a week
past 2 weeks
❏
❏
❏
❏
❏
10. Heart failure symptoms can worsen for a number of reasons. How sure are you that you
know what to do, or whom to call, if your heart failure gets worse?
Not at
Not very
Somewhat
Mostly
Completely
all sure
sure
sure
sure
❏
sure
❏
❏
❏
❏
11. How well do you understand what things you are able to do to keep your heart failure
symptoms from getting worse? (for example, weighing yourself, eating a low salt diet etc.)
Do not
Do not understand
Somewhat
Mostly understand Completely
understand at all
very well
understand
❏
understand
❏
❏
❏
❏
12. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life?
It has extremely
It has limited my
It has 
moderately
It has slightly
It has not
limited my
limited my
enjoyment of life
limited my
limited my
enjoyment of 
life
enjoyment of life
quite a bit
enjoyment of life enjoyment of life
at all
❏
❏
❏
❏
❏
13. If you had to spend the rest of your life with your heart failure the way it is right now, how 
would you feel about this?


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Not at all
Mostly
Somewhat
Mostly
Completely 
satisfied
satisfied
dissatisfied
satisfied
satisfied
❏
❏
❏
❏
❏
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of 
your heart failure?
I felt that way all
I felt that way most  I occasionally I rarely felt that I never felt that
of the time
of the time
felt that way
way
way
❏
❏
❏
❏
❏
15. How much does your heart failure affect your lifestyle? Please indicate how your heart 
failure may have limited your participation in the following activities over the past 2 weeks. 
Please place an X in one box on each line
Does not
Severely
Limited
Moderately Slightly
Did not
apply or
Activity
limit at
did not do
limited
quite a bit limited
limited
all
for other
reasons
Hobbies,
Recreational                ❏
❏
❏
❏
❏
❏
activities
Working or
doing
❏
❏
❏
❏
❏
❏
household
chores
Visiting
family
❏
❏
❏
❏
❏
❏
or friends out
of your home
Intimate
relationships
❏
❏
❏
❏
❏
❏
with loved
ones
Copyright © 1992 –2005 John Spertus, MD, MPH
Original US English


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Appendix K
EQ-5D-5L Questionnaire
Health Questionnaire
Under each heading, please check the ONE box that best describes your health TODAY
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

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



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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



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
We would like to know how good or bad your health is
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box below.


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USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
YOUR HEALTH TODAY = 


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Appendix L
Patient Global Impression of Severity for Heart Failure 
Symptoms
Patient Global Impression of Severity for Heart Failure Symptoms
Overall, how would you rate the severity of your heart failure symptoms today?
No symptoms
Very mild
Mild
Moderate
Severe
Very Severe


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d169cc00001-csp-v4
Document Title:
D169CC00001 Clinical Study Protocol version 4
Document ID:
Doc ID-003827083
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Nov-2020 13:23 UTC
Content Approval
16-Nov-2020 16:15 UTC
Content Approval
13-Nov-2020 07:36 UTC
Content Approval
16-Nov-2020 08:56 UTC
Content Approval
13-Nov-2020 08:29 UTC
Qualified Person Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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Statistical Analysis Plan
Study Code
D169CC00001
Edition Number
5.0
Date
8 December 2021
An International, Double-blind, Randomised, Placebo-Controlled 
Phase III Study to Evaluate the Effect of Dapagliflozin on 
Reducing CV Death or Worsening Heart Failure in Patients with 
Heart Failure with Preserved Ejection Fraction (HFpEF)
DELIVER - Dapagliflozin Evaluation to Improve the LIVEs of 
Patients with PReserved Ejection Fraction Heart Failure


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An International, Double-blind, Randomised, Placebo-Controlled 
Phase III Study to Evaluate the Effect of Dapagliflozin on 
Reducing CV Death or Worsening Heart Failure in Patients with 
Heart Failure with Preserved Ejection Fraction (HFpEF)
DELIVER - Dapagliflozin Evaluation to improve the LIVEs of 
patients with pReserved ejection fraction heart failure
Study Statistician
Date
PPD


Statistical Analysis Plan 
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An International, Double-blind, Randomised, Placebo-Controlled 
Phase III Study to Evaluate the Effect of Dapagliflozin on 
Reducing CV Death or Worsening Heart Failure in Patients with 
Heart Failure with Preserved Ejection Fraction (HFpEF)
DELIVER - Dapagliflozin Evaluation to improve the LIVEs of 
patients with pReserved ejection fraction heart failure
Global Product Statistician
Date
PPD


Statistical Analysis Plan 
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TABLE OF CONTENTS
TABLE OF CONTENTS...................................................................................................... 4
AMENDMENT HISTORY................................................................................................... 8
1
STUDY DETAILS ........................................................................................... 16
1.1
Study Objectives............................................................................................... 16
1.1.1
Primary Objective............................................................................................. 16
1.1.2
Secondary Objectives........................................................................................ 16
1.1.3
Safety Objectives.............................................................................................. 16
1.1.4
Exploratory Objectives ..................................................................................... 17
1.2
Definitions........................................................................................................ 17
1.2.1
Primary Analysis Censoring Date ..................................................................... 17
1.2.2
Withdrawal of Consent ..................................................................................... 18
1.2.3
Discontinuation of Investigational Product........................................................ 18
1.2.4
Vital Status....................................................................................................... 18
1.2.5
Lost to Follow-up ............................................................................................. 18
1.3
Study Design .................................................................................................... 18
1.3.1
Randomisation.................................................................................................. 19
1.4
Number of Subjects .......................................................................................... 20
2
ANALYSIS SETS ............................................................................................ 22
2.1
Definition of Analysis Sets ............................................................................... 22
2.1.1
Full Analysis Set............................................................................................... 22
2.1.2
Safety Analysis Set........................................................................................... 22
2.2
Violations and Deviations................................................................................. 22
3
PRIMARY AND SECONDARY VARIABLES ............................................... 23
3.1
Primary Variable............................................................................................... 23
3.2
Secondary Variables ......................................................................................... 24
3.2.1
Total Number of Heart Failure Events (First and Recurrent) and 
Cardiovascular Death........................................................................................ 24
3.2.2
Change from Baseline at 8 Months in the KCCQ Total Symptom Score ........... 24
3.2.3
Cardiovascular Death........................................................................................ 25
3.2.4
Death from Any Cause...................................................................................... 25
3.3
Safety Variables................................................................................................ 25
3.4
Laboratory Values and Vital Signs.................................................................... 26
3.4.1
Baseline Laboratory Values and Vital Signs...................................................... 26
4
ANALYSIS METHODS................................................................................... 26
4.1
General Principles............................................................................................. 26
4.1.1
Estimand for Primary and Secondary Outcomes................................................ 27
4.1.2
Hypotheses ....................................................................................................... 27
4.1.3
Confirmatory Testing Procedure....................................................................... 28
4.1.4
Presentation of Time-to-Event Analyses ........................................................... 30
4.1.5
Vital Status and Follow-up of Endpoints........................................................... 31


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4.2
Analysis Methods ............................................................................................. 31
4.2.1
Demographics and Baseline Characteristics ...................................................... 31
4.2.2
Concomitant and Baseline Medication.............................................................. 32
4.2.3
Analysis of the Primary Efficacy Variables....................................................... 32
4.2.4
Analysis of the Secondary Efficacy Variables................................................... 35
4.2.5
Analysis of Safety Variables............................................................................. 41
4.2.6
Analysis of Exploratory Objectives................................................................... 43
5
INTERIM ANALYSES.................................................................................... 44
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 45
7
REFERENCES................................................................................................. 46
Appendix A Estimation of Clinically Meaningful Thresholds for KCCQ Total Symptom 
Score ................................................................................................................ 49
Appendix B Programming Code for Calculating Significance Level for LVEF <60% 
Subpopulation................................................................................................... 57
LIST OF TABLES
Table 1
Level of α1 Depending on Proportion of Events in LVEF < 60% 
Subpopulation.......................................................................................... 29
Table 2
Characteristics and Categories for Subgroup Analysis of the Primary 
Endpoint.................................................................................................. 33
Table A1
Categories of Change from Baseline PGIS in Heart Failure Symptoms at 
8 Months ................................................................................................. 50
Table A2
Distribution of Change from Baseline KCCQ-TSS at 8 months by 
Change from Baseline PGIS 8 Months..................................................... 52
Table A3
Distribution-Based Cut-offs for a Minimal Clinically Important 
Difference in the KCCQ-TSS .................................................................. 56
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 19
Figure A1
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 Months versus Change from Baseline PGIS at 8 Months 
with 7 Categories..................................................................................... 53
Figure A2
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 Months Versus Change from Baseline PGIS at 8 
Months with 5 Categories (Collapsing “Moderate” and “Large”) ............. 54
Figure A3
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 months Versus Change from Baseline PGIS at 8 
Months with 5 Categories (Collapsing “Small” and “Moderate”)............. 55


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
AE
Adverse event
ATC
Anatomical therapeutic chemical
BP
Blood pressure
CDF
Cumulative distribution function
CEA
Clinical event adjudication
CKD-EPI
Chronic kidney disease epidemiology collaboration equation
CMH
Cochran-Mantel-Haenszel test
CMWPC
Clinically meaningful within-patient change
COVID-19
Corona Virus Disease 2019
CSP
Clinical study protocol
CV
Cardiovascular
DAE
Adverse events leading to discontinuation of investigational product
DBP
Diastolic blood pressure
DKA
Diabetic ketoacidosis
DMC 
Data monitoring committee 
eCDF
Empirical cumulative distribution function
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
FAS
Full analysis set
HbA1c
Haemoglobin A1c
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction
HR
Hazard ratio
IP
Investigational product (dapagliflozin or matching placebo)
ITT
Intention to treat
IxRS
Interactive Voice/Web Response System
KCCQ
Kansas City Cardiomyopathy Questionnaire
KM
Kaplan-Meier
LTFU
Lost to follow-up
LVEF
Left ventricular ejection fraction
MCID
Minimal clinically important difference
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed Model Repeated Measures


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Abbreviation or special 
term
Explanation
MTP
Multiple testing procedure
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association
PACD
Primary analysis censoring date
PGIS
Patient global impression of severity
PRAC
European Medicines Agency’s Pharmacovigilance Risk Assessment Committee
PT
MedDRA preferred term
PTDV
Premature treatment discontinuation visit 
QoL
Quality of life
SAE
Serious adverse event
SAS
Safety analysis set
SBP
Systolic blood pressure
SCV
Study closure visit
SD
Standard deviation
SEM
Standard error of measurement
SGLT2
Sodium-glucose co-transporter 2
SOC
MedDRA system organ class
T2D
Type 2 diabetes
TSS
Total symptom score 
WHO
World Health Organization
WoC
Withdrawal of consent
WR
Win ratio


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AMENDMENT HISTORY
Date
Brief description of change
Version 1
27 August 2018
Version 1.0 signed


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Version 2
6 November 2020
[1.1 Study objectives]
Updated primary objective with dual primary analyses: 
Primary analysis to be analysed in full study population and subpopulation with LVEF 
< 60%
Updated secondary objectives: 
First secondary to be analysed in full study population and subpopulation with LVEF 
< 60%. Adding urgent HF visits to total number of HF events (first and recurrent) and 
CV death. 
Moved NYHA class from secondary objective to exploratory.
Added CV death as secondary objective.
Updated exploratory objectives:
Added NYHA class objective from secondary objective and removed PGIS objective.
Rewording of EQ-5D-5L objective and endpoint.
[1.2.1 Primary analysis censoring date]
Increased target number of primary endpoint events from 844 to 1117.
[1.3 Study design]
Updated definition of subacute patients, increasing hospitalisation from within 21 days 
to within 30 days.
Increased number of randomised patients from 4700 to 6100 and number of enrolled 
patients from 8000 to 11000.
Updated target number of primary endpoint events from 844 to 1117.
Updated anticipated total study duration from 33 months to 39 months.
[1.4 Number of subjects]
Updated power, study duration, number of events and proportion of subacute.
[2.1.1 Full analysis set]
Updated with subpopulation information: “A subset of the full analysis set consisting 
of patients with baseline LVEF of < 60% (or LVEF < 60% subpopulation) will be 
analysed separately as part of the confirmatory statistical testing procedure.”
[3.2 Secondary variables]
Updated with dual primary endpoints. 
Updated with new definition of total number of events, including urgent HF visits.
Added Figure 2 with updated multiple testing procedure with dual primary analyses.
[3.2.1 Total number of (first and recurrent) hospitalisations for HF and CV death]
Updated with definition of total number of events.
Updated with information regarding prioritisation, which event to be counted in 
recurrent event analysis, if HF event and CV death occur at same day.
[3.2.2 Change from baseline at 8 months in the KCCQ total symptom score]
Added definition regarding ranking.
[Previous 3.2.3 Proportion of patients with worsened NYHA class at 8 months]
Removed entire paragraph.
[3.2.3 Cardiovascular death]
Added paragraph with secondary objective concerning CV death.
[3.3 Safety variables]


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Date
Brief description of change
Added adjudication of potential DKA events.
Added major hypoglycaemic events to list of safety variables.
[4.1.1 Estimand for primary and secondary outcomes]
Added estimand for KCCQ TSS.
[4.1.2 Hypotheses]
Added dual primary hypotheses.
[4.1.3 Confirmatory testing procedure]
Updated with handling of alpha for split primary analyses.
Added Figure 2.
[4.2.3.2 Sensitivity analysis of the primary endpoint]
Updated with information that sensitivity analyses related to impact of COVID-19 will 
be added at next SAP update prior to interim analysis.
[4.2.4.1 Analysis of recurrent HF events and CV death]
Updated definition of HF events, including urgent HF visits.
Added handling on priority of events occurring on the same day.
[4.2.4.2 Analysis of change from baseline to 8 months in the KCCQ total symptom 
score]
Added information on how to handle analysis under COVID-19 pandemic.
Added information on ranking. 
Added information on handling of missing response for reasons other than death.
Estimation of treatment effect updated.
Added update on handling of ceiling and floor effects.
Information on imputation updated.
Updated information on TSS responder analyses.
[4.2.4.3 NYHA]
Section removed and moved to 4.2.6 Analysis of exploratory objectives.
[4.2.4.3 CV death]
Section on analysis of CV death added.
[4.2.5.4 Amputations and preceding events]
Section renamed to “Specific adverse events” and paragraphs on DKA, major 
hypoglycaemic events and genital infections added.
[4.2.6 Analysis of exploratory objectives]
Section on NYHA added (moved from previous Section 4.2.4.3).
Section on PGIS removed.
[5 Interim analysis]
Removed futility analysis.
[Reference]
Added references: FDA guidance during COVID-19 2020 and Spiessen and Debois 
2010
Removed references: Kawaguchi and Koch 2015 and Neal et al 2017


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Version 3.0
9 December 2020
[4.2.4.2 Analysis of change from baseline to 8 months in the KCCQ total symptom 
score]
Added information on responder analysis:
“Additional responder analysis will be performed in the same way as for 5 points 
improvement and deterioration described above, using the thresholds of clinically 
meaningful within-patient change from baseline TSS derived from anchor-based 
analyses of blinded study data as described in Appendix A, with “ceiling” and “floor” 
values handled consistently.”
[Reference]
Added reference: Coon and Cook 2018.
[Appendix]
Added Appendix A describing how to estimate clinically meaningful thresholds for 
KCCQ total symptom score, using PGIS. 


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Version 4.0
20 May 2021
Minor edits done throughout entire document. 
[1.2.1 Primary analysis censoring date]
Updated to be consistent with CSP, that SCV should be performed within 6 weeks 
after PACD, which can be extended if decided by Global Study Team. 
Added that patients will stop taking IP at the SCV.
[1.4 Number of subjects]
Added information that final allocation of alpha and full testing procedure can be 
found in section 4.1.3. Added text that the power considerations stated in this section 
are examples for the dual primary analysis.
[3.2.1 Total number of HF events (first and recurrent) and CV death]
Removed: “Recurrent HF events (hospitalisation for HF or urgent HF visit), CV death 
and censoring processes all have continuous distributions so that HF events and death 
cannot happen at the same time.”
Updated for clarification: “For patients who did not have a HF event or CV death, and 
following last event in patients with one or more HF events, censoring will follow the 
same rule as for the primary endpoint.“
[3.2.3 Cardiovascular death]
Added “or died after WoC” for specification on patients to be censored.
[3.2.4 Death from any cause]
Added “or with unknown vital status” for specification on patients to be censored.
[3.3 Safety variables]
Updated list of safety variables, adding myocardial infarction, unstable angina, stroke, 
major hypoglycaemic events, potential diabetic ketoacidosis and amputations.
Updated for clarification: “These events will be recorded as AEs or if they fulfil 
seriousness criteria as SAEs in the database, but SAEs will not be reported to health 
authorities to avoid unnecessary unblinding.”
[4.1 General principles]
Added for clarification: “If the number of tablets dispensed or the number of 
tablets returned is missing for at least one observation, compliance is not 
calculated for that patient.” and
“IP compliance will be presented descriptively, including mean, SD, median, quartiles 
and 5% and 95% percentiles for safety analysis set by treatment group.”
[4.1.1 Estimand for primary and secondary outcomes]
Sentence removed: “The time-to-first-event analysis by Cox proportional hazards 
regression and the analysis of recurrent events (Section 4.2.4) assume that missing 
data is at random.”
[4.1.2 Hypotheses]
Removed reference to Haybittle-Peto function as that method will not to be used.
Updated alpha level for final analysis and added/removed details for clarification: 
“With alpha 0.2% allocated to one planned interim analysis including 67% of the 
target number of primary endpoints, the significance level in the final analysis will be 
4.8%, to be split between the dual hypothesis.”
[4.1.3 Confirmatory testing procedure]
Section updated with details on significance levels. 
Added table: “Table 1 Level of α1 depending on proportion of events in LVEF < 60% 
subpopulation”.
Updated for clarity: “If the study is stopped at the efficacy interim analysis (Section 
5), testing of remaining secondary endpoints will be performed in the full study 


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population only, in fixed sequence at two-sided alpha of 0.2% in the order described 
in the right branch of Figure 2.”
[4.1.5 Vital status and follow-up of endpoints]
Added for clarification: “The denominator, representing maximum complete follow-
up, will be the time from randomisation until the earliest of first primary endpoint 
event, death or PACD.”
[4.2.2 Concomitant and baseline medication]
Added for clarification: “The proportion of patients taking baseline and concomitant 
medication will be presented for the FAS per ATC class and treatment group.”
[4.2.3.1 Subgroup analysis of the primary endpoint]
Added for clarification: “A test of interaction between randomised treatment group 
and the subgroup variable will be performed using Cox proportional hazard model 
stratified by T2D status at randomisation with factors for treatment group, the 
subgroup variable and the interaction between treatment and subgroup.”
Added: “Hazard ratio estimates, confidence intervals and p-values are not presented 
for subgroups with less than 15 events in total, both arms combined.”
Table 1 renamed to Table 2
Table 2: Updated subgroups for LVEF at enrollment to ≤ 49%, 50% to 59%, ≥ 60%
[4.2.3.2 Sensitivity analysis of the primary endpoint]
Added information that further sensitivity analyses will be added at a later update: 
“We will monitor the blinded study data to assess the impact of COVID-19 on the 
study and will add supportive and sensitivity analyses related to the impact of 
COVID-19 on both primary and secondary endpoints in a SAP update prior to clinical 
data lock. Also, additional covariates might be added to analyses, if deemed 
necessary based on blinded data.”
[4.2.4.1 Analysis of total number of HF events (first and recurrent) and CV death]
Added for consistency: “The composite outcome of total number of HF events (first 
and recurrent) and CV death with onset on or prior to PACD, adjudicated and 
confirmed by the CEA committee,”
Sentence removed: “Recurrent HF events, CV death and censoring processes all have 
continuous distributions so that a HF event and death cannot happen at the same 
time.”
[4.2.4.2 Analysis of change from baseline at 8 months in the KCCQ total symptom 
score]
Added for clarification: “In the ranking, patients who die prior to the first follow-up 
visit where KCCQ-KSS is assessed, at 1 month, will be defined as having a zero 
change from baseline while alive.”
Added cut-off date to define population to be used in primary KCCQ-TSS analysis: 
“As a consequence, the main analysis of this endpoint will be done in the population 
with patients who had a planned visit 5 (8 months) prior to the major COVID-19 
outbreak, defined as 11th March 2020 (the date when WHO declared COVID-19 a 
pandemic) thus unaffected by the pandemic’s possible impact on health-related 
quality of life”
Removed: “The section regarding these analyses and exact date for data cut-off will be 
updated prior to the interim analysis.”
Added that formal inference will be based on Win ratio method.
Section on responder analysis updated.
Section on handling of missing KCCQ data updated, including numbers from anchor-


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Brief description of change
based analyses.
Clarifications made in section on “Handling of missing KCCQ data”.
[4.2.4.3 Analysis of CV death]
Clarifications that CV deaths are confirmed in adjudication and how censoring is 
handled.
[4.2.4.4 Analysis of all-cause mortality]
Clarification that analysis includes deaths from any cause.
[4.2.5 Analysis of safety variables]
Updated that summaries of AEs will be presented both for the on-treatment period and 
on- and off-treatment period.
[4.2.5.1 Adverse events]
Updated list of safety variables, adding myocardial infarction, unstable angina, stroke, 
major hypoglycaemic events, potential DKA and amputations.
[4.2.5.4 Specific adverse events]
Added: “AEs leading to amputations” to list.
Added that event rate will be presented for AEs leading to amputations and preceding 
events, DKA and major hypoglycaemic events, as well as definition of event rate 
calculation.
Added for clarification: “Events of genital area infections and necrotising fasciitis 
potential of Fournier’s gangrene”.
[4.2.5.5 Laboratory evaluation and vital signs]
Removed PTDV and SCV from list of visits and added range to descriptive statistics.
[4.2.6 Analysis of exploratory objectives]
Added: “Only NYHA assessments made at site or through phone visits with the 
patients to be used in analyses.”
Added clarification on exploratory KCCQ analyses.
[5 Interim Analyses]
Removed reference to Haybittle-Peto function as that method will not to be used.
[6 Changes of Analysis from Protocol]
Added: “The alpha for final analysis adjusted for interim analysis at alpha 0.2% 
will be set to 5% minus 0.2% = 4.8%, rather than 4.98% as determined by the 
Haybittle-Peto function for 67% of events (sections 9.1 and 9.5 of the protocol).”
[References]
Added reference: Burman et al 2009.
[Appendix A]
Earlier Appendix A renamed A1 Methods. 
[Appendix A2]
Added appendix including summary of results of anchor-based analysis on blinded 
study data.
[Appendix B]
Added appendix with R code for calculation of significance level. 


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Date
Brief description of change
Version 5.0
08 December 2021
Formatting updated throughout entire document.
[3.3 Safety Variables]
Minor clarifications added
[4.1.3 Confirmatory Testing Procedure]
Sentence added:
“For the calculation of α1, the correlation will be based on the square root of the 
lower bound of a two-sided 95% confidence interval for the proportion of events 
in the subpopulation with LVEF◦<◦60%, using a normal approximation 
confidence interval for the proportion.”
Table 1 updated presenting number of events in LVEF < 60% subpopulation and full 
population instead of presenting proportion of events in the subpopulation. Confidence 
intervals added and numbers for α1 in the different scenarios updated.
Last bullet in the list clarified.
[4.1.5 Vital Status and Follow-up of Endpoints]
Clarified that non-CV death includes undetermined.
[4.2.3.1 Subgroup Analysis of the Primary Endpoint]
Updated that subgroup analysis will be done both for full population and LVEF < 60% 
subpopulation.
[4.2.3.2 Sensitivity Analysis of the Primary Endpoint]
Added description of a sensitivity analysis where patients with premature censoring 
have imputed time to event information and more detailed information about the 
planned tipping point analysis.
Added sensitivity analysis where patients and events are censored at the onset date of 
AE associated with COVID-19 infection.
[4.2.4.1 Analysis of Total Number of HF Events (First and Recurrent) and CV Death]
Added sensitivity analysis where patients and events are censored at the onset date of 
AE associated with COVID-19 infection.
[4.2.4.2 Analysis of Change from Baseline at 8 Months in the KCCQ Total Symptom 
Score]
Added that both planned and performed 8 month assessments are to be included in 
COVID-19 supplementary analysis for KCCQ TSS.
[4.2.4.3 Analysis of CV Death]
Added sensitivity analysis where patients and events are censored at the onset date of 
AE associated with COVID-19 infection.
[4.2.5.1 Adverse Events]
Clarification that on-treatment period will be used for primary analysis of all safety 
variables, except for amputations and preceding events. 
Added that MedDRA 24.1 will be used.
Information previously in section “4.2.5.4 Specific adverse events” added to this 
section.
[4.2.5.4 Specific Adverse Events]
Text moved to be included in Section 4.2.5.1 and section removed.
[4.2.6 Analysis of Explorative Objectives]
Updated that KCCQ QoL will be reported descriptively only.
[Appendix B]
Updated to include R and SAS code.


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1
STUDY DETAILS
1.1
Study Objectives
1.1.1
Primary Objective
Primary objective
Endpoint/variable
To determine whether dapagliflozin is superior to 
placebo, when added to standard of care, in reducing 
the composite of CV death and HF events 
(hospitalisation for HF or urgent HF visit) in patients 
with HF and preserved systolic function, in 

full study population

subpopulation with LVEF < 60%
Time to the first occurrence of any of the 
components of this composite:
1.
CV death
2.
Hospitalisation for HF
3.
Urgent HF visit (eg, emergency 
department or outpatient visit)
1.1.2
Secondary Objectives
Secondary objective
Endpoint/variable
To determine whether dapagliflozin is superior to 
placebo in reducing the total number of recurrent HF 
events (hospitalisations for HF or urgent HF visit) and 
CV death, in

full study population

subpopulation with LVEF < 60%
Total number of HF events (first and recurrent) and 
CV death
To determine whether dapagliflozin is superior to 
placebo in improving Patient Reported Outcomes 
measured by KCCQ
Change from baseline in the TSS of the KCCQ at 
8 months
To determine whether dapagliflozin is superior to 
placebo in reducing CV death
Time to the occurrence of CV death
To determine whether dapagliflozin is superior to 
placebo in reducing all-cause mortality
Time to the occurrence of death from any cause
1.1.3
Safety Objectives
Safety Objective
Outcome Measure 
To evaluate the safety and tolerability of dapagliflozin 
compared to placebo in patients with HFpEF

SAEs

DAEs

Amputations, AEs leading to amputation 
and potential risk factor AEs for 
amputations affecting lower limbs


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1.1.4
Exploratory Objectives
Exploratory Objective
Endpoint/Variable
To determine whether dapagliflozin is superior to 
placebo in reducing all-cause hospitalisation
Time to the first occurrence of hospitalisation from 
any cause
To determine whether dapagliflozin is superior to 
placebo in reducing the proportion of patients with 
worsened NYHA class
Proportion of patients with worsened NYHA class 
from baseline to 8 months
To describe health status assessed by EQ-5D-5L to 
support health economic analysis and health 
technology assessment
Results will be reported separately in a health 
economic report
To determine whether dapagliflozin compared with 
placebo will have an effect on SBP
Change in SBP from baseline 
To determine whether dapagliflozin compared with 
placebo will have an effect on body weight
Change in body weight from baseline 
To determine whether dapagliflozin compared with 
placebo will have an effect on eGFR
Change in eGFR from baseline
To explore whether dapagliflozin compared to placebo 
improves KCCQ summary scores, sub-scores of TSS 
(symptom frequency and symptom burden) and 
domains 
Change in Clinical summary score, TSS sub-scores, 
Overall summary score, QoL score
To collect and store blood samples for future 
exploratory genetic research
Not applicable. Results will be reported
separately
1.2
Definitions
1.2.1
Primary Analysis Censoring Date
The executive committee and AstraZeneca will monitor the accrual of endpoint events and 
when appropriate define the PACD at which time at least the pre-defined target number of 
1117 events for the primary composite endpoint is expected to have occurred. The study sites 
will be instructed to plan for SCV to be performed within 6 weeks after PACD, which can be 
extended if decided by the Global Study Team. Patients will stop taking IP at the SCV.
Analyses of efficacy endpoint events will include events with onset on or prior to PACD. 
Event free patients who have not been prematurely censored due to incomplete information 
(see Section 3.1) will be censored at PACD. HF events and deaths with onset after PACD will 
also be adjudicated.


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1.2.2
Withdrawal of Consent
Withdrawal of consent should only occur if the patient has received appropriate information 
about options for modified study follow-up and does not agree to any kind of further 
assessment or follow-up. Information regarding vital status (dead or alive) at the end of the 
study will be collected from public sources, to be included in the analysis of death from any 
cause as a sole outcome and in patient disposition summaries. 
1.2.3
Discontinuation of Investigational Product
Discontinuation of IP does not mean discontinuation from study follow-up or WoC. Patients 
who discontinue from IP should continue study visits according to plan until study closure. If 
the patient does not agree to this approach, modified follow-up capturing the essential 
information for the objectives of the study should be arranged. Data will be included in the 
ITT analyses irrespective of whether the event occurred before or following discontinuation of 
IP. 
1.2.4
Vital Status
Known vital status at the end of the study will be defined when the patient is dead or has date 
last know alive on or after the PACD.
For patients who have withdrawn consent, the investigator will attempt to collect vital status 
from publicly available sources at study closure in compliance with local privacy 
laws/practices.
1.2.5
Lost to Follow-up
The term 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 completeness of follow-up 
of the primary endpoint (Section 4.1.5).
1.3
Study Design
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind, 
placebo-controlled study in patients with HFpEF, evaluating the effect of dapagliflozin 10 mg 
versus placebo, given once daily in addition to background regional standard of care therapy, 
including treatments to control co-morbidities, in reducing the composite of CV death or HF 
events.
HFpEF is defined for the purposes of this study as LVEF > 40% and evidence of structural 
heart disease. Adult patients with HFpEF, aged ≥ 40 years and with NYHA class II to IV will 
be randomised in a 1:1 ratio to receive either dapagliflozin 10 mg or placebo once daily. A 
proportion of patients, here denoted as the subacute group, will be randomised during 
hospitalisation for HF or within 30 days of discharge from hospitalisation for HF.




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The number of randomised patients with T2D will be monitored in order to ensure a minimum 
of 30% patients in each group of patients with and without T2D. Randomisation may be 
capped (ie, no more patients can be randomised in a specific sub-population) if the pre-
determined limit is reached.
Randomisation of patients based on geographic region will be monitored to ensure global 
representation. LVEF value, NYHA class, subacute/non-subacute group, and atrial fibrillation 
status at Visit 1 may be capped in IxRS to avoid over- or under-representation of these patient 
subgroups.
1.4
Number of Subjects
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo added to standard of care in reducing the composite of CV death and HF events 
(hospitalisation for HF or urgent HF visit). Two hypotheses will be tested simultaneously (ie, 
dual primary analyses) for this primary objective: (1) in the full population and (2) in an 
LVEF < 60% subpopulation, with alpha allocated to each test. 
Originally, assuming a true HR of 0.80 between dapagliflozin and placebo, using a two-sided 
alpha of 5%, 844 primary endpoint events were targeted in order to provide a statistical power 
of 90% for the test of the primary composite endpoint. 
To allow testing for the dual primary analyses, alpha will be allocated to each test to ensure 
strong control of the overall type I error rate. The target number of patients with a primary 
endpoint has been increased to 1117 in order to provide adequate statistical power for each 
test. The power to reject the dual primary hypotheses depends on how alpha is allocated 
between the two hypotheses and the proportion of primary events in the LVEF < 60% 
subpopulation. It is anticipated that at least 70% of the primary endpoint events (ie, 
approximately 780 events) will be available for the LVEF < 60% subpopulation. The final 
allocation of alpha and full testing procedure is specified in Section 4.1.3 and the alpha levels 
used in the following text are just examples used to illustrate the power considerations for the 
dual primary analysis. For illustration, testing the effect on the primary endpoint in the LVEF 
< 60% subpopulation, a true HR of 0.80 and approximately 1117 primary endpoint events in 
the full population (at least 780 events in the subpopulation) would then provide at least:

80% power for a two-sided nominal alpha of 2.4%

85% power for a two-sided nominal alpha of 3.7%
For testing the effect on the primary endpoint in the full study population, a true HR of 0.80 
and approximately 1117 primary endpoint events would also provide:

90% power for a two-sided nominal alpha of 1.5%


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
93% power for a two-sided nominal alpha of 2.4%.
This is based on an overall 1:1 allocation between dapagliflozin and placebo.
The HR 0.80 was originally chosen as a conservative assumption based on the observed 
HR 0.72 (95% confidence interval 0.50-1.04) for the composite of HF hospitalisation and CV 
death in patients with HF at baseline in the EMPA-REG OUTCOME trial (Fitchett et al 2016) 
and HR 0.61 (0.46-0.80) for patients with history of HF in the CANVAS program (Rådholm 
et al 2018) considering that these were post-hoc analyses in subgroups with limited 
documentation of baseline HF diagnosis, not characterised by ejection fraction. 
The event rate assumptions are based on sub analyses of the TOPCAT and I-PRESERVE 
studies by geographic region, NT-proBNP levels, prior hospitalisation for HF, and T2D status 
(Pfeffer et al 2015, Kristensen et al 2015, Kristensen et al 2017). The sample size calculation 
builds on the assumption of an annual event rate of 9% in the placebo group for the majority 
of prevalent HFpEF patients, importantly all with NT-proBNP ≥ 300 pg/ml by inclusion 
criterion. Additionally, a subgroup of patients due to be discharged or recently discharged 
from a HF hospitalisation (here denoted ‘subacute’ patients) with a higher event rate is 
planned to be included. Assuming 20% of patients from the subacute category with an annual 
event rate of 24% during the first year and 9% thereafter for the remainder of the study, the 
original sample size of 4700 was estimated to provide 844 events during a recruitment period 
of 18 months and a minimum follow-up of 15 months. 
Based on the ongoing blinded monitoring of event accrual (including the percentage of 
patients from the subacute category), the sample size was increased from original 4700 to 
approximately 6100 randomised patients. Accordingly, the recruitment period was anticipated 
to increase from the original 18 months to 26 months. Recruitment might be marginally 
prolonged in a few countries to meet local targets. The study is event driven and the number 
of patients or duration may further change.
With the same event rate assumptions as above, assuming 11% of patients from the subacute 
category, approximately 6100 patients were estimated to provide the required number of 
1117 patients with a primary event in the full study population, during an anticipated 
recruitment period of 26 months and a minimum follow-up period of 13.5 months (total study 
duration 39 months).  
In addition, the expected number of patients who will be LTFU is expected to be small; hence, 
these are not considered in the determination of the sample size.


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2
ANALYSIS SETS
2.1
Definition of Analysis Sets
2.1.1
Full Analysis Set
All patients who have been randomised to IP will be included in the 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 ITT analysis of primary and 
secondary variables and for the exploratory efficacy variables. A subset of the FAS consisting 
of patients with baseline LVEF of < 60% (or LVEF < 60% subpopulation) will be analysed 
separately as part of the confirmatory statistical testing procedure (see CSP Section 4.2 for 
justification of testing LVEF < 60% subpopulation).
2.1.2
Safety Analysis Set
All randomised patients who received at least 1 dose of randomised treatment will be included 
in the SAS. Patients will be analysed according to the treatment actually received. For any 
patients given incorrect treatment, ie, 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.
The SAS will be considered the primary analysis set for all safety variables.
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 criteria, or met exclusion 
criteria

Patients who received the wrong IP at any time during the study.

Patients who received prohibited concomitant medication, which for this study is limited 
to open label SGLT2 inhibitors taken in combination with IP.
As the primary analysis is ITT analysis, protocol deviation will not imply exclusion from the 
primary analysis.


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3
PRIMARY AND SECONDARY VARIABLES
Deaths and potential HF events will be adjudicated by an independent CEA committee. The 
CEA committee members will not have access to the treatment codes for any patient. The 
CEA procedures and event definitions will be described in the CEA charter according to the 
CDISC definitions (Hicks et al 2018).
Only HF hospitalisations and urgent HF visits confirmed by the CEA will be used in the 
analysis of the primary and secondary endpoints and their components. 
The primary analyses of the endpoints concerning CV deaths, either as a component of a 
composite or on its own, will include deaths adjudicated as CV cause. Deaths adjudicated as 
“cause undetermined” will be considered as non-CV deaths in these analyses. 
Adjudicated events occurring from randomisation until WoC or PACD will be included in the 
analysis of primary and secondary endpoints. The analysis of all-cause death as a sole 
outcome will in addition include any deaths (not adjudicated) after WoC, but on or before 
PACD.
3.1
Primary Variable
The primary efficacy variable is time from randomisation to the first occurrence of any event 
in the composite of CV death, hospitalisation for HF or an urgent HF visit.
Patients who did not have an adjudicated primary endpoint event on or prior to PACD will be 
censored at the earliest of date of WoC or non-CV death when applicable, and otherwise at the 
date of the last clinical event assessment or the PACD, whichever occurs first. It is expected 
that patients alive and under study follow-up will have a clinical event assessment at their 
SCV after PACD. Last clinical event assessment is defined as the last date when the event 
assessment question for a potential HF event was completed on the eCRF event assessment 
page. 
In analysis of the individual components hospitalisation for HF and urgent HF visit, to 
examine their contribution to the composite endpoint, date of death from any cause will be an 
additional point of censoring.
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).


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3.2
Secondary Variables
The secondary endpoints are included in hierarchical testing sequences following the dual 
primary analysis as described in Section 4.1.3 and depicted in Figure 2.
3.2.1
Total Number of Heart Failure Events (First and Recurrent) and 
Cardiovascular Death
The efficacy variable is the total number of first and recurrent HF events (hospitalisations for 
HF or urgent HF visits) and CV death.
For the analysis of first and recurrent HF events and CV death, the data will be expressed in 
counting process style for input to the analysis as described in Section 4.2.4.1, as follows. The 
time from randomisation to end of follow-up/censoring will be split into one or more interval 
with variables for start of interval, end of interval and a variable indicating if an event 
occurred at the end of each respective interval, or if the patient was censored. If a HF event 
and CV death occurred at the same day, then only the CV death will be counted.
For patients who did not have a HF event or CV death, and following last event in patients 
with one or more HF events, censoring will follow the same rule as for the primary endpoint.
3.2.2
Change from Baseline at 8 Months in the KCCQ Total Symptom Score
The efficacy variable is the change from baseline at 8 months of the KCCQ-TSS. 
The KCCQ is a self-administered disease specific instrument for patients with HF (Green et al 
2000, Spertus et al 2005). The KCCQ consists of 23 items measuring HF-related symptoms, 
physical limitations, social limitations, self-efficacy, and health-related quality of life. The 
TSS incorporates the symptom burden and symptom frequency domains into a single score. 
Scores are transformed to a range of 0 to 100. Higher scores represent better outcomes.
Baseline is defined as the value at randomisation visit (Visit 2). Change from baseline at each 
post-baseline analysis time point will be calculated as the value at the corresponding post-
baseline analysis time point minus the baseline value. The KCCQ is assessed by the patient at 
randomisation, at the visits targeted 1, 4 and 8 months following randomisation and at PTDV 
and SCV. By the ITT principle, the analysis will include all data irrespective of whether the 
patient has discontinued IP.
In order to account for patients who die prior to the 8-month assessment and to accommodate 
non-normal distribution of KCCQ scores, a composite rank-based endpoint will be used. The 
values of change from baseline at 8 months in TSS of patients who survive to 8 months will 
be converted to ranks (across both treatment groups combined) with lower ranks attributed to 
worse outcomes (ie, lower ranks corresponding to negative or smaller values of change from 


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baseline). Patients who die prior to the 8-month assessment will be assigned the worst rank, ie, 
worse than any patient surviving to 8 months, but among the deceased the relative ranking 
will be based on their last value of change from baseline in TSS while alive.
3.2.3
Cardiovascular Death
The efficacy variable is time from randomisation to CV death, confirmed in adjudication. All 
CV deaths on or prior to PACD will be included. Patients who are alive or died after WoC 
will be censored at the earliest of date of WoC, last known alive and PACD. Patients who die 
of any other cause are censored at their date of death.
3.2.4
Death from Any Cause
The efficacy variable is time from randomisation to death from any cause. All deaths on or 
prior to PACD, including any deaths after WoC, will be included. Patients who are alive or 
with unknown vital status will be censored at the earliest of date last known alive and PACD.
3.3
Safety Variables
The safety and tolerability of dapagliflozin in patients with HFpEF will be evaluated from 
SAEs, DAEs, amputations, AEs leading to amputation and AEs reflecting potential risk 
factors for lower limb amputations (“preceding events”).
In addition to amputation, non-serious and serious events potentially placing the patient at risk 
for a lower limb amputation, in this document denoted “preceding events”, should also be 
recorded in the eCRF as AE/SAE, whether or not an amputation has taken place. Preceding 
events will be defined for analysis by a predefined list of PRAC PTs. Additional information 
about amputations with underlying conditions and preceding events will be collected on 
dedicated eCRF pages.
SAEs will be collected from time of informed consent until and including the patient’s last 
visit. Non-serious AEs will be collected from randomisation until and including the patient’s 
last visit. Collection of non-serious AEs includes cardiac ischaemic events (myocardial 
infarction and unstable angina), stroke, major hypoglycaemic events, potential 
DKA, amputations, AE leading to amputation, and preceding events, AEs leading to a 
potential endpoint, DAEs and AEs which are the reason for interruption of IP.
Efficacy endpoints (deaths and potential HF events) will be adjudicated. These events will be 
recorded as AEs or, if they fulfil seriousness criteria, as SAEs in the database, but SAEs will 
not be reported to health authorities to avoid unnecessary unblinding. However, if it is 
determined by the CEA committee that a potential endpoint does not meet the endpoint 
criteria, the event will be reported to AstraZeneca patient safety data entry site and if 
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For SAEs or DAEs reported by the Investigator as potential DKA, additional information will 
be recorded on specific eCRF pages in addition to the AE/SAE form. All potential DKA 
events will be adjudicated by an independent committee and adjudicated outcomes will be 
considered the main analysis for DKA events.
For myocardial infarctions, unstable angina, stroke, major hypoglycaemic events and 
amputations, additional information will be recorded on specific eCRF pages in addition to the 
AE/SAE form.
3.4
Laboratory Values and Vital Signs
Blood samples will be taken for central laboratory assessment of creatinine and calculation of 
eGFR at enrolment visit, at the visits targeted 1, 4, and 12 months following randomisation, 
then annually and at PTDV and SCV. eGFR will be calculated (in mL/min/1.73 m2) using the 
CKD-EPI formula (Levey at al 2009). 
Central laboratory assessment of NT-proBNP and HbA1c will be taken at Visit 1.
Systolic blood pressure, DBP, and pulse rate will be measured at Visit 1, Visit 2, at 1 and 
12 months visit, then annually and at PTDV and SCV.
Weight will be measured at Visit 1, at the 12 months visit, then annually and at PTDV and 
SCV.
3.4.1
Baseline Laboratory Values and Vital Signs
In principle, baseline will be defined as the last value on or prior to date of first dose of 
randomised IP, or for patients who did not receive treatment, the last value on or prior to date 
of randomisation. Except for cases of rescreening this will be Visit 1 measurement of weight, 
NT-proBNP, eGFR and HbA1c, and Visit 2 measurement of SBP, DBP, and pulse rate.
4
ANALYSIS METHODS
4.1
General Principles
No multiplicity adjustment will be made to confidence intervals 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.
Primary and secondary analyses of HF events and death include adjudicated events occurring 
on or prior to PACD.  
Stratification of analyses for T2D status will be performed using the stratification values as 
entered in IxRS to determine the randomisation assignment. 


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Incomplete dates
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 eg, dates will not be imputed as 
prior to randomisation, after death or start date after end date.
IP compliance
The percentage of IP compliance for the overall treatment period will be derived for each 
patient based on pill counts as the number of pills taken (dispensed – returned), relative to the 
expected number of pills taken. The expected number of pills taken is defined as 
1 × (date of last dose – date of first dose + 1), excluding days of interruption. If the number of 
tablets dispensed or the number of tablets returned is missing for at least 1 observation, 
compliance is not calculated for that patient. 
IP compliance will be presented descriptively, including mean, SD, median, quartiles and 5% 
and 95% percentiles for SAS by treatment group.
4.1.1
Estimand for Primary and Secondary Outcomes
The primary and secondary event-based objectives will be evaluated under the treatment 
policy estimand including differences in outcomes over the entire study period until PACD to 
reflect the effect of the initially assigned randomised IP, irrespective of exposure to IP, 
concomitant treatment as well as subsequent treatment after discontinuation of IP. The 
analysis will be performed for the FAS including all events that occurred on or prior to PACD, 
including events following premature discontinuation of IP. 
The estimand for the change from baseline in KCCQ-TSS at 8 months will employ a 
combination of a treatment policy strategy and a composite strategy. For the intercurrent event 
of death (due to any cause) prior to the KCCQ assessment at 8 months, a composite strategy 
will be used, where death will be considered unfavorable and represented by a lowest (worst) 
rank of a combined outcome variable as described in Section 3.2.2. For all other types of 
intercurrent events, including but not limited to a premature discontinuation of randomised 
treatment, a treatment policy strategy will be used. 
4.1.2
Hypotheses
The primary endpoint will be tested twice, simultaneously: (1) in the full study population, 
and (2) in the LVEF < 60% subpopulation.
To control the overall type I error rate at 5% two-sided, the significance level will be adjusted 
for interim analysis of efficacy performed by the DMC (Section 5). With alpha 0.2% allocated 
to one planned interim analysis, the significance level in the final analysis will be 4.8%, to be 


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split between the dual hypotheses. The following null hypothesis will be tested for both the 
dual analyses of the primary endpoint
H0: HR [dapagliflozin:placebo] = 1
versus the alternative hypothesis
H1: HR [dapagliflozin:placebo] ≠ 1
The secondary endpoints included in confirmatory statistical testing using a closed testing 
procedure (Section 4.1.3) will be based on similar two-sided alternative hypotheses for the 
respective treatment difference.
4.1.3
Confirmatory Testing Procedure
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilised, with recycling of alpha following the framework of 
Burman et al 2009. The Type I error will be controlled at an overall two-sided 5% level across 
primary and secondary endpoints and in consideration of the planned interim analysis. Two-
sided nominal p-values will be reported for each hypothesis. Statistical significance for a 
given hypothesis will be declared if the point estimate is in favour of the dapagliflozin arm, in 
addition to the two-sided p-value meeting the corresponding p-value threshold. 
At the final analysis, statistical significance will be assessed in two branches in the pre-
specified order of the endpoints and populations as specified in Figure 2. The total 
significance level, alpha, will be split for the two primary analyses of the primary endpoint, 
allocating α1 to test the subpopulation and α2 to test the full population. 
For derivation of the two-sided nominal p-value thresholds α1 and α2, in the first step of the 
MTP, a two-sided alpha of 0.2% will be allocated to the interim analysis and 4.8% to the final 
analysis. The significance level α2 (for the primary analysis in the full population at the final 
analysis) will be fixed at 2.4% two-sided. The inherent correlation structure between the full 
population and the LVEF < 60% subpopulation, where the corresponding test statistics for the 
primary endpoint are bivariate normal with correlation equal to the proportion of events in the 
LVEF < 60% subpopulation, will be taken into account when calculating α1 (Spiessen and 
Debois 2010). For the calculation of α1, the correlation will be based on the square root of the 
lower bound of a two-sided 95% confidence interval for the proportion of events in the 
subpopulation with LVEF < 60%, using a normal approximation confidence interval for the 
proportion. The threshold α1 will be such that for α2 = 2.4% two-sided; the two-sided 
probability of rejecting at least one true null hypothesis at the final analysis will be 4.8%. It 
then follows that if the primary endpoint in the full population at interim analysis is assessed 
versus a two-sided p-value of 0.2%, the two-sided probability of rejecting at least one true 
primary null hypothesis at any analysis can be no larger than 5%. Table 2 shows how the two-


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sided nominal p-value threshold α1 depends on the proportion of events in the LVEF < 60% 
subpopulation at the final analysis. R and SAS code for calculating α1 is provided in 
Appendix B.
Table 2
Level of α1 Depending on Proportion of Events in LVEF < 60% 
Subpopulation
Patients 
with event 
(LVEF 
< 60% / 
overall)
Proportion
(95% CI)
Correlation
= sqrt of 
lower 
confidence 
limit
Two-sided alpha (%) for primary endpoint 
Interim analysis
Full population 
Final analysis (α2)
Full population 
Final analysis (α1)
Subpopulation 
LVEF < 60%
780/1117
0.698 
(0.671, 0.725)
0.819
0.2
2.4
3.647
790/1117
0.707
(0.681, 0.734)
0.825 
0.2
2.4
3.674
800/1117
0.716
(0.690, 0.743)
0.831 
0.2
2.4
3.701
810/1117
0.725 
(0.699, 0.751)
0.836
0.2
2.4
3.730
820/1117
   0.734 
(0.708, 0.760)
0.842 
0.2
2.4
3.758
830/1117
0.743 
(0.717, 0.769)
0.847 
0.2
2.4
3.788
CI, Confidence interval; LVEF, left ventricular ejection fraction; sqrt square root.

If both the primary null hypotheses can be rejected, the following hypotheses in each 
branch will be tested at 2.4%, in the order described in Figure 2. 

The following will apply if only one of the tests of the primary endpoint can be rejected at 
respective levels 2.4% (in the full population) and α(in the LVEF < 60% subpopulation):
the remaining hypotheses in the branch where the primary hypothesis was rejected will be 
tested in fixed sequence at the following two-sided significance levels

4.8% – 2.4% = 2.4% in the left branch only (in case the primary endpoint in the 
subpopulation was significant at level αbut not in the full population at level 2.4%)

4.8% – αin the right branch only (in case the primary endpoint in the full 
population was significant at level 2.4% but not in the subpopulation at level α)

If all hypotheses in one branch are rejected, alpha will be recycled to the other branch, 
where remaining unrejected hypotheses can be tested at full alpha adjusted for interim 
analysis (ie, 4.8%) in the order described in Figure 2.

If the first secondary hypothesis (recurrent HF events and CV death) in full study 
population is rejected in one of the branches, it does not have to be re-tested in the other 
branch. If the primary hypothesis is rejected in both branches and the first secondary 


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hypothesis (recurrent events) is rejected in the LVEF < 60% subpopulation, then the first 
secondary hypothesis in full population can be tested at full alpha adjusted for interim 
analysis (4.8%).
If the study is stopped at the efficacy interim analysis (Section 5), testing of remaining 
secondary endpoints will be performed in the full study population only, in fixed sequence at 
two-sided alpha of 0.2% in the order described in the right branch of Figure 2.
Figure 2
Testing Procedure
CV, cardiovascular; HF, heart failure; KCCQ, Kansas city cardiomyopathy questionnaire; LVEF, left ventricular 
ejection fraction; TSS, total symptom score
4.1.4
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, event rate, HR with 95% confidence interval and p-
value. The event rate will be derived as the number of patients with event divided by the total 
duration of follow-up across all patients in the given group.
Kaplan-Meier 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.


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4.1.5
Vital Status and Follow-up of Endpoints
Potential HF endpoints and deaths will be collected and adjudicated 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 has date 
last know alive on or after the PACD. In patient disposition the number of patients who are 
dead, alive or with unknown vital status will be reported separately for patients who did/did 
not withdraw consent. The term LTFU will be limited to only patients with unknown vital 
status.
Follow-up of the primary endpoint will be defined in terms of completion of the event 
assessment question for a potential HF event as described for censoring in Section 3.1. Thus, a 
patient that is not LTFU, ie, with known vital status, may have incomplete follow-up of 
endpoints.
Complete follow up of the primary endpoint will be defined when the patient had a primary 
endpoint event, died from non-CV death (including undetermined death) or had complete 
event assessment on or after the PACD (ie, the patient was not censored due to incomplete 
follow-up of endpoints).
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, death, WoC, censoring where last complete event 
assessment is prior to PACD or PACD. The denominator, representing maximum complete 
follow-up, will be the time from randomisation until the earliest of first primary endpoint 
event, death or PACD.
4.2
Analysis Methods
4.2.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics, including medical history, will be summarized, 
using frequency distributions and summary statistics based on the FAS, 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. 


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4.2.2
Concomitant and Baseline Medication
Baseline medication is defined as medication with at least one dose taken before date of 
randomisation and with no stop date before date of randomisation. 
Concomitant medication is defined as medications taken post randomisation, irrespective of 
IP.
The proportion of patients taking baseline and concomitant medication will be presented for 
the FAS per ATC class and treatment group. Summaries of prohibited medication, in this 
study limited to open label SGLT2 inhibitor taken while on IP, will be presented.
4.2.3
Analysis of the Primary Efficacy Variables
Dual primary analyses will be performed simultaneously for the primary composite endpoint, 
(1) in the full population based on the FAS as well as (2) in the LVEF < 60% subpopulation. 
The same procedure described below will be used for both of these analyses.
The primary variable is the time to first event included in the primary composite endpoint.  
The primary analysis will be based on the ITT principle using the FAS, including events with 
onset on or prior to PACD, adjudicated and confirmed by the CEA 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 T2D status at randomisation. The analysis will use WoC, non-CV death, last 
clinical event assessment and PACD for censoring of patients without any primary event as 
described in Section 3.1. The Efron method for ties and p-value based on the Wald statistic 
will be used. Event rates, p-value, HR, and 95% confidence interval will be reported.  
The contribution of each component of the primary 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 individual events in the 
component analysis will be larger than the number of patients with a composite outcome. 
Methods similar to those described for the primary analysis will be used to separately analyse 
the time from randomisation to the first occurrence of each component of the primary 
composite endpoint. 
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.
4.2.3.1
Subgroup Analysis of the Primary Endpoint
Exploratory subgroup analyses of the primary composite endpoint will be performed for the 
characteristics listed in Table 3 for both full population and LVEF < 60% subpopulation. A 


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test of interaction between randomised treatment group and the subgroup variable will be 
performed using Cox proportional hazard model stratified by T2D status at randomisation 
with factors for treatment group, the subgroup variable and the interaction between treatment 
and subgroup. In addition to the number and percent of patients with event, event rate 
estimate, HR with 95% confidence interval and p-value for each subgroup, the interaction p-
value will be presented. Hazard ratio estimates, confidence intervals and p-values are not 
presented for subgroups with less than 15 events in total, both arms combined. HRs with 
confidence interval will be presented in a forest plot, including number of patients with event 
and interaction p-value. The p-values for the subgroup analyses and interaction will not be 
adjusted for multiple comparisons as the tests are exploratory and will be interpreted 
descriptively.  
Table 3
Characteristics and Categories for Subgroup Analysis of the Primary 
Endpoint
Characteristic
Categories
Age at enrolment (years)
≤ median, > median
Sex
Male, Female
Race
White, Black or African American, Asian, Other
Geographic region
Asia (China, Japan, Taiwan, Vietnam)
Europe and Saudi Arabia (Belgium, Bulgaria, 
Czech Republic, France, Hungary, Netherlands,
Poland, Romania, Russia, Saudi Arabia, Spain)
North America (Canada, US)
Latin America (Argentina, Brazil, Mexico, Peru)
NYHA class at enrolment
II, III/IV
LVEF at enrollment (%)
≤ 49, 50 to 59, ≥ 60
NT-proBNP at enrollment (pg/mL)
≤ median, > median
Randomised during hospitalisation for HF or within 
30 days of discharge.
Yes, No
eGFR at enrolment (mL/min/1.73m2 ) 
< 60, ≥ 60
BMI at enrolment (kg/m2) 
< 30, ≥ 30
T2D at enrolment a
Yes, No
SBP at randomisation
≤ median, > median
Atrial fibrillation or flutter at enrolment ECG
Yes, No
a
The subgroup analysis by T2D status will be based on eCRF medical history record and exclude T2D as a 
stratification factor from the model 
BMI, body mass index; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HF, heart failure; 
LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New 
York Heart Association; SBP, systolic blood pressure; T2D, type 2 diabetes


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The subgroup analyses will be repeated for CV death and the HF event (hospitalisation for HF 
and urgent HF visit) component of the primary composite endpoint.
4.2.3.2
Sensitivity Analysis of the Primary Endpoint
Undetermined cause of death
A sensitivity analysis of the primary analysis where deaths adjudicated as ‘undetermined’ 
cause are considered as CV deaths and included as endpoint 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 will be described 
eg, in terms of the number of patients and patient time with incomplete follow-up as described 
in Section 4.1.5.
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 effect of incomplete follow up of the primary endpoint, a sensitivity analysis 
may be performed where time to event information is imputed for patients with premature 
censoring (censored before PACD due to WoC or incomplete primary event assessment). 
Event rates will be estimated separately in the two T2DM strata by an exponential distribution 
with constant hazard rate over time. Using the hazard ratio from the primary analysis, the 
event rates will be calculated for the dapagliflozin group, separately for the T2DM strata (by 
multiplying the corresponding placebo group rates by the hazard ratio estimated in the primary 
analysis). Using the estimated event rates, new event times will be simulated for patients with 
premature censoring from the exponential distribution. If the simulated time is in the interval 
from the censoring date to PACD (or death date, whichever came first), a new event will be 
imputed at the resulting event time. Otherwise, if the simulated time is outside the interval 
from the original censoring to PACD or death, the patient will be considered censored at 
PACD or death. The primary analysis will thereafter be conducted again, supplemented by the 
simulated time-to-event information. The process is to be repeated 1000 times and the 
resulting hazard ratios and standard errors will be combined using the Rubin’s rule.
A tipping point analysis may be conducted to assess the robustness of the statistical 
significance of the primary analysis. While keeping the placebo event rates constant at the
estimated values, the event rates in the dapagliflozin group will gradually be increased by 
increasing the hazard ratio from the primary analysis until the test of the primary endpoint no 
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COVID-19
Subjects affected by COVID-19 infection will be defined by pre-specified preferred terms for 
adverse events associated with COVID-19 infection. A COVID-19 sensitivity analysis of the 
primary endpoint (and components) will be performed where the main analysis of the primary 
endpoint will be done, where patients and events are censored at the onset date of AE 
associated with COVID-19 infection. In this setting, onset of COVID-19 can be assumed to be 
unrelated to randomised treatment and as such should not introduce informative censoring 
while accounting for impact of COVID-19 infection in the main analysis.
4.2.4
Analysis of the Secondary Efficacy Variables
4.2.4.1
Analysis of Total Number of HF Events (First and Recurrent) and CV Death
The composite outcome of total number of HF events (first and recurrent) and CV death with 
onset on or prior to PACD, adjudicated and confirmed by the CEA committee, will be 
analysed by the semi-parametric proportional rates model (Lin et al 2000; known as the 
LWYY 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. If a HF event and CV death 
occurred at the same day, then only CV death will be counted.
In addition, the two components in the composite endpoint (total number of HF events and 
CV death) will be analysed separately to quantify the respective treatment effects and check 
the consistency between the composite and the components. For the analysis of total number 
of HF events 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 
events (dilution of effect size if the drug has a positive effect on both components). To address 
this concern and to account for the correlation between the two components, the joint 
modelling (frailty model) approach (Rogers et al 2016) will be used for the component 
analyses. Non-parametric estimates of HF event rates over time allowing for death as terminal 
event will be provided as well (Ghosh and Lin 2000).
COVID-19
A COVID-19 sensitivity analysis of the first secondary endpoint (and components) will be 
performed where the main analysis LWYY will be applied and where patients and events are 
censored at the onset date of AE associated with COVID-19 infection. In this setting, onset of 
COVID-19 can be assumed to be unrelated to randomised treatment and as such should not 
introduce informative censoring while accounting for impact of COVID-19 infection in the 
main analysis.


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4.2.4.2
Analysis of Change from Baseline at 8 Months in the KCCQ Total Symptom 
Score
Hypothesis testing
The composite rank-based endpoint representing the patients’ vital status at 8 months and the 
change from baseline at 8 months in KCCQ-TSS in surviving patients, as defined in Section 
3.2.2, will be analysed using the rank ANCOVA method (Stokes et al 2012) to test the null 
hypothesis of no difference in the distributions of ranked outcomes between the two treatment 
groups. Analysis will be stratified by T2D status at randomisation, and adjusted for the 
baseline KCCQ-TSS value as follows. 
First the change from baseline at 8 months in KCCQ-TSS and vital status at 8 months, as well 
as values of the baseline KCCQ-TSS covariate will be transformed to standardised ranks 
within each T2D randomisation stratum, using fractional ranks and mean method for ties. 
Ranking for the composite endpoint will be done so that patients who died prior to the 8-
month assessment are assigned the worst ranks within each stratum. Among the deceased, the 
relative ranking will be based on their last value of change from baseline in KCCQ-TSS while 
alive before deriving fractional ranks. In the ranking, patients who die prior to the first follow-
up visit where KCCQ-TSS is assessed, at 1 month, will be defined as having a zero change 
from baseline while alive. Then, separate regression models will be fit to the ranked data for 
each randomisation stratum using a regression model for the ranked composite variable as 
dependent variable, adjusting for the ranked baseline covariate. Residuals from this regression 
model will be captured for testing of differences between treatment groups. The CMH test, 
stratified by T2D status at randomisation, using the values of the residuals as scores will be 
used to compare treatment groups. 
KCCQ data missing for reasons other than death will be imputed as described in Section 
“Handling of missing KCCQ data”.
The p-value from the CMH test of treatment effect at 8 months will be the used for the 
confirmatory testing of the secondary endpoint in the MTP described in Section 4.1.3.
COVID-19
Due to COVID-19 pandemic, on-site assessments could not be performed in a substantial 
number of sites, where some were done remotely and some cancelled. Furthermore, it could 
be assumed that lock-downs and other measures could impact PRO assessments. As a 
consequence, the main analysis of this endpoint includes the population with patients who had 
a planned or performed 8 month assessment (Visit 5) prior to the major COVID-19 outbreak, 
defined as 11th March 2020 (the date when WHO declared COVID-19 a pandemic) thus 
unaffected by the pandemic’s possible impact on health-related quality of life (FDA 2020). 
The KCCQ-TSS in the presence of COVID-19 pandemic will be described. 


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Estimation of treatment effect
Win ratio
For a summary statistic that uses the same ranking as that used in the hypothesis test, but has a 
clinical interpretation, the WR and the corresponding 95% confidence interval (Wang and 
Pocock 2016) will be reported. It is noted that the WR differs from the statistic used for 
hypothesis testing, so that exact consistency is not expected between these two analyses, eg on 
rare occasions, the 95% confidence interval for WR could exclude unity while the p-value for 
the pre-planned hypothesis test could be > 0.05, or the hypothesis test could be < 0.05 with the 
confidence interval for WR including unity. Formal inference for the superiority of the 
treatment over control will be made only from the pre-planned hypothesis test based on the 
WR.
The win ratio represents the odds of having a more favourable outcome versus a less 
favourable outcome when assigned to the dapagliflozin 10 mg treatment group as opposed to 
placebo. More specifically, each patient in the dapagliflozin group is compared with each 
patient in the placebo group and each pair is labelled as “winner”, “loser”, or “tie”, depending 
on whether the patient on dapagliflozin has a more favourable, less favourable, or the same 
outcome, respectively, with respect to the composite ranked endpoint compared to the patient 
on placebo. Win ratio is defined as the ratio of the number of “winner” pairs to the number of 
“loser” pairs for the dapagliflozin arm. If the estimated win ratio is greater than 1 then the 
treatment effect is in favour of dapagliflozin.
The win ratio statistic adjusted for the randomisation stratification factor and baseline KCCQ-
TSS will be obtained using the methodology in (Koch et al 1998, Kawaguchi et al 2011) for 
the stratified Mann-Whitney estimators for the comparison of two treatments with 
randomisation based covariance adjustment. The win ratio statistic will be calculated as 
Mann-Whitney odds, ie, WR = MW ⁄ (1 – MW), where MW is the adjusted Mann-Whitney 
estimate. This transformation is monotonous in the domain of the Mann-Whitney estimate. 
The 95% confidence interval for the win ratio will be obtained  by transforming the bounds of 
the confidence interval (Koch et al 1998) for the Mann-Whitney estimate, using the same 
transformation as for the win ratio.
Responder analysis
Number and percentage of patients in each treatment group will be summarised across the 
following categories, where change from baseline is defined as KCCQ-TSS at 8 months minus 
KCCQ-TSS at baseline:   
Thirteen point improvement from baseline at 8 months in KCCQ-TSS, identified as a 
clinically meaningful improvement in anchor-based analyses (see Appendix A), vs no 
clinically meaningful improvement:


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
Change from baseline in KCCQ-TSS ≥ 13 points, vs

Death prior to the 8 months assessment or change from baseline in KCCQ-TSS < 13 
points. 
Five point deterioration from baseline at 8 months in KCCQ-TSS, identified as a clinically 
meaningful deterioration in anchor-based analyses (see Appendix A), vs no clinically 
meaningful deterioration:

Death prior to the 8 months assessment or a negative change from baseline in KCCQ-TSS 
≥ 5 points, vs

Change from baseline at 8 months in KCCQ-TSS that is positive or, if negative, is smaller 
than 5 points.
Patients who had a baseline value of KCCQ-TSS ≥ 100 – 13 = 87 points (ie, too close to the 
“ceiling” to have a clinically meaningful improvement based on the instrument), will be 
defined as having achieved “responder status” for improvement only if the following 
conditions are both met: KCCQ-TSS remains ≥ 87 points at 8 months and KCCQ-TSS 
≥baseline at 8 months (ie, they had no deterioration from their baseline score). Similarly, for 
clinically meaningful deterioration, patients who had a baseline value of KCCQ-TSS ≤ 5 
points (ie, too close to the “floor” to have a clinically meaningful deterioration based on the 
instrument), will be defined as having achieved “responder status” for deterioration only if 
KCCQ-TSS remains ≤ 5 points at 8 months and KCCQ-TSS ≤ baseline at 8 months (ie, they 
had no improvement from their baseline score).
The proportion of patients in the different KCCQ-TSS responder categories will be compared 
between treatment groups using a logistic regression model including treatment group, 
stratification variable (T2D at randomisation) and baseline KCCQ-TSS value. The observed 
number and proportion of KCCQ-TSS responders, odds ratio between treatment groups, its 
corresponding 2-sided 95% confidence interval and p-value estimated from each imputed 
dataset will be combined using Rubin’s rule, and the combined results will be presented.
Additional responder analysis will be performed in the same way as described above, for 
17 points improvement (“large improvement”) and 14 points deterioration (“large 
deterioration”). These thresholds of clinically meaningful change from baseline KCCQ-TSS 
were derived from anchor-based analyses of blinded study data as described in Appendix A. 
In these analyses, “ceiling” and “floor” values are handled in an analogous way as for the 
analysis of 13 points improvement and 5 points deterioration.
Empirical cumulative distribution function plots will be presented by treatment group to 
summarize the distribution of change from baseline at 8 months in KCCQ-TSS values, where 
patients who die prior to the 8-month assessment will be represented with the value of 
-101 (a value below the worst possible change from baseline).


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Handling of missing KCCQ data
The number of patients with missing vital status at 8 months is expected to be negligible. If 
some patients are LTFU or withdrew consent and have unknown vital status, the main analysis 
will be done with these patients assigned the worst ranks (same as deaths, described below).
In the context of analysing the composite ranked endpoint as described above, missing data 
may arise when patients miss the 8-month KCCQ assessment while remaining in the study 
during the 8-month assessment window (+/- 14 days will be used), or when patients withdraw 
consent from the study prior to 8 months. If a patient is known to have died prior to the 8-
month assessment, the patient is considered to have a non-missing composite outcome and 
will be handled as described above (assigned the worst rank). Otherwise, patients who are 
alive at 8 months and have missing baseline or 8-month KCCQ assessments will have their 
missing KCCQ-TSS imputed using the multiple imputation methodology as follows.
Missing KCCQ-TSS values at baseline or at 8 months will be imputed under the Missing at 
Random assumption. The imputation will be done using a predictive mean matching multiple 
imputation model and a method of Fully Conditional Specification as implemented in the SAS 
Procedure MI (FCS statement). The predictive mean matching method ensures that the 
imputed values remain in the permissible range of the KCCQ-TSS values. Imputation will be 
done sequentially, ie, imputing each time point in their chronological order and the 
imputations at a given time point will be informed by preceding imputed time points. The 
imputation model will include the treatment group, T2D randomisation stratum, prior KCCQ-
TSS (at baseline, month 1 and month 4), and three categorical variables representing the 
number of HF events (categorised as 0, 1 or ≥ 2) in the intervals from randomisation to 1 
month, from 1 to 4 months, and from 4 to 8 months, respectively, depending on the time point 
being imputed. Occurrences of HF events will be determined based on the investigator-
reported potential HF events. Auxiliary variables related to HF events are included in the 
imputation model to improve the imputation accuracy, because the occurrence of HF events is 
expected to be associated with HF symptoms as assessed by KCCQ-TSS.
The number of closest observations used to sample an imputed value by the predictive mean 
matching method will be 5 (SAS default setting).
Each imputed dataset will be analysed using the methods described in the “Hypothesis 
testing” and “Estimation of treatment effect” sub-sections above. The results from multiple 
imputed datasets will be combined using Rubin’s rule as implemented in the SAS Procedure 
MIANALYZE.

In the analysis of rank ANCOVA, the CMH tests statistic used for the hypothesis test has 
a chi-square distribution. In order to apply Rubin’s combination rule, which assumes 
approximate normal distribution of the statistics being combined, a normalising Wilson-


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Hilferty transformation will be applied to the CMH test statistics from each imputed 
dataset (Ratitch et al 2013). The standardized transformed statistic will be computed as 
follows:
_	

(
) =
ℎ(
)


−1 −
2
9 × 

2
9 × 

where ℎ(
)is the CMH statistic from the mth imputed dataset and  is the number of 
degrees of freedom associated with the statistic (in this case equal 1). The transformed 
statistics are approximately normally distributed with mean of 0 and variance of 1 and can 
be combined using Rubin’s rule.

For the estimation of the win ratio, a combined Mann-Whitney estimate and its standard 
error will first be obtained by applying Rubin’s rule to the corresponding estimates from 
multiple imputed datasets. Then the win ratio and its 95% confidence interval will be 
obtained based on the combined Mann-Whitney estimate and its standard error as 
previously described. 

For the summaries of number and percentage of subjects in the categories of significant 
improvement and deterioration from baseline, the number and percent of subjects with 
actual observed improvement and observed deterioration/death respectively will be 
reported. The estimation of odds ratio and confidence intervals for the KCCQ-TSS 
responder analyses will use the imputation datasets created for the main analysis. 
Therefore, deaths will be defined as non-responders, and responder status will be 
determined based on the imputed KCCQ-TSS values for the patients who have missing 
KCCQ-TSS due to reasons other than death.
Supportive analyses and sensitivity analyses for KCCQ
The number and percent of patients who die prior to the 8-month assessment will be 
summarized by treatment group.
Descriptive statistics of scores and change from baseline at 1, 4 and 8 months will be 
presented for TSS, overall summary score, clinical summary score and domains (physical 
limitation, symptom stability, symptom frequency, symptom burden, quality of life, self-
efficacy and social limitation). 
The testing and estimation described for change from baseline at 8 months in KCCQ-TSS, 
will be repeated in an exploratory fashion for change from baseline in KCCQ-TSS at 1 and 4 
months, and for the overall summary score and clinical summary scores at 1, 4 and 8 months.


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4.2.4.3
Analysis of CV death
Time to CV death will be analysed using Cox regression in the same manner as the primary 
composite endpoint, with stratification for T2D status at randomisation. The analysis will 
include CV deaths, confirmed in adjudication, occurring on or prior to PACD. Patients who 
did not die from CV death, will be censored at the earliest of death due to other cause, WoC, 
PACD, or for any patients who are LTFU, at last date known to be alive.
COVID-19
As part of the COVID-19 related sensitivity analysis of the primary endpoint, the component 
CV death will be reported (Section 4.2.3.2).
4.2.4.4
Analysis of All-Cause Mortality
Time to death from any cause will be analysed using Cox regression in the same manner as 
the primary composite endpoint, with stratification for T2D status at randomisation. The 
analysis will include deaths from any cause occurring on or prior to PACD. Patients who are 
alive will be censored at PACD, or for any patients who are LTFU, at last date known to be 
alive.
4.2.5
Analysis of Safety Variables
Analysis set
For safety analyses, all summaries will be based on the SAS (Section 2.1.2).
Exposure
The total exposure to IP will be defined as the length of period on IP, calculated for each 
patient as date of last dose – date of first dose +1.
An alternative measure where days of interruption are removed will be calculated and termed 
actual exposure.
Total and actual 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 IP and on or before 30 days after last dose of IP. Additional 
presentations will include all events with onset on or after first dose of IP regardless of 
whether patients are on or off IP at the time of the event (the “on- and off-“ treatment period.). 
Patients who complete the study on IP will discontinue treatment on the SCV. Thus, there will 
in general be no events after completion of the IP period, and censoring of events for on-
treatment analysis affects only patients who prematurely and permanently discontinue IP.
All summaries of AEs described in Section 4.2.5.1 to 4.2.5.4 below will be presented for the 
on-treatment period and on- and off- treatment period. 


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4.2.5.1
Adverse Events 
The on-treatment period was used for primary analysis of all safety variables, except for 
amputations and preceding events, for which the on- and off-treatment period was considered 
the primary approach. 
In addition to SAEs, the collection of AEs that are not serious includes myocardial infarction, 
unstable angina, stroke, major hypoglycaemic events, potential DKAs, amputations, AEs 
leading to amputation, and preceding events, AEs leading to a potential endpoint, DAEs, and 
AEs which are the reason for interruption of IP (see Section 3.3). Thus, summaries of AEs 
will be limited to these categories and general summaries of all non-serious AEs are not 
planned. 
AEs will be classified according to MedDRA by the medical coding team at AstraZeneca data 
management center, using MedDRA 24.1.
Summaries by SOC and PT will be sorted by international order for SOC and by descending 
order of PT in the dapagliflozin treatment group.
No statistical tests to compare crude AE frequencies between treatment groups are planned. A 
summary table of the total number and percent of patients with AE with outcome death, AEs 
of definite or probable DKA, any major hypoglycemic event, SAE, DAE, AE leading to 
temporary interruption of IP, AEs possibly related to IP, amputations and preceding events per 
treatment group will be provided.
Amputations, AEs leading to amputations, and preceding events (see Section 3.3) will be 
presented in summary tables including the number and percent of patients with any event in 
the AE category, SAE, DAE and AE leading to interruption, and tabulated with frequency by 
PT. 
In addition to presentations of the number of patients with event, the total number of events 
counting multiple events per subject will be presented.
All potential events of DKA will be submitted to an independent DKA Adjudication 
Committee. The adjudicated outcome, definite or probable, will be considered the main 
analysis for DKA. 
For major hypoglycaemic events a summary table including the total number of subjects with 
events, the number and percent of patients with event in the AE intensity category, SAE, 
DAE, AE leading to interruption, possible relation to IP will be presented. The presentation of 
on-treatment events, on- and off-treatment presentations will be provided for all major 
hypoglycaemic events.


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For AEs leading to amputations and preceding events, DKA and major hypoglycaemic events, 
event rate per 100 subject years will also be presented, calculated as 100 times the number of 
patients with event divided by the total duration of treatment (including 30 days after last 
dose) in the given group for the on-treatment presentation, and total duration of follow-up in 
the given group for on and off treatment.
Events of genital area infections and necrotising fasciitis to be medically assessed in a blinded 
fashion prior to clinical data lock as potential events of Fournier’s gangrene will be presented 
in a summary table including the number and percent of patients with any event in the SAE or 
DAE category, and tabulated with frequency by PT.
4.2.5.2
Serious Adverse Events 
SAEs will be presented as described below both on treatment and on and off treatment.
The number and percent of patients with SAEs will be presented by SOC, PT and treatment 
group. The most common SAEs will also be presented by PT only. 
AEs with outcome death will be presented separately by SOC and PT.
4.2.5.3
Adverse Events Leading to Discontinuation or Interruption of Investigational 
Product
The number and percent of patients with event will be presented by SOC and PT for AEs 
leading to discontinuation of IP and AEs leading to temporary interruption (separately for the 
two categories based on action taken “Drug Permanently Discontinued” and “Drug 
Interrupted” respectively, recorded in the CRF AE module).
4.2.5.4
Laboratory Evaluation and Vital Signs
Summaries of creatinine and calculated eGFR will be based on creatine samples analysed at 
the central laboratory.
The result and the change from baseline of creatinine, eGFR and vital signs, will be 
summarized by treatment group at each visit (excluding PTDV and SCV) with scheduled 
measurement (see Section 3.4) using descriptive statistics, including n, mean, SD, range, 
median, and quartiles.
4.2.6
Analysis of Exploratory Objectives
Time to the first occurrence of hospitalisation from any cause will be analysed with the same 
method as the primary endpoint, based on information on the SAE eCRF form.
The proportion of patients with worsened (higher) NYHA class at 8 months compared to 
baseline, including patients who died prior to 8 months in the worsened category, versus 
patient with improved or unchanged NYHA class, will be analyzed by logistic regression with 


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treatment group, baseline NYHA class and T2D status at randomisation as factors, presented 
as an odds ratio with corresponding 95% confidence interval. Only NYHA assessments made 
at site or through phone visits with the patient to be used in analyses. 
Change from baseline to each scheduled assessment visit (see Section 3.4) for body weight, 
SBP and eGFR will be analysed with a MMRM. All non-missing visit data will be used, 
including measurements after discontinuation of IP. The model will include terms for 
treatment group, visit, visit by treatment group interaction, the baseline measurement and T2D 
stratification status at randomisation as covariates. The model will be used to derive a least-
squares estimate of the treatment difference with 95% confidence interval and corresponding 
two-sided p-value. Missing data will not be imputed.
For eGFR, the MMRM model above will additionally be used to derive the “total” slopes 
(between randomisation and eg, 1 year and 2 years respectively) and the “chronic” slopes 
(between a post randomisation time point to eg, 1 year and 2 years respectively) will be 
estimated via linear contrasts. 
The analysis of change from baseline in KCCQ clinical summary score, overall summary 
score and KCCQ-TSS sub-scores (symptom burden and symptom frequency) will follow the 
analysis of KCCQ-TSS in Section 4.2.4.2. QoL score will be summarised using descriptive 
statistics.
EQ-5D-5L derived utility score will be summarised by descriptive statistics, and used for 
health economic modelling and reported in a separate health economic report. 
5
INTERIM ANALYSES
An interim analysis is planned to be performed including approximately 67% of the target 
number of patients with adjudicated primary endpoint events (approximately 748 events). 
There will in principle be one planned interim analysis for efficacy, with the possibility of the 
DMC to conduct subsequent interim analysis if they deem necessary. The significance level 
for final analysis will be based on the actual number of interim analyses. The interim analysis 
will assess superiority of dapagliflozin to placebo. The interim analysis will have a nominal 
two-sided alpha level of 0.2%. At the interim analysis, the primary composite endpoint will be 
tested in the full study population at the specified alpha level. If superiority is achieved for the 
primary endpoint, then the superiority of dapagliflozin to placebo on CV deaths will be tested 
in the full study population at a two-sided level of 0.2%. If CV death is significant, then an 
action is triggered whereby the DMC will evaluate the totality of the efficacy data and safety 
data, to determine if benefit is unequivocal and overwhelming such that the DMC 
recommends ending the study.


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If the interim analysis leads to a decision to terminate the study early based on pre-defined 
stopping guidelines, the executive committee will define a PACD, on or after which SCVs 
will commence. The study report will be based on all events occurring on prior to the PACD. 
If the study is stopped at the efficacy interim analysis, testing of remaining secondary 
endpoints will be performed on the final database in the full population only, in fixed 
sequence described in the right branch of Figure 2 (Section 4.1.3) at two-sided significance 
level 0.2%. 
6
CHANGES OF ANALYSIS FROM PROTOCOL
The alpha for final analysis adjusted for interim analysis at alpha 0.2% will be set to 5% 
minus 0.2% = 4.8%, rather than 4.98% as determined by the Haybittle-Peto function for 67% 
of events (Sections 9.1 and 9.5 of the CSP).


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7
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Appendix A
Estimation of Clinically Meaningful Thresholds for KCCQ 
Total Symptom Score
A 1
Methods
Thresholds for CMWPC will be estimated according to predefined algorithms using an 
anchor-based approach, supplemented with graphical visualisations of the distribution across 
anchor categories. Clinically meaningful thresholds will be estimated for change from 
baseline KCCQ-TSS at 8 months.
This appendix describes the methods which were applied to blinded study data prior to 
database lock and unblinding of the study, with results and derived thresholds presented in this 
SAP prior to the interim analysis. The threshold analyses were performed on the FAS 
population used in the main analysis for KCCQ (the population with patients who had a 
planned Visit 5, ie, at 8 months, prior to the major COVID-19 outbreak; see 4.2.4.2), on 
blinded study data across both treatment arms only including patients with complete data at 
baseline and 8 months.
Anchor-based approaches
Anchor-based approaches estimate a threshold by ‘anchoring’ the results on a separate 
variable, often a patient-reported outcome. The anchor-based analysis will employ the PGIS in 
HF symptoms. Meaningful change will be evaluated using observed scores according to a 
predefined algorithm. The responses to PGIS at baseline and 8 months will be used in the 
analysis.
Categorisation of anchors
The change from baseline PGIS at 8 months will be categorized and categories will be 
collapsed in different ways, to provide a clearer distinction between patients who have and 
have not experienced a meaningful change according to this anchor. 
The ordinal responses to PGIS at baseline and 8 months will be assigned the following 
numeric values:

1 (‘no symptoms’)

2 (‘very mild’)

3 (‘mild’)

4 (‘moderate’)

5 (‘severe’)

6 (‘very severe’)
Change from baseline PGIS at 8 months will be categorized as small, moderate or large 
improvement/deterioration or stable as defined in Table A1.


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Table A1
Categories of Change from Baseline PGIS in Heart Failure Symptoms 
at 8 Months
PGIS at baseline
PGIS at 8 months
No 
symptoms
Very mild
Mild
Moderate
Severe
Very 
Severe
1
2
3
4
5
6
No symptoms  
1
0
Stable
+1
SD
+2
MD
+3
LD
+4
LD
+5
LD
Very mild
2
-1
SI
0 
Stable
+1
SD
+2
MD
+3
LD
+4
LD
Mild
3
-2
MI
-1
SI
0
Stable
+1
SD
+2
MD
+3
LD
Moderate
4
-3
LI
-2
MI
-1 
SI
0
Stable
+1
SD
+2
MD
Severe
5
-4
LI
-3
LI
-2
MI
-1
SI
0
Stable
+1
SD
Very severe
6
-5
LI
-4
LI
-3
LI
-2
MI
-1
SI
0
Stable
LD, large deterioration; LI, large improvement; MD, moderate deterioration; MI, moderate improvement; SD, 
small deterioration; SI, small improvement
The categories in Table A1 will be further collapsed as 

‘moderate or large deterioration’ in the categorisation with 5 categories (version A)

‘small or moderate deterioration’ in the categorisation with 5 categories (version B)

‘small or moderate improvement’ in the categorisation with 5 categories (version B)

‘moderate or large improvement’ in the categorisation with 5 categories (version A)
The change from baseline KCCQ-TSS at 8 months, will be used repeatedly in the anchor-
based analyses. To explore the adequateness of each anchor categorisation, the Spearman 
correlation coefficient between change from baseline KCCQ-TSS and change from baseline 
PGIS at 8 months will be assessed.
The larger the correlation coefficient between an anchor and the endpoint, the greater the 
confidence in the classifications. An anchor is considered adequate if it has a correlation 
coefficient of 0.3 or greater (Coon and Cook 2018).
Descriptive statistics (mean, SD, median, quartiles, minimum and maximum) and an eCDF is 
presented for each categorisation in Section A 2. The eCDF curves display a continuous plot 


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of the change from baseline on the horizontal axis, and the cumulative proportion of patients 
experiencing changes from baseline up to that level, on the vertical axis. If the eCDF curves 
show very poor distinction between categories, they may be complemented with curves 
illustrating the probability density function for that categorisation.
Establishing the clinically meaningful threshold
The various estimates from the different streams of evidence (tables and plots of the 
distribution) will be examined for convergence in an effort to triangulate onto a single 
threshold value which represents CMWPC (for improvement and deterioration, respectively) 
and the KCCQ-TSS responder analysis will be performed for this threshold. However, if the 
values are too disparate, a range of clinically relevant thresholds may be identified. CMWPC 
thresholds identified will be indicated in the eCDF for change from baseline KCCQ-TSS by 
treatment, in the unblinded results, and responder analysis will be performed for the 
thresholds.
A 2
Summary of Results of Anchor-Based Analysis on Blinded Study 
Data
The anchor-based analysis of change from baseline KCCQ-TSS at 8 months in different 
categories of change from baseline PGIS at 8 months, is presented in Table A2. As this 
analysis is done on blinded study data and only includes patients with observed values for 
both KCCQ-TSS and PGIS at 8 months (patients who died and all other patients with missing 
data are excluded), the “mean” is selected as a representation of the average of a group. This 
anchor-based analysis indicates that small or moderate improvement corresponds to a mean 
increase in KCCQ-TSS of 13 points. A large improvement in PGIS corresponds to a mean 
increase in KCCQ-TSS of about 17 points. A large deterioration in PGIS corresponds to a 
mean decrease in KCCQ-TSS of about 14 points, whereas a moderate deterioration in PGIS 
corresponds to a mean decrease in KCCQ-TSS of 5 points. It is important to note that the 
group of patients who were categorized as being “stable” in terms of their HF symptoms at 8 
months had a mean increase in KCCQ-TSS of almost 5 points.
In the responder analysis of the third secondary efficacy endpoint, change from baseline 
measured at 8 months in the TSS of the KCCQ (Section 4.2.4.2), an increase of 13 points or 
more in KCCQ-TSS will be considered a clinically meaningful improvement and a decrease 
of 5 points or more will be considered a clinically meaningful deterioration. The anchor-based 
analysis and the distribution curves indicate that a “small” improvement cannot be 
distinguished from a “moderate” improvement, while they are both clearly separated from the 
“stable” category. Likewise, the anchor-based analysis and distribution curves indicate that a 
“small” deterioration cannot be distinguished from the “stable” category. The Spearman’s 
correlation coefficient between change from baseline at 8 months in KCCQ-TSS and PGIS 
was around 0.29-0.30, where a correlation of 0.3 or greater between an anchor and the 
anchored scale is considered adequate (Coon and Cook 2018). 


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Table A2
Distribution of Change from Baseline KCCQ-TSS at 8 months by 
Change from Baseline PGIS 8 Months
N
(%)
Mean
SD
Min
Q1
Median
Q3
Max
Correlatio
n a
PGIS at 8 Months: 7 
0.29
Large Improvement
120
(6)
17.4
22.51
-54.2
0.5
15.1
32.8
70.8
Moderate Improvement
275
(13)
12.9
20.13
-76.0
0.0
12.5
25.0
72.9
Small Improvement
453
(21)
13.0
19.63
-47.9
0.0
11.5
24.0
85.4
Stable
811
(38)
4.5
19.01
-64.6
-5.2
2.1
16.7
66.7
Small Deterioration
277
(13)
1.7
17.32
-37.5
-8.3
0.0
11.5
55.2
Moderate Deterioration
111
(5)
-4.7
20.43
-59.4
-16.7
-4.2
6.3
58.3
Large Deterioration
64
(3)
-13.7
27.85
-91.7
-30.2
-7.8
4.2
29.2
PGIS at 8 Months: 5 
Categories (collapsing 
“moderate” and “large”)
0.29
Moderate or Large 
395
(19)
14.3
20.96
-76.0
0.0
12.5
27.1
72.9
Small Improvement
453
(21)
13.0
19.63
-47.9
0.0
11.5
24.0
85.4
Stable
811
(38)
4.5
19.01
-64.6
-5.2
2.1
16.7
66.7
Small Deterioration
277
(13)
1.7
17.32
-37.5
-8.3
0.0
11.5
55.2
Moderate or Large 
175
(8)
-8.0
23.74
-91.7
-20.8
-4.2
5.2
58.3
PGIS at 8 Months: 5 
Categories (collapsing 
“small” and “moderate”)
0.30
Large Improvement
120
(6)
17.4
22.51
-54.2
0.5
15.1
32.8
70.8
Small or Moderate 
728
(34)
13.0
19.81
-76.0
0.0
11.5
25.0
85.4
Stable
811
(38)
4.5
19.01
-64.6
-5.2
2.1
16.7
66.7
Small or Moderate 
388
(18)
-0.1
18.46
-59.4
-10.4
0.0
10.4
58.3
Large Deterioration
64
(3)
-13.7
27.85
-91.7
-30.2
-7.8
4.2
29.2
a
Absolute value of the Spearman correlation coefficient for change from baseline KCCQ-TSS at 8 months 
and change from baseline PGIS at 8 months with each categorisation.
Categories of change from baseline PGIS at 8 months as defined in Table A1. 
KCCQ, Kansas City Cardiomyopathy Questionnaire; PGIS, patient global impression of severity; TSS, total 
symptom score
The eCDF curves in Figure A1 demonstrate a clear separation between all categories of 
improvement and the “stable” category, in the interval between 5 and 40 points increase in 
KCCQ-TSS at 8 months, where separation is expected for these curves. However, the 
separation is less distinct between the categories of “small” and “moderate” improvement. For 
deterioration, the “large” and “moderate” deterioration categories are clearly separated from 
the “small” and the “stable” category, in the interval between 5 and 40 points decrease in 
KCCQ-TSS at 8 months, where separation is expected for these curves. The combined 
“moderate or large” categories of deterioration and improvement in Figure A2 are separated 


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from the “stable” category. This is also observed for combined “small or moderate” categories 
of deterioration and improvement in Figure A3.
Figure A1
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 Months versus Change from Baseline PGIS at 8 
Months with 7 Categories
KCCQ, Kansas City Cardiomyopathy Questionnaire; PGIS, patient global impression of severity; TSS, total 
symptom score 


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Figure A2
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 Months Versus Change from Baseline PGIS at 8 
Months with 5 Categories (Collapsing “Moderate” and “Large”)
KCCQ, Kansas City Cardiomyopathy Questionnaire; PGIS, patient global impression of severity; TSS, total 
symptom score 


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Figure A3
Empirical Cumulative Distribution Function for Change from Baseline 
KCCQ-TSS at 8 months Versus Change from Baseline PGIS at 8 
Months with 5 Categories (Collapsing “Small” and “Moderate”) 
KCCQ, Kansas City Cardiomyopathy Questionnaire; PGIS, patient global impression of severity; TSS, total 
symptom score 
A 3
Summary of Results of Distribution-Based Analysis on Blinded 
Baseline Study Data
Distribution-based methods (0.5 SD and 1 SEM) were used to explore the MCID in the 
KCCQ-TSS, in patients with HFpEF. The MCID is a value to which between-group 
differences in average change from baseline are compared, to assess clinical relevance of the 
difference between treatment groups.
The SEM was calculated as   = !" ∗$1 −%"" , where σx is the SD at baseline and rxx is 
the reliability (internal consistency) of the scale at baseline. The internal consistency of the 
KCCQ-TSS was assessed by Cronbach’s alpha. The distribution-based analyses indicated that 
0.5 SD (based on Cohen’s “medium” effect size) of the baseline KCCQ-TSS score was equal 
to 11.0 and that 1 SEM was equal to 8.6 (Table A3). Based on these distribution-based 
analyses, a rounded mid-point between these values of 10 points is expected to represent a 


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MCID for KCCQ-TSS in patients with HFpEF. The MCID will not be used to inform 
responder analyses, as the MCID is not based on within-patient change and is therefore not 
appropriate for assessing an individual’s “response”.
Table A3
Distribution-Based Cut-offs for a Minimal Clinically Important 
Difference in the KCCQ-TSS 
N1
One-half SD
N2
1 SEM
Baseline KCCQ-TSS
4730
11.0
4562
8.6
N1  The SD is based on the number of patients with an observed baseline KCCQ-TSS.
N2  The SEM is based on the number of patients with an observed scorable responses to each of the items in the 
KCCQ-TSS.
KCCQ, Kansas City Cardiomyopathy Questionnaire; N, number of patients in treatment group; SD, standard 
deviation, SEM, standard error of measurement; TSS, total symptom score


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Appendix B
Programming Code for Calculating Significance Level for 
LVEF <60% Subpopulation
Let &' and  &( denote the standardized test statistic for testing the hypothesis of treatment effect in the 
LVEF < 60% subgroup and the full population respectively. &' and  &( are bivariate normal with 
correlation equal to the proportion of events in the LVEF < 60% subpopulation (Spiessen and Debois 
2010).  To control the familywise error rate below α, for a pre-specified significance level )( for the 
full population, we need to define )'for the subgroup such that, under the null hypothesis,
(1)
*+&' > -./ OR &( > -.2 = )                                                                 
where -./ and -. are the corresponding critical values from the standard normal distribution.
Equation (1) can be rewritten as 
*+&( > -.2 + *+&' > -./, &( ≤-.2
= )( + *+&' > -./, &( ≤-.2
= )
Thus we need to find )'  such that  
*+&' > -./, &( ≤-.2 = ) −)(
As noted by Spiessen and Debois 2010, this corresponds to error spending for group sequential 
methods where &( is the test statistic at interim analysis and &' is the test statistic at the final analysis. 
Accordingly, standard software for group sequential designs can be used to calculate the significance 
level )' as shown below using the R package gsDesign or the SAS procedure SEQDESIGN
For the proportion of events in the LVEF <60% subgroup we use the lower bound of a 95% confidence 
interval for the estimated proportion calculated using normal approximation as 
6 −-(.8$6(1 −6)/:
where -(.8 is the upper 2.5% percentile of the standard normal distribution and 6 = :;</: for :;<
events in the subgroup and : events in total.
In an example of 810 (72.5%) in the subgroup out of a total of 1117 event, the lower confidence limit 
for the proportion is 0.699, which will be used in the example R and SAS code below.


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R gsDesign package
Example with lower proportion 0.699 (lower confidence limit) events in the subgroup:
gsd <-  
   gsDesign(k=2, timing=c(0.699,1),
      # 69.9% events at interim, corresponding to proportion in subgroup
   test.type=1, sfu=sfLinear,
   sfupar=c(0.699,1,0.5,1),
      # proportion 0.5 of total alpha spent at interim, corresponding to 
      # alpha2 = 0.5*0.048=0.024 two-sided set for the full population
    alpha=0.024)
      #total one-sided alpha 0.048/2
                       # 
(alpha1 <- 2*100*(1-pnorm(gsd$upper$bound[2])))  
       # alpha1 now holds the two-sided significance level for final
       # analysis, corresponding to alpha1 for the subgroup
SAS proc SEQDESIGN
Example with lower proportion 0.699 (lower confidence limit) events in the subgroup:
proc seqdesign bscale=pvalue;
     design nstages=2 info=cum(69.9 100)  
     /* 69.9% events at interim, corresponding to proportion in subgroup */
     method=peto(pvalue=0.012)  
     /* alpha 0.012 one-sided spent at interim, corresponding to 
        0.024 two-sided set for the full population */
         stop=reject  
         alt=lower alpha=0.024;   
     /*   0.048/2 total one-sided alpha  */    
     ods output boundary = bound;
  run;
  
  data alpha1;
    set bound;    
    if _stage_=2;
    alpha1=100*2*bound_la;
  run;
   /* alpha1 now holds the two-sided significance level for final analysis,    
      corresponding to alpha1 for the subgroup */


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