Clinical trial NCT03036124
Conditions: Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)
Keywords: HFrEF Heart Failure (HF) Cardiovascular Events (CV) Phase III outcome trial
Sponsor: AstraZeneca
Start date: 2017-02-08; Completion date: 2019-07-17
Enrollment: 4744 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of dapagliflozin on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure with reduced ejection fraction

Detailed description:
This is an international, multicentre, parallel group, event-driven, randomized, double-blind, placebo-controlled study in patients with chronic heart failure with reduced ejection fraction (HFrEF), evaluating the effect of dapagliflozin versus placebo, given once daily in addition to background regional standard of care therapy, for the prevention of cardiovascular (CV) death or reduction of heart failure (HF) events.

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 or 5 mg tablets given once daily, per oral use. intervention 2: Placebo matching dapagliflozin 10 mg or 5 mg.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol (CSP), ANGEL
Version 17.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
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.
Clinical Study Protocol 
Drug Substance
Dapagliflozin
Study Code
D1699C00001
Version
2.0
Date
26 October 2017
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening 
Heart Failure or Cardiovascular Death in Patients with Chronic Heart 
Failure with Reduced Ejection Fraction
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
2 (102)
VERSION HISTORY
Version 1.0,  26 October 2016
Initial creation
Version 2.0, 25 October 2017
Section 
Summary of change
Multiple
Correcting typos, cross-references and AstraZeneca (AZ) House 
style.
Protocol synopsis
2.2 Secondary objectives
8.5.4 Analysis of the secondary 
variable(s)
Changing Kansas City Cardiomyopathy Questionnaire (KCCQ) 
clinical/overall symptom score to total symptom score.
1.4 Study Design
2.4 Exploratory Objectives
4. Study plan timing of 
procedures
4.2.1 Visit 2, Randomisation 
(Day 0)
4.2.4 Visit 6 (Day 240±14)
Adding information related to the Echocardiographic Sub-study
2.3 Safety objectives
6.3.1 Time period for collection 
of adverse events
6.3.2.6 Adverse events (AEs) 
leading to amputation and AEs 
leading to a risk for lower limb 
amputations (“preceding events”)
Expanding the adverse event of interest category of amputations 
to also include: AEs leading to a risk for lower limb amputations 
(“preceding events”). This AE of interest was added based on 
discussion with regulatory authorities. 
3.2 Exclusion criteria
Clarifying exclusion criteria number 3 and 13. 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
3 (102)
Extending requirement for contraceptives (exclusion criteria 16), 
based on feedback from some regulatory authorities and to 
harmonise with informed consent form (ICF).
3.4 Procedures for handling 
incorrectly randomised patients
Clarifying text regarding how to handle incorrectly randomised 
patients.
3.9.1 Evaluation of volume status 
and investigational product (IP) 
dose reduction/interruption
Changing around the order of the subsections “IP dose reduction” 
and “Essential Treatments”
3.9.1 Evaluation of volume status 
and investigational product (IP) 
dose reduction/interruption
Clarification added to provide additional guidelines regarding 
essential treatment in the setting of acute worsening of heart 
failure (HF) or other acute situations.
4.2.7 Study closure visit (SCV)
Clarification regarding the investigator responsibility in terms of 
standard of care treatment after the patient stops IP.
5.1.1 Endpoint reporting 
overview
5.1.4 Potential renal endpoints
Removing the requirement of adjudicating potential endpoints 
related to estimated glomerular filtration rate (eGFR) decline.  
The rational for this change is that the endpoint criteria is not 
justifying adjudication of these events. 
5.8 Echocardiographic Sub-
study
An additional section has been added in order to capture 
information related to the echocardiographic sub-study.
6.3 Recording of adverse events 
(AEs)
6.3.2.2 Renal events
Clarification added based on feedback that the criteria was too 
vague, regarding what is considered an AE of interest in terms of 
renal events. 
6.3 Recording of adverse events
6.3.5 Adverse events based on 
examination and tests
Limiting the recording of AEs to not include potential renal 
endpoints that are based on examination and tests, i.e., laboratory 
results only, unless fulfilling the serious adverse event (SAE) 
criteria or adverse event leading to discontinuation of IP (DAE) 
criteria. The reason not to record these endpoints related to 
laboratory findings is that protocol mandated laboratory values 
will be systematically analysed.  
6.4.1 Reporting of SAEs 
considered to be potential 
endpoints
Limiting the event types that are being withheld from reporting to 
health authorities to include only HF endpoints and fatal AEs, i.e., 
AEs related to renal endpoints will not be withheld. The rationale 
for this limitation is to simplify the SAE reporting and to 
minimise the risk for withholding renal AEs of interest, which 
should be reported, and which could be confused for being a 


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
4 (102)
primary or secondary renal endpoint. 
6.9 Medication Error
Adding information about Medication Error definition and 
reporting.
7.7.1 Prohibited medication
Clarifying that open label treatment with sodium glucose co-
transporter 2 (SGLT2) in combination with IP is not allowed and 
that open label treatment with SGLT2 inhibitors should be 
avoided during the course of the study, i.e., clarifying that usage 
of open label treatment with SGLT2 inhibitors is not prohibited if 
the patient is not taking study medication but should be avoided. 
The rational for this update is to clarify that it is administration of 
an open label SGLT2 inhibition in combination with IP that is a 
protocol deviation and not if the patient is off IP.
7.7.2 Recording of concomitant 
medication
Including cardiovascular (CV) medications to be recorded in 
detail in the Electronic Case Report Form (eCRF) during the 
course of the study.
7.7.5.1 Cardiac and heart failure 
related procedures
An additional sub-section has been added in order to capture 
cardiac and heart failure related procedures. 
8.5.6 Interim analysis
Clarifying that the Data Monitoring Committee (DMC) have the 
possibility to do more than one interim analysis of efficacy if they 
deem necessary, and that the stopping rule includes significance 
for the primary endpoint and CV Death
Appendix D
Appendix D has in the previous version been separated from the 
main Clinical Study Protocol (CSP) but is now incorporated for 
practical reasons. No changes made to the content.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
5 (102)
PROTOCOL SYNOPSIS
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening 
Heart Failure or Cardiovascular Death in Patients with Chronic Heart 
Failure with Reduced Ejection Fraction
International Co-ordinating Investigator
Professor 
 BSc (Hons), MB ChB (Hons), MD, FRCP, FESC, FACC, FAHA, 
FRSE, FMedSci 
Professor of Medical Cardiology & Honorary Consultant Cardiologist
Institute of Cardiovascular & Medical Sciences 
BHF Cardiovascular Research Centre
University of Glasgow
Glasgow, G12 8TA, United Kingdom
Study site(s) and number of patients planned
It is estimated that approximately 7000 patients at 500-600 sites in 20-25 countries will be 
enrolled to reach the target of approximately 4500 randomised patients.
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2017
Phase III
Estimated date of last patient completed
Q4 2019
Study design
This is an international, multicentre, parallel group, event-driven, randomised, double-blind, 
placebo-controlled study in patients with chronic heart failure with reduced ejection fraction 
(HFrEF), evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in 
addition to background regional standard of care therapy, for the prevention of cardiovascular 
(CV) death or reduction of heart failure (HF) events.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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Objectives
Primary Objective:
Outcome Measure:
To determine whether dapagliflozin is superior 
to placebo, when added to standard of care, in 
reducing the incidence of CV death or a HF 
event (hospitalisation for HF or equivalent HF 
event, i.e., an urgent HF visit).  
Time to the first occurrence of any of the components 
of this composite: 
1.
CV death
2.
Hospitalisation for HF
3.
An urgent HF visit 
Secondary Objective:
Outcome Measure :
To compare the effect of dapagliflozin versus 
placebo on CV death or hospitalisation for HF.
Time to the first occurrence of any of the components 
of this composite: 
1.
CV death 
2.
Hospitalisation for HF
To compare the effect of dapagliflozin versus 
placebo on total number of recurrent HF 
hospitalisations and CV death.  
Total number of recurrent HF hospitalisations and 
CV death.  
To compare the effect of treatment with 
dapagliflozin versus placebo on the Kansas 
City Cardiomyopathy Questionnaire (KCCQ) 
total symptom score for HF symptoms and 
physical limitations.
Change from baseline measured at 8 months in the 
total symptom score of the KCCQ, a specific HF 
patient reported outcome questionnaire.


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Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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Secondary Objective:
Outcome Measure :
To determine if dapagliflozin compared with 
placebo reduces the incidence of a worsening 
renal function composite outcome.  
Time to the first occurrence of any of the 
components of this composite:
1.
≥50% sustained* decline in  estimated 
glomerular filtration rate (eGFR) 
2.
Reaching End Stage Renal Disease 

Sustained* eGFR 
<15 ml/min/1.73m2 or, 

Chronic* dialysis treatment or, 

Receiving a renal transplant
3.
Renal death 
*As defined in the Clinical Event Adjudication (CEA) charter
To determine whether dapagliflozin, compared 
with placebo, reduces the incidence of all-
cause mortality.  
Time to death from any cause.
Safety Objective:
Outcome Measure :
To evaluate the safety and tolerability of 
dapagliflozin in this patient population.  
1.
Serious Adverse Events (SAEs)
2.
Discontinuation of Investigational Product 
(IP) due to Adverse Events (DAEs)
3.
Changes in clinical 
chemistry/haematology parameters 
4.
AEs of interest (volume depletion, renal 
events, major hypoglycaemic events, 
fractures, diabetic ketoacidosis, AEs 
leading to amputation and AEs leading to 
a risk for lower limb amputations 
[“preceding events”])


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
8 (102)
Target patient population
The target population includes male and female patients with an established diagnosis of 
HFrEF for ≥2 months, and at high risk of cardiovascular death or heart failure events.  
The study population will include patients with New York Heart Association (NYHA) Class 
II-IV HF with reduced left ventricular ejection fraction (LVEF≤40%), increased N-terminal 
pro-B-type natriuretic peptide (NT-proBNP) levels and eGFR ≥30 ml/min/1.73 m2.  Patients 
should be clinically stable and optimized on heart failure therapies according to local 
guidelines at the time of enrolment (and background standard of care therapy for type 2 
diabetes when applicable).  To ensure stability, doses of evidence based heart failure 
medications (other than diuretics) can neither have been increased nor decreased for at least 4 
weeks prior to inclusion in the study.
The study population will include patients both with and without type 2 diabetes, as the 
beneficial haemodynamic effects of dapagliflozin appear to be independent of the glycaemic 
effect, and can therefore be expected in both groups.  To ensure balance between the diabetic 
and non-diabetic cohorts, stratification will be employed, with inclusion of at least 30% of 
each cohort.
Duration of treatment
This study is event driven.  The anticipated duration of the study is approximately 33 months 
with an estimated mean treatment period for a patient of 24 months.  The study closure 
procedures will be initiated when the predetermined number of primary endpoints are 
predicted to have occurred (n=844) i.e., the study end date (SED).  The study duration may be 
changed if the event rate or randomisation rate is different than anticipated.  The study may be 
terminated early if either a clear beneficial or harmful effect of the study treatment is detected 
during the Data Monitoring Committee (DMC) review.
Investigational product, dosage and mode of administration
Patients will be randomised 1:1 to either dapagliflozin 10 mg or placebo.  Every attempt 
should be made to maintain patients on dapagliflozin 10 mg or matching placebo during the 
course of the study.  In addition to the preferred 10 mg dose, the 5 mg dose of dapagliflozin 
can be used in the study when clinically indicated.  If the dose has been decreased to 5 mg, the 
dose should be increased back to dapagliflozin 10 mg or matching placebo as soon as, in the 
opinion of the investigator, the patient’s condition is stable.
Statistical methods
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint.  Assuming a true hazard 
ratio of 0.80 between dapagliflozin and placebo, using a one-sided alpha of 2.5%, 844 primary 
endpoint events will provide a statistical power of 90% for the test of the primary composite 
endpoint.  This is based on an overall 1:1 allocation between dapagliflozin and placebo.  


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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The study is event-driven.  With an annual event rate of 11% in the placebo treatment group, 
4500 patients are estimated to provide the required number of primary events, based on an 
anticipated recruitment period of 18 months and an average follow-up period of 
approximately 24 months.   
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, using events confirmed by adjudication.
In the analysis of the primary composite endpoint, treatments (dapagliflozin versus placebo) 
will be compared using a Cox proportional hazards model with a factor for treatment group, 
stratified by type 2 diabetes (T2D) status at randomisation, and adjusting for history of
hospitalisation for heart failure.  The p-value, hazard ratio and 95% confidence interval will be 
reported.
An interim analysis is planned to be performed when 75% of the primary endpoints are 
adjudicated, using a Haybittle-Peto rule.  The interim analysis will assess superiority of 
dapagliflozin to placebo.  
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilized.  No multiplicity control is placed on the exploratory 
endpoints.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
10 (102)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
PROTOCOL SYNOPSIS.....................................................................................................5
TABLE OF CONTENTS................................................................................................... 10
1.
INTRODUCTION ............................................................................................. 20
1.1
Background and rationale for conducting this study ........................................... 20
1.2
Rationale for study design, doses and control groups.......................................... 21
1.2.1
Rationale for study design and population.......................................................... 21
1.2.2
Rationale for primary outcome measure ............................................................. 22
1.2.3
Rationale for secondary outcome measure.......................................................... 23
1.2.4
Rationale for dose selection................................................................................ 23
1.3
Benefit/risk and ethical assessment .................................................................... 24
1.3.1
Potential risks .................................................................................................... 24
1.3.1.1
Protection against risks ...................................................................................... 25
1.3.2
Potential benefits to patients............................................................................... 25
1.3.3
Conclusion......................................................................................................... 25
1.4
Study Design...................................................................................................... 25
2.
STUDY OBJECTIVES...................................................................................... 28
2.1
Primary objective............................................................................................... 28
2.2
Secondary objectives.......................................................................................... 28
2.3
Safety objectives................................................................................................ 29
2.4
Exploratory objectives ....................................................................................... 30
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 31
3.1
Inclusion criteria ................................................................................................ 31
3.2
Exclusion criteria ............................................................................................... 33
3.3
Patient enrolment and randomisation.................................................................. 34
3.4
Procedures for handling incorrectly enrolled or randomised patients .................. 35
3.5
Methods for assigning treatment groups............................................................. 35
3.5.1
Stratification and capping................................................................................... 36
3.5.1.1
Stratification ...................................................................................................... 36
3.5.1.2
Capping ............................................................................................................. 36


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Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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3.6
Methods for ensuring blinding ........................................................................... 36
3.7
Methods for unblinding...................................................................................... 37
3.7.1
Unblinding for bioanalytical laboratory personnel.............................................. 37
3.8
Restrictions........................................................................................................ 37
3.9
Discontinuation of investigational product (IP) .................................................. 37
3.9.1
Evaluation of volume status and investigational product (IP) dose 
reduction/interruption......................................................................................... 38
3.9.2
Investigational product (IP) restart or dose increase from dapagliflozin 5 
mg to 10 mg or matching placebo ...................................................................... 39
3.9.3
Procedures for discontinuation of a patient from investigational product 
(IP) .................................................................................................................... 39
3.9.3.1
Patient undergoes the premature treatment discontinuation visit (PTDV) 
and continues according to plan ......................................................................... 40
3.9.3.2
Patient agrees to undergo modified follow-up .................................................... 40
3.10
Criteria for withdrawal....................................................................................... 40
3.10.1
Screen failures ................................................................................................... 40
3.10.2
Withdrawal of informed consent ........................................................................ 40
3.11
Discontinuation of the study............................................................................... 41
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 42
4.1
Enrolment period ............................................................................................... 46
4.1.1
Visit 1, Enrolment (Day -14±7).......................................................................... 46
4.2
Treatment period................................................................................................ 47
4.2.1
Visit 2, Randomisation (Day 0).......................................................................... 47
4.2.2
Visit 3 (Day 14±3) and Visit 4 (Day 60±7)......................................................... 48
4.2.3
Visit 5 (Day 120±7) ........................................................................................... 48
4.2.4
Visit 6 (Day 240±14) ......................................................................................... 49
4.2.5
Visit 7, 8, 9 etc (Day 360±14; and every 4th month ±14 days)............................. 50
4.2.6
Premature Treatment Discontinuation Visit (PTDV) .......................................... 50
4.2.7
Study Closure Visit (SCV)................................................................................. 51
4.2.8
Unscheduled visits ............................................................................................. 52
4.3
Follow-up period (Not applicable)...................................................................... 52
5.
STUDY ASSESSMENTS.................................................................................. 52
5.1
Efficacy assessments.......................................................................................... 52
5.1.1
Endpoint reporting overview.............................................................................. 52
5.1.2
Classification of Death....................................................................................... 53
5.1.3
Heart failure (HF) events.................................................................................... 53
5.1.4
Potential renal endpoints .................................................................................... 54
5.1.4.1
Endpoints related to eGFR decline ..................................................................... 54
5.1.4.2
Dialysis and renal transplantation....................................................................... 54
5.1.4.3
Doubling of serum creatinine ............................................................................. 54


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Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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5.1.5
Initiation of new, or increased dose of existing oral treatment for 
worsening of heart failure (HF) .......................................................................... 54
5.1.6
New York Heart Association (NYHA) class....................................................... 55
5.1.7
New diagnosis of Atrial Fibrillation (AF)........................................................... 55
5.1.8
New diagnosis of type 2 diabetes ....................................................................... 55
5.1.9
Cardiac ischaemic events ................................................................................... 55
5.1.10
Cerebrovascular (CV) events.............................................................................. 55
5.1.11
Patient reported outcomes (PROs)...................................................................... 55
5.1.11.1
Patient global impression of severity (PGIS)...................................................... 55
5.1.11.2
Patient global impression of change (PGIC)....................................................... 56
5.1.11.3
Kansas City Cardiomyopathy Questionnaire (KCCQ) ........................................ 56
5.1.11.4
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L)......................... 56
5.1.11.5
Administration of patient reported outcomes (PRO)........................................... 56
5.2
Safety assessments............................................................................................. 57
5.2.1
Laboratory assessments...................................................................................... 57
5.2.1.1
Unscheduled laboratory assessments.................................................................. 58
5.2.2
Physical examination ......................................................................................... 58
5.2.3
Electrocardiogram (ECG)................................................................................... 58
5.2.4
Vital signs.......................................................................................................... 58
5.2.4.1
Pulse and blood pressure (BP)............................................................................ 58
5.2.4.2
Body weight and height...................................................................................... 59
5.3
Other assessments (Not applicable).................................................................... 59
5.4
Pharmacokinetics (PK)....................................................................................... 59
5.4.1
Collection of samples......................................................................................... 59
5.4.2
Determination of drug concentration.................................................................. 59
5.4.3
Storage and destruction of pharmacokinetic samples.......................................... 59
5.5
Pharmacodynamics (Not applicable) .................................................................. 60
5.6
Pharmacogenetics (Not applicable) .................................................................... 60
5.7
Biomarker analysis............................................................................................. 60
5.7.1
Storage, re-use and destruction of biological samples......................................... 60
5.7.2
Labelling and shipment of biological samples .................................................... 60
5.7.3
Chain of custody of biological samples .............................................................. 60
5.7.4
Withdrawal of Informed Consent for donated biological samples....................... 61
5.8
Echocardiographic Sub-study............................................................................. 61
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 62
6.1
Definition of adverse events (AEs)..................................................................... 62
6.2
Definitions of serious adverse event (SAE) ........................................................ 62
6.3
Recording of adverse events............................................................................... 63
6.3.1
Time period for collection of adverse events ...................................................... 63
6.3.2
Adverse events of interest .................................................................................. 63
6.3.2.1
Volume depletion............................................................................................... 63


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Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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6.3.2.2
Renal events....................................................................................................... 64
6.3.2.3
Major hypoglycaemic event ............................................................................... 64
6.3.2.4
Fractures............................................................................................................ 64
6.3.2.5
Diabetic ketoacidosis (DKA).............................................................................. 64
6.3.2.6
Adverse events (AEs) leading to amputation and AEs leading to a risk for 
lower limb amputations (“preceding events”)..................................................... 64
6.3.1
Follow-up of unresolved adverse events............................................................. 64
6.3.2
Variables............................................................................................................ 64
6.3.3
Causality collection............................................................................................ 66
6.3.4
Adverse events based on signs and symptoms.................................................... 66
6.3.5
Adverse events based on examinations and tests ................................................ 66
6.4
Reporting of serious adverse events (SAEs) ....................................................... 66
6.4.1
Reporting of SAEs considered to be potential endpoints..................................... 67
6.5
Overdose............................................................................................................ 67
6.6
Pregnancy .......................................................................................................... 68
6.6.1
Maternal exposure.............................................................................................. 68
6.7
Management of IP related toxicities (not applicable).......................................... 69
6.8
Study governance and oversight......................................................................... 69
6.8.1
Executive Committee......................................................................................... 69
6.8.2
National Lead Investigator (NLI) Committee ..................................................... 69
6.8.3
Data Monitoring Committee (DMC) .................................................................. 69
6.8.4
Clinical Event Adjudication (CEA) Committee.................................................. 69
6.8.5
Diabetic Ketoacidosis Adjudication Committee T2D ......................................... 70
6.9
Medication Error................................................................................................ 70
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 71
7.1
Identity of investigational product...................................................................... 71
7.2
Dose and treatment regimens ............................................................................. 71
7.3
Labelling............................................................................................................ 72
7.4
Storage............................................................................................................... 72
7.5
Compliance........................................................................................................ 72
7.6
Accountability.................................................................................................... 72
7.7
Concomitant medications and other treatments................................................... 73
7.7.1
Prohibited medication ........................................................................................ 73
7.7.2
Recording of concomitant treatment................................................................... 73
7.7.3
Heart failure (HF) medications........................................................................... 73
7.7.4
Anti-diabetes treatment ...................................................................................... 74
7.7.4.1
Background........................................................................................................ 74
7.7.4.2
Treatment of patients with established diagnosis of type 2 diabetes.................... 74
7.7.4.3
Use of medications known to cause hypoglycaemia in type 2 diabetes ............... 74


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Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
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7.7.5
Other concomitant treatment .............................................................................. 74
7.7.5.1
Cardiac and heart failure related procedures....................................................... 74
7.8
Post Study Access to Study Treatment ............................................................... 75
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 75
8.1
Statistical considerations .................................................................................... 75
8.2
Sample size estimate .......................................................................................... 75
8.3
Definitions of analysis sets................................................................................. 75
8.3.1
Full analysis set.................................................................................................. 75
8.3.2
Safety analysis set.............................................................................................. 76
8.4
Outcome measures for analyses.......................................................................... 76
8.4.1
Primary outcome measure.................................................................................. 76
8.4.2
Secondary outcome measure .............................................................................. 76
8.4.3
Safety outcome measure..................................................................................... 76
8.4.4
Exploratory outcome measure............................................................................ 76
8.5
Methods for statistical analyses.......................................................................... 76
8.5.1
Hypotheses ........................................................................................................ 76
8.5.2
Closed testing procedure.................................................................................... 76
8.5.3
Analysis of the primary variable(s)..................................................................... 77
8.5.4
Analysis of the secondary variable(s) ................................................................. 77
8.5.5
Subgroup analysis.............................................................................................. 77
8.5.6
Interim analysis.................................................................................................. 78
8.5.7
Sensitivity analysis............................................................................................. 78
8.5.8
Analysis of safety variables................................................................................ 78
8.5.9
Exploratory analysis........................................................................................... 78
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 78
9.1
Training of study site personnel ......................................................................... 78
9.2
Monitoring of the study...................................................................................... 79
9.2.1
Risk based quality management ......................................................................... 79
9.2.2
Source data ........................................................................................................ 80
9.2.3
Study agreements............................................................................................... 80
9.2.4
Archiving of study documents............................................................................ 80
9.3
Study timetable and end of study........................................................................ 80
9.4
Data management by AstraZeneca ..................................................................... 80
9.5
Serious Adverse Event (SAE) Reconciliation..................................................... 81
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 81
10.1
Ethical conduct of the study ............................................................................... 81
10.2
Patient data protection........................................................................................ 81
10.3
Ethics and regulatory review .............................................................................. 81


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10.4
Informed consent ............................................................................................... 82
10.5
Changes to the protocol and informed consent form........................................... 82
10.6
Audits and inspections ....................................................................................... 83
11.
LIST OF REFERENCES ................................................................................... 83
LIST OF TABLES
Table 1
Study plan.............................................................................................42
Table 2
Laboratory variables..............................................................................57
Table 3
Investigational Product..........................................................................71
LIST OF FIGURES
Figure 1
Study flow chart ....................................................................................27
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................87
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................89
Appendix C 
Clinical data interchange standards consortium (CDISC) definition 
for Hospitalisation for heart failure (HF) and urgent heart failure 
visit.......................................................................................................90
Appendix D
New York Heart Association (NYHA) Functional Classification...........93
Appendix E
Patient Reported Outcome (PRO) questionnaires ..................................94


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ACE-I
Angiotensin converting enzyme inhibitor
ADA
American Diabetes Association
AE 
Adverse event
AF
Atrial fibrillation
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ARB
Angiotensin receptor blockers
AST
Aspartate transaminase
AZ
AstraZeneca, sponsor
BNP
B-type natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
CHF
Congestive Heart Failure
CABG
Coronary Artery Bypass Grafting 
CDISC
Clinical Data Interchange Standards Consortium
CEA
Clinical Event Adjudication
CI
Confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration equation
CRO
Clinical research organisation
CRT
Cardiac resynchronization therapy
CSA
Clinical study agreement
CSP
Clinical study protocol
CSR
Clinical study report
CV
Cardiovascular
CVD
Cardiovascular disease
DAE
Adverse event leading to discontinuation of investigational product 
DGR
Dangerous Goods Regulations


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Abbreviation or 
special term
Explanation
DKA
Diabetic ketoacidosis
DMC
Data Monitoring Committee
DMP
Data Management Plan
EASD
European Association for the Study of Diabetes
ECG
Electrocardiogram
E-code
Enrolment code
eCRF
Electronic Case Report Form
ePRO
Electronic patient reported outcome
eGFR
Estimated glomerular filtration rate
ESRD
End stage renal disease
EQ-5D-5L
EuroQol five-dimensional five-level questionnaire
FAS
Full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HbA1c
Glycosylated haemoglobin
hCG
Human chorionic gonadotropin
HCP
Health care professional
HF
Heart Failure
HFrEF
Heart failure with reduced ejection fraction
HIV
Human immunodeficiency virus
HR
Hazard ratio
IATA
International Airline Transportation Association
IB
Investigator´s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ID
Identification
International 
Co-ordinating
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
IP
Investigational Product (dapagliflozin or matching placebo) 
IRB/IEC
Institutional review board/ Independent ethics committee


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Abbreviation or 
special term
Explanation
ITT
Intention to treat
IxRS
Interactive Voice/Web Response System
KCCQ
Kansas City Cardiomyopathy Questionnaire
LSLV
Last Subject Last Visit
LIMS
Laboratory information management system
LV
Left ventricular
LVEF
Left ventricular ejection fraction
LVOT
Left ventricular outflow tract
MedDRA
Medical dictionary for regulatory activities
MI
Myocardial infarction
MRA
Mineralcorticoid receptor antagonist
MRI
Magnetic Resonance Imaging
NB
Nota bene
NLI
National lead investigator
NSAIDs
Non-steroidal anti-inflammatory drugs
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association
PCI
Percutaneous Coronary Intervention
PGIC
Patient global impression of change
PGIS
Patient global impression of severity
PGx
Pharmacogenetics research
PI
Principal Investigator 
PK
Pharmacokinetic
PRO
Patient reported outcomes
PTDV
Premature treatment discontinuation visit
RAA
Renin-angiotensin-aldosterone
RAAS
Renin-angiotensin-aldosterone system
RRR
Relative risk reduction
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SCV
Study closure visit
SED
Study end date


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Abbreviation or 
special term
Explanation
SGLT2
Sodium glucose co-transporter 2
SU
Sulfonylurea
T1D
Type 1 diabetes mellitus
T2D
Type 2 diabetes
TIA
Transient ischemic attack
TVI
Time velocity integral
ULN
Upper limit of normal
VAD
Ventricular assistance device
VAS
Visual analogue scale
WBDC
Web Based Data Capture
WHO
Word Health Organization


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Despite advances in management and treatment of chronic heart failure (HF) with reduced 
ejection fraction (HFrEF), HF continues to be a major cause of mortality, initial and recurrent 
hospitalisations, and suboptimal quality of life.  The prevalence and incidence of HF continues 
to increase globally.  An estimated 38 million people are affected by HF worldwide 
(Braunwald 2015) with over 1 million hospitalisations annually in 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) and is projected to increase dramatically as the population 
ages.
The current treatment paradigm for HF involves the simultaneous targeting of multiple 
pathways including the renin-angiotensin-aldosterone axis (RAA), the autonomic system, and 
symptomatic treatment with diuretics.  
Although increased efficacy in the sacubitril/valsartan arm led to early closure of the 
PARADIGM-HF trial, the mortality rate remained high (McMurray et al 2014, Sacks et al 
2014).  Even with best possible treatment, the five year survival rate for HF is worse than for 
most cancers (Braunwald 2015). For patients with chronic HF, worsening symptoms require 
prompt medical attention, add to the burden of hospital and non-hospital settings and also 
have a considerable economic impact (
Ponikowski et al 2016, Okumura et al 2016).
Recently, in patients with type 2 diabetes (T2D) and high cardiovascular (CV) risk, the 
sodium glucose co-transporter 2 (SGLT2) inhibitor, empagliflozin (JARDIANCE™), 
demonstrated a marked reduction in CV mortality (38% relative risk reduction [RRR]), all-
cause mortality (32% RRR) as well as 35% RRR in hospitalisation from HF compared with 
placebo when added to background standard of care treatment (Zinman et al 2015).  In a 
secondary analysis of HF outcomes, empagliflozin reduced the risk of hospitalisation for HF 
or cardiovascular death by 28 % in patients with HF at baseline (Fitchett et al 2016).  
Dapagliflozin (Forxiga™/Farxiga™) is a highly selective and reversible inhibitor of human 
renal SGLT2, the major transporter responsible for glucose reabsorption in the kidney.  
Dapagliflozin’s mechanism of action results in a direct and insulin-independent elimination of 
glucose by the kidneys.  In addition to the improved glycaemic control, the persistent loss of 
glucose with associated calories in the urine, results in a consistent and maintained reduction 
of the total body weight.  Further, dapagliflozin induces a diuresis, natriuresis and a decrease 
in blood pressure without a concomitant increase in heart rate.  
Possible mechanisms for SGLT2 inhibitor benefit in patients with heart failure could include 
osmotic diuresis and reductions in arterial stiffness, weight, blood pressure, serum uric acid 


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and albuminuria.  Other potential mediators include a shift in fat oxidation and increased 
circulating concentrations of ketone bodies which may serve as a more efficient fuel source 
for the failing heart (Ferrannini et al 2016). The alterations in haemodynamics and renal 
physiology are attributed to glucose-independent mechanisms and can therefore be expected 
to be similar even in the absence of diabetes (Rajasekeran et al 2016).
Data on the effect of SGLT2 inhibition in patients without diabetes is limited.  However, 
dapagliflozin has safely been administered in healthy volunteers over a broad dose range (up 
to 500 mg given as single dose) (Kasichayanula et al 2014).  Dapagliflozin effectively 
inhibited SGLT2 also in healthy volunteers without any observed events of hypoglycaemia.  
Furthermore, a clinical study with canagliflozin (INVOKANA™), showed clinically relevant 
blood pressure and weight reductions in obese non-diabetic patients without an increased 
incidence of hypoglycaemia (Bays et al 2013).  
Dapagliflozin has been investigated in a thorough T2D clinical development program.  In 
addition, the trial DECLARE-TIMI58 (D1693C00001) is ongoing and includes >17,000 T2D 
patients with elevated CV risk to evaluate dapagliflozin 10 mg on CV outcome.  
Available data from a CV outcome meta-analysis showed that dapagliflozin is not associated 
with increased CV risk and the results even suggested the potential for a beneficial effect on 
heart failure hospitalisations (Sonesson et al 2016).  In a post-hoc analysis from the pooled 
database from the dapagliflozin development program, patients with a history of T2D and 
concomitant heart failure (171 patients received dapagliflozin 10 mg and 149 patients received 
placebo), had a significant reduction in weight, blood pressure (BP) and glycosylated
haemoglobin (HbA1c) and dapagliflozin was well tolerated.  Volume depletion and 
hypoglycaemia adverse events (AEs) were balanced between the groups (Kosiborod et al 
2015).  Although very few HF hospitalisation events occurred, numerically these favoured 
dapagliflozin vs placebo.
The aim of the proposed study is to investigate the efficacy and safety of dapagliflozin in 
patients with an established diagnosis of HFrEF (with or without T2D) where the prevalence 
and unmet needs for reducing CV mortality and heart failure events as well as improving 
symptoms remain high.
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design and population
This is a randomised, double-blind, parallel-group study.  Randomisation and double blinding 
will minimize potential bias.  This will be a multicentre study in numerous geographic regions 
to provide a wide applicability of results.
The target population includes male and female patients with an established diagnosis of 
HFrEF for ≥2 months, and at high risk of CV death or HF events.  
Although patients may have been previously hospitalised for HF (but prior hospitalisation is 
not required) they must be clinically stable and optimized on HF therapies according to local 


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guidelines at the time of enrolment.  To ensure stability, doses of evidence based HF 
medications (other than diuretics) can neither have been increased nor decreased for at least 4 
weeks prior to inclusion in the study.
The study population will include patients both with and without T2D, as the beneficial 
hemodynamic effects appear to be independent of the glycaemic effect, and can therefore be 
expected in both groups.  It was notable in EMPA-REG outcome study, studying the effect of 
empagliflozin that the reduction in CV death and HF was similar across baseline HbA1c 
subgroups, i.e., did not seem to be dependent on the level of baseline glycaemia.  From 
published data we anticipate that approximately 40% of the HFrEF study population will have 
diabetes (Kristensen et al 2016).  To ensure balance between the diabetic and non-diabetic 
cohorts, stratification will be employed, with inclusion of at least 30% of each of these 
cohorts.  
The control group will receive placebo.  All patients will be treated for their HFrEF according 
to local guidelines on standard of care treatment for HF.
1.2.2
Rationale for primary outcome measure
The main objective of the study is to investigate whether dapagliflozin, compared with 
placebo, reduces the incidence of CV death or hospitalisation for HF or equivalent event (i.e. 
an urgent HF visit) when added to background standard of care treatment.  A HF event is 
defined as hospitalisation for worsening HF or an equivalent event (i.e., an urgent HF visit 
leading to an urgent, unplanned, assessment by a physician (e.g., in an Emergency 
Department) and requiring treatment for worsening heart failure (other than just an increase in 
oral diuretics), in accordance with the draft definition CDISC: Standardized Definitions for 
Cardiovascular and Stroke Endpoint Events in Clinical Trials (Hicks et al 2014).
Acknowledging changing practice patterns and geographic variability in the use of 
hospitalisation in HF treatment, the more inclusive definition of “a heart failure event” is used. 
HF events consisting of both HF hospitalisations and urgent HF visits requiring urgent 
intensification of treatment (as described in the CDISC [Hicks et al 2014]) are components of 
the primary endpoint.  Given the current financial pressures, particularly in the USA, to reduce 
HF hospitalisation, using the more traditional measure of HF hospitalisation only, risks 
missing a significant number of events.
The CDISC definitions of urgent HF visit are similar to those for heart failure hospitalisation 
(except that an increase in oral diuretic is not sufficient to qualify as a significant increase in 
HF therapy) and provide robust and objective criteria for accurately capturing true cases of 
worsening HF.  The rationale for including outpatient urgent 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.  Importantly, episodes of 
worsening HF treated in the outpatient or emergency department setting are associated with an 
increased risk of subsequent death similar to that seen following a hospital admission 
(Okumura et al 2016).  


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1.2.3
Rationale for secondary outcome measure
The rationale for including CV death or hospitalisation for HF, but excluding non-hospitalised 
urgent HF visits, is that this is the more conventional composite HF endpoint, may be 
regarded as including “harder” outcomes and will allow direct comparison with other HF 
trials.  
The rationale for including total number of hospitalisations (including re-hospitalisations) for 
HF is to capture the impact of recurrent non-fatal HF hospitalisations.  Taken together with 
CV death, these events give a better estimate of the full burden of HF on patients and health-
care systems than time-to-first event analysis.  This outcome also provides a more detailed 
understanding of the potential treatment benefit in patients with chronic HF as it takes account 
of the effect of therapy on additional as well as first events.  
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 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 (Green et al 2000, Spertus et al 2005).
The rationale for the secondary renal composite endpoint is that renal dysfunction is very 
common in heart failure, may lead to discontinuation of disease-modifying therapies and is 
associated with poor outcomes.  SGLT2 inhibition has previously shown beneficial effects on 
renal outcomes in patients with T2D and concurrent established cardiovascular disease (CVD) 
(
Wanner et al 2016) and if this effect was also found in HF it could be of considerable benefit.  
This potential renal benefit is simultaneously being evaluated in a separate study evaluating 
dapagliflozin treatment on renal outcomes in patients with chronic kidney disease (CKD).
All-cause mortality will be assessed as a secondary endpoint because it is important to 
evaluate the effect of dapagliflozin on non-cardiovascular, as well as cardiovascular, mortality 
and hence overall mortality.  
1.2.4
Rationale for dose selection
The marketed dose (10 mg) of dapagliflozin has been demonstrated to be well tolerated and 
effective for the treatment of T2D but the efficacy on CV mortality and/or HF outcomes in 
patients with HF has not been evaluated.  From a pharmacokinetic and pharmacodynamics 
perspective, 10 mg dapagliflozin is appropriate for use in patients with HF as this dose is 
expected to near maximally inhibit SGLT2 in the kidney.  Also this dose was found to be well 
tolerated in a CKD stage 3 study (estimated glomerular filtration rate (eGFR) 30 to 60 
mL/min/1.73m2) (Kohan et al 2014).  In addition to the preferred 10 mg dose, the marketed 5 
mg dose of dapagliflozin may be used in the study when clinically indicated, however, it is 
expected to provide less inhibition of renal SGLT2 and thus exert less pharmacodynamics 
effects, see Section 3.9.1, for details.


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1.3
Benefit/risk and ethical assessment
Dapagliflozin has global market approval and based on global cumulative sale figures up to 
March 2016 it is estimated that dapagliflozin has been administered  for >1 000 000 patient 
years.  
1.3.1
Potential risks
Details regarding potential risks associated with administration of dapagliflozin once daily are 
provided in the Investigator’s Brochure (IB). Additional considerations relevant for the target 
population are described below.
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.
Events related to volume depletion (including reports of dehydration, hypovolemia, or 
hypotension) and events related to changes in renal function have been thoroughly evaluated 
in the dapagliflozin phase III program. In a large pool consisting of 21 active- and placebo-
controlled studies, serious adverse events (SAEs) of volume depletion were infrequently 
reported and the proportion was lower for patients treated with dapagliflozin than control 
(0.1% versus 0.2%). SAEs of renal impairment/failure were also rarely reported and balanced 
between treatment groups in the clinical trial program. Nine (0.2%) SAEs were reported in the 
dapagliflozin group and 5 (0.1%) SAEs were reported in the control group.
In a recent analysis of patients with pre-existing HF using pooled data from previous 
dapagliflozin studies (Kosiborod et al 2016), the rate of hypovolemic events was similar 
between dapagliflozin and placebo.
Although the phase III data in patients with CKD 3 show an increased frequency of overall 
renal events in patients treated with dapagliflozin as compared with placebo, most of these 
events have been related to laboratory detected transient increases in creatinine.  
In an analysis using pooled data on a subset of patients with CKD 3, micro or macro 
albuminuria and treatment with angiotensin converting enzyme inhibitor (ACE-I) or 
angiotensin receptor blockers (ARB) there was no meaningful difference between 
dapagliflozin and placebo in terms of SAEs of renal impairment/failure or SAEs of volume 
depletion (Sjöström et al 2015).
Loop-diuretics are widely used in the target patient population and are also allowed in this 
study.  In the dapagliflozin phase III program, patients using loop diuretics were more likely 
to have an event related to volume depletion regardless of whether they were treated with 
dapagliflozin or placebo. During the short-term period a pooled analysis showed 6 (2.5%) 
subjects with events in patients on dapagliflozin 10 mg and 4 (1.5%) in patients on placebo.  
When including the long-term extension periods of the phase III trials in the analysis, the 
corresponding values were 7 (3.0%) versus 7 (2.7%) for dapagliflozin and placebo, 
respectively.  


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Furthermore, other post hoc safety analyses of importance to the current target population 
have not identified any indication of an increased risk of marked abnormalities in potassium 
levels ( ≥ 6mmol/L) in either patients with CKD 3 and ACE-I/ARB treatment (Sjöström et al 
2015) or in patients on concomitant treatment with potassium sparing agents (Kosiborod et al 
2016).
1.3.1.1
Protection against risks
This study has been designed with appropriate measures in place to monitor and minimize any 
potential health risks to participating patients. In order 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.  
1.3.2
Potential benefits to patients
All HF patients in the study will be optimally treated according to standard of care and 
dapagliflozin or placebo will be administered on top of this treatment. The hypothesis is that 
dapagliflozin will reduce CV mortality or hospitalisation of HF or equivalent event in patients 
randomised to active drug. Dapagliflozin is also known to decrease body weight (or prevent 
weight gain) as well as lower BP and is believed to be nephroprotective through non-
glycaemic mechanisms.
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.  
1.3.3
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 patients who meet the inclusion/exclusion criteria and consent to take part in 
the study.  At the time of writing this clinical study protocol, no available SGLT2 inhibitor is 
indicated for HF risk reduction in patients with HFrEF.  The Phase IIb/III program in T2D has 
established the efficacy and safety of dapagliflozin in lowering glucose (as assessed by 
HbA1c).  Another SGLT2 inhibitor, empagliflozin, has demonstrated reduction in HF 
hospitalisation and CV mortality in patients with T2D and CVD (Zinman et al 2015).  The 
dapagliflozin programme has also provided hypothesis-generating data suggesting lower 
incidence of hospitalisation for HF with dapagliflozin treatment.  This clinical study will test 
this hypothesis in a rigorous fashion. The potential results could offer substantial benefit to 
patients with HFrEF.  
1.4
Study Design 
This is an international, multicentre, parallel group, event-driven, randomised, double-blind, 
placebo-controlled study in patients with chronic HFrEF, evaluating the effect of dapagliflozin 


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10 mg versus placebo, given once daily in addition to background standard of care therapy, 
for the prevention of CV death or reduction of HF events.  
It is estimated that approximately 7000 patients at approximately 500-600 sites in 20-25 
countries will be enrolled to reach the target of approximately 4500 randomised patients.  The 
investigational product (IP) will be added to the prescribed background therapy for HF (and 
background therapy for T2D when applicable) as considered appropriate by the investigator 
and in accordance with regional standards of care.  
The anticipated duration of the study is approximately 33 months.  The study closure 
procedures will be initiated when the predetermined number of primary endpoints is predicted 
to have occurred (n=844), i.e., the study end date (SED) (see Figure 1).  The study duration 
may be changed if the event rate or randomisation rate is different than anticipated.  The study 
may be terminated early if either a clear beneficial or harmful effect of the study treatment is 
detected during the DMC review.
An echocardiographic sub-study is planned to be conducted in a subset of patients (approx. 
300-400 patients) in the Dapa-HF trial. The sub-study is designed to evaluate the impact of 
dapagliflozin at a dose of 10 mg daily, compared to placebo, in addition to conventional heart 
failure treatment, on changes in cardiac structure and function as determined by 
echocardiography.


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Figure 1
Study flow chart 


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine whether dapagliflozin is superior 
to placebo, when added to standard of care, in 
reducing the incidence of CV death or a HF 
event (hospitalisation for HF or equivalent HF 
event, i.e., an urgent HF visit).  
Time to the first occurrence of any of the components 
of this composite: 
1.
CV death
2.
Hospitalisation for HF
3.
An urgent HF visit 
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To compare the effect of dapagliflozin versus 
placebo on CV death or hospitalisation for HF.
Time to the first occurrence of either of the 
components of this composite: 
1.
CV death 
2.
Hospitalisation for HF
To compare the effect of dapagliflozin versus 
placebo on total number of recurrent HF 
hospitalisations and CV death.  
Total number of (first and recurrent) HF 
hospitalisations and CV death.  
To compare the effect of treatment with 
dapagliflozin versus placebo on the KCCQ 
total symptom score for HF symptoms and 
physical limitations.
Change from baseline measured at 8 months in the 
total symptom score of the KCCQ, a specific HF 
patient reported outcome questionnaire.


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To determine if dapagliflozin compared with 
placebo reduces the incidence of a composite 
endpoint of worsening renal function.  
Time to the first occurrence of any of the components 
of this composite:
1.
≥50% sustained* decline in eGFR
2.
Reaching End Stage Renal Disease 
(ESRD) 

Sustained* eGFR 
<15 ml/min/1.73m2 or,

Chronic* dialysis treatment or,

Receiving a renal transplant
3.
Renal death 
*As defined in the Clinical Event Adjudication (CEA) charter
To determine whether dapagliflozin, compared 
with placebo, reduces the incidence of all-
cause mortality.  
Time to death from any cause.
2.3
Safety objectives
Safety Objective:
Outcome Measure :
To evaluate the safety and tolerability of 
dapagliflozin in this patient population.  
1.
Serious Adverse Events (SAEs)
2.
Discontinuation of IP due to Adverse 
Events (DAEs)
3.
Changes in clinical 
chemistry/haematology parameters 
4.
AEs of interest (volume depletion, renal 
events, major hypoglycaemic events, 
fractures, Diabetic ketoacidosis (DKA), 
AEs leading to amputation and AEs 
leading to a risk for lower limb 
amputations [“preceding events”])


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2.4
Exploratory objectives
Exploratory Objective:
Outcome Measure :
To compare the effect of dapagliflozin versus 
placebo on an expanded composite outcome 
reflecting worsening of HF.  
Time to the first occurrence of any of the components 
of the expanded composite worsening HF outcome: 
1.
CV death
2.
Hospitalisation for HF
3.
An urgent HF visit
4.
Documented evidence of worsening HF 
symptoms/signs leading to initiation of a 
new treatment for HF sustained for at least 
4 weeks or augmentation of existing oral 
therapy for HF (eg, increase in dose of 
diuretic) sustained for at least 4 weeks.  
To determine whether dapagliflozin compared 
with placebo will have effect on New York 
Heart Association (NYHA) class.
Change in NYHA class from baseline.
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of 
diagnosis of atrial fibrillation (AF) in patients 
without history of AF at baseline.
Proportion of patients without history of AF at 
baseline with a new diagnosis of AF during the study.
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of hyper – and hypokalaemia.  
Time to the first occurrence of each of any of the 
following central lab levels of serum potassium:

>6.0 mmol/L

>5.5 mmol/L

<3.5 mmol/L

<3.0 mmol/L
To determine whether dapagliflozin compared 
with placebo will affect the number of events 
of doubling of serum creatinine.
Number of events with doubling of serum creatinine 
(compared with the most recent laboratory 
measurement).
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of 
diagnosis of T2D in patients without diabetes 
at baseline.  
Proportion of patients without T2D at baseline with a 
new diagnosis of T2D during the study.  
To determine whether dapagliflozin compared 
with placebo will have effect on HbA1c in 
T2D subgroup.
Changes in HbA1c from baseline.  
To determine whether dapagliflozin compared 
with placebo will have an effect on systolic 
BP.
Change in systolic BP from baseline.


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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 reduce the incidence of 
myocardial infarction (MI).
Time to first fatal or non-fatal MI.
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of any 
stroke (ischemic, haemorrhagic, or 
undetermined).
Time to first fatal or non-fatal stroke of any cause.
To compare the effect of dapagliflozin versus 
placebo on health status assessed by Patient 
Global Impression of Change (PGIC) and 
Patient global impression of severity (PGIS) 
questionnaires.
Changes in health status measured by PGIC and 
PGIS.
To compare the effect of dapagliflozin versus 
placebo on health status assessed by EuroQol 
five-dimensional five-level questionnaire (EQ-
5D-5L) to support health economic analysis 
and health technology assessment.
Changes in health status measured by EQ-5D-5L.
To collect and analyse pharmacokinetic (PK) 
samples for dapagliflozin concentration.
Not applicable.  Results will be reported separately.
To assess cardiac structure and function with 
echocardiography at baseline and 8 months 
follow-up.
Not applicable.  Results will be reported separately.
To collect and store samples of plasma and 
serum for future exploratory biomarker 
research.
Not applicable.  Results will be reported separately.
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of signed informed consent prior to any study specific procedures
2.
Male or female, aged ≥18 years at the time of consent


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3.
Established documented diagnosis of symptomatic HFrEF (New York Heart 
Association (NYHA) functional class II-IV), which has been present for at least 2 
months and is optimally treated with pharmacological and/or device therapy, as 
indicated
NB: Patients in which additional pharmacological or device therapy is 
contemplated, or should be considered, must not be enrolled until therapy has been 
optimized and is stable for ≥1 month.  
4.
Left ventricular ejection fraction (LVEF) ≤40% (echocardiogram, radionuclide 
ventriculogram, contrast angiography or cardiac MRI ) within the last 12 months 
prior to enrolment (Visit 1):

If there is more than one assessment of LVEF the value from the most recent 
measurement should be used in assessing eligibility

Patients undergoing coronary revascularization (percutaneous coronary 
intervention (PCI) or coronary artery bypass grafting (CABG)), valve 
repair/replacement or implantation of a cardiac resynchronization therapy 
(CRT) device or any other surgical, device or pharmacological intervention (ie 
initiation of a beta-blocker) that might improve LVEF must have a 
measurement of LVEF at least 3 months after the intervention in order to be 
eligible
NB: Patients with known HFrEF but without a recent (≤12 months) assessment of 
left ventricular (LV) function will undergo a local echocardiogram at the time of 
enrolment.  
5.
N-terminal pro b-type natriuretic peptide (NT-proBNP)  >600 pg/ml (or if 
hospitalised for heart failure within the previous 12 months, NT-proBNP ≥400 
pg/ml) at enrolment (visit 1)

If concomitant atrial fibrillation or atrial flutter at Visit 1, NT-proBNP must be 
≥900 pg/ml (irrespective of history of heart failure hospitalisation)
6.
Patients should receive background standard of care for HFrEF and be treated 
according to locally recognized guidelines with both drugs and devices, as 
appropriate.  Guideline-recommended medications should be used at recommended 
doses unless contraindicated or not tolerated.  Therapy should have been 
individually optimized and stable for ≥4 weeks (this does not apply to diuretics –
see NB below) before visit 1 and include (unless contraindicated or not tolerated): 

an ACE inhibitor, or ARB or sacubitril/valsartan  
and

a beta-blocker


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and

if considered appropriate by the patient’s treating physician; a 
mineralocorticoid receptor antagonist (MRA)
NB: Most patients with heart failure require treatment with a diuretic to control 
sodium and water retention leading to volume overload.  It is recognized that 
diuretic dosing may be titrated to symptoms, signs, weight and other information 
and may thus vary.  Each patient should, however, be treated with a diuretic 
regimen aimed at achieving optimal fluid/volume status for that individual.
7.
eGFR ≥30 ml/min/1.73 m2 (CKD-EPI formula) at enrolment (visit 1)
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or
previous intolerance of an SGLT2 inhibitor
2.
Type 1 diabetes mellitus (T1D)
3.
Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements 
either at visit 1 or visit 2.
4.
Current acute decompensated HF or hospitalisation due to decompensated HF <4
weeks prior to enrolment
5.
MI, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior 
to enrolment
6.
Coronary revascularization (percutaneous coronary intervention [PCI] or coronary 
artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks 
prior to enrolment or planned to undergo any of these operations after 
randomisation  
7.
Implantation of a CRT within 12 weeks prior to enrolment or intent to implant a 
CRT device
8.
Previous cardiac transplantation or implantation of a ventricular assistance device 
(VAD) or similar device, or implantation expected after randomisation
9.
HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, 
hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease
10.
Symptomatic bradycardia or second or third degree heart block without a 
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11.
Any condition outside the CV and renal disease area, such as but not limited to 
malignancy, with a life expectancy of less than 2 years based on investigator´s
clinical judgement
12.
Active malignancy requiring treatment at the time of visit 1(with the exception of 
successfully treated basal cell or treated squamous cell carcinoma)
13.
Hepatic impairment (aspartate transaminase [AST] or alanine transaminase [ALT] 
>3x the upper limit of normal [ULN]; or total bilirubin >2x ULN at time of 
enrolment). An isolated increase in bilirubin in patients with known Gilbert’s 
syndrome is not a reason for exclusion.   
14.
Known blood-borne diseases such as specified in Appendix B (category A and B)
15.
Severe (eGFR <30 mL/min/1.73 m2 by CKD-EPI), unstable or rapidly progressing 
renal disease at the time of randomisation
16.
Women of child-bearing potential (i.e., those who are not chemically or surgically 
sterilised or who are not post-menopausal) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator, from the time of signing the informed consent throughout the study 
and 4 weeks thereafter, OR women who have a positive pregnancy test at enrolment 
or randomisation OR women who are breast-feeding
17.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca personnel and/or personnel at the study site)
18.
Previous randomisation in the present study
19.
Participation in another clinical study with an IP during the last month prior to 
enrolment
20.
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
NB: Patients who cannot complete the electronic patient reported outcome (ePRO) 
assessments can still participate in the study (see Section 5.1.11.5 for details regarding 
the patient exclusion from the ePRO assessments during certain circumstances).
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.


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The Investigator(s) will:
1.
Obtain signed informed consent from the patient or their guardian/legal 
representative before any study specific procedures are performed.
2.
Assign patient a unique enrolment number, beginning with ‘E#’, which will be used 
to identify the patient throughout the study.  The enrolment code (E-code) will be 
assigned in the Interactive Voice/Web Response System (IxRS).
3.
Determine patient eligibility, see Section 3.
4.
At visit 2, perform the randomisation transaction in the IxRS system.
Re-enrolment one single time is allowed considering that the patient has not been previously 
randomised.  The same E-code that the patient received at the first enrolment will be used.  All 
enrolment assessments and procedures, including re-signing the informed consent form, 
should be performed again.
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment.  Study treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the patient. In those cases where continuation of study therapy 
is judged not to present a concern related to safety and disease management, the rationale for 
continuing study therapy must be clearly documented. Regardless of what is decided about IP, 
all randomised patients should remain in the study and the patients should continue to be 
followed up in accordance with defined study procedures.  
3.5
Methods for assigning treatment groups
Randomisation to IP will be performed via IxRS at Visit 2 in balanced blocks to ensure 
approximate balance between the treatment groups (1:1).  
The IxRS will allocate the IP through a randomisation scheme and provide the randomisation 
number and the appropriate Kit IDs from IP available at the study site.  The randomisation
codes will be computer generated and loaded into the IxRS database.  


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At all visits where IP is dispensed, site personnel will do a kit verification in IxRS before
providing the IP bottle to the patient.  Detailed instruction on how to use the IxRS system will 
be provided to study sites.  
3.5.1
Stratification and capping
The recruitment will be continuously monitored in order to achieve adequate proportions of 
patient sub-populations.  
3.5.1.1
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.  T2D at the time of randomisation is based on: 

Established diagnosis of T2D 
OR 

HbA1c more or equal to 6.5% (48 mmol/mol) shown at central laboratory 
test at enrolment (visit 1) 
3.5.1.2
Capping
The intent is to enrol as typical cross-section of patients with HFrEF 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 and atrial fibrillation status may be capped in IxRS 
to avoid over- or under-representation of these patient subgroups.  
3.6
Methods for ensuring blinding
The blinding of treatment is ensured by using a double-blind technique.  The dapagliflozin 
tablets and the respective placebo tablets will be identical in size, colour, smell, and taste.  The 
bottles with IP will be labelled with unique identification numbers.
No member of the extended AZ study team, personnel at study sites, or any clinical research 
organisation (CRO) handling study data will have access to the randomisation scheme during 
the study.  The AstraZeneca (AZ) personnel or delegate generating the randomisation scheme 
and the Supply Chain Study Management may be able to access the randomisation scheme as 
appropriate.


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3.7
Methods for unblinding 
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 treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
investigator documents and reports the action to AZ, without revealing the treatment given to 
patient to the AZ personnel.  It is always the investigator who decides when to unblind but it is 
recommended that the investigator first contacts the AZ study physician for consultation 
regarding the need for unblinding.  If unblinding is deemed necessary, the investigator can 
perform the unblinding in IxRS and must document all actions taken.  The number of 
individuals at the study site who become aware of treatment status should be kept to the 
absolute minimum (including keeping the patient blinded if possible).  Treatment with study 
medication should be continued if possible.  
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 regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.
3.7.1
Unblinding for bioanalytical laboratory personnel
PK samples will be analysed at the bioanalytical laboratory only for patients on active IP.  The 
bioanalytical laboratory will therefore have access to the treatment codes but will not share the 
codes with the sponsor or others involved in the study until the blinding is broken for the 
study after closure.
3.8
Restrictions
There are no specific dietary or activity restrictions.  For restricted concomitant medications 
see Section 7.7.
3.9
Discontinuation of investigational product (IP)
If the patient temporarily or permanently discontinues from IP, it is important that the 
scheduled study visits, data collection and procedures continue according to the study protocol 
until study closure (see Section 3.9.3).
Patients may be discontinued from IP in the following situations:
1.
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.  
2.
AE or other safety reasons that, in the opinion of the investigator, contraindicates 
further dosing with IP.


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3.
Severe non-compliance with the study protocol. 
4.
DKA, consider to temporary interrupt IP if DKA is suspected.  If DKA is 
confirmed, IP should be discontinued permanently.
5.
Positive pregnancy test (discontinue IP and notify AZ representative).
3.9.1
Evaluation of volume status and investigational product (IP) dose 
reduction/interruption
Dapagliflozin is a SGLT2 inhibitor which by its mechanism of action reduces the reabsorption 
of glucose and sodium in the proximal tubules in the kidney.  SGLT2 inhibition has a mild 
diuretic effect and an initial haemodynamic change with an initial increase in creatinine may 
occur.  
Unexpected acute declines in eGFR
If an unexpected, acute decline in kidney function is observed, the patient should be evaluated.  
Volume depletion, hypotension, inter-current medical problems and concomitant drugs may 
cause increases in blood creatinine.  Urinary tract infection and urinary obstruction should be 
considered (the latter especially in men).  Several drugs may cause a decline in kidney 
function, especially non-steroidal anti-inflammatory drugs (NSAIDs) 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.
Volume depletion/hypotension
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should have their regular medication reviewed, and consideration given to 
reducing the dose of, or stopping concomitant non-essential medications, as assessed on an 
individual basis, including diuretics and drugs that lower blood pressure (except essential 
treatments – see below).  The need for conventional diuretics (or the dose of diuretic used) 
should be re-evaluated in light of the patient’s symptoms and signs.  In patients with heart 
failure, discontinuation of diuretic should only be undertaken cautiously.  Hypotension may 
also occur with other blood pressure lowering drugs and once again the need for (and dose of) 
non-essential agents of this type (e.g., calcium channel blockers, alpha adrenoceptor 
antagonists and nitrates) should also be re-considered.
IP dose reduction
If the above mentioned measures do not lead to a resolution of clinically relevant volume 
depletion, hypotension and/or unexpected worsening of kidney function, a dose reduction of 
IP to dapagliflozin 5 mg or matching placebo may be considered and the patient’s condition 
re-evaluated after any dose adjustment. 


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Essential treatments
Essential disease modifying/evidence based treatments such as ACE-I or ARBs or 
sacubitril/valsartan, mineralocorticoid receptor antagonists and beta-blockers for patients with 
HF, should NOT be reduced in dose or discontinued unless all other measures fail to improve 
the patient’s situation. In the setting of acute worsening of HF or other acute situations it may 
be acceptable to interrupt treatment on a temporary basis in certain circumstances (eg, an 
ACE-I/ARB if the patient has experienced a significant deterioration in renal function, a beta-
blocker if the patient is unduly bradycardic or hypotensive, an MRA if the patient has 
hyperkalaemia).
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.
3.9.2
Investigational product (IP) restart or dose increase from dapagliflozin 5 mg to 
10 mg or matching placebo
Restart of randomised IP is always encouraged.  Whenever possible, randomised IP should be 
restarted if stopped or the dose increased if previously reduced.  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.
Every attempt should be made to maintain patients on dapagliflozin 10 mg or matching 
placebo during the course of the study.  If the dose has been decreased to 5 mg or interrupted, 
the dose should be increased back to dapagliflozin 10 mg or matching placebo or re-
introduced as soon as, in the opinion of the investigator, the patient’s condition is stable.
3.9.3
Procedures for discontinuation of a patient from investigational product (IP) 
At any time, patients are free to discontinue IP.  A patient that decides to discontinue will 
always be asked about the reason(s) and the presence of any AEs.  If possible, the patient will 
be seen and assessed by an investigator.  Adverse events will be followed up, see Section 6, 
and all IP should be returned by the patient.
Generally AEs, SAEs and potential endpoint events should not lead to IP discontinuation, 
unless there is a clear clinical rationale to do so.
Discontinuation from IP is not the same as complete withdrawal from the study.  If a patient is 
completely withdrawn from study, see Section 3.10.2.


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It is essential to collect data for all patients throughout the study.  Optimally, a patient who 
discontinue from IP should for that reason attend all study visits according to plan until study 
closure.  Alternatively, if the patient does not agree to this approach, modified follow-up 
should be arranged.  Patients who agree to some kind of modified follow up are still 
participating in the study.  The modified visits and procedures that are done will be recorded 
in the electronic Case Report Form (eCRF).
If a patient for some reason cannot be reached during the study, every attempt should be made 
to retrieve as much information regarding this patient as possible.  The site should 
continuously try to reach the patient, the patient’s family or pre-identified contact person and 
search for information regarding the patient’s status in applicable sources to protect the 
validity of data.  The attempts should be registered in the medical records.  
3.9.3.1
Patient undergoes the premature treatment discontinuation visit (PTDV) and 
continues according to plan
The preferred follow-up approach for all patients who prematurely and permanently 
discontinue IP is that the patient undergoes the premature treatment discontinuation visit 
(PTDV) and then continues study visits according to plan (see Table 1).  The PTDV should be 
done as soon as possible after last IP dose.  
3.9.3.2
Patient agrees to undergo modified follow-up
If the patient does not agree to continue study visits according to plan, but agrees to undergo 
modified follow up, a PTDV should be done (see Section 4.2.6).  The subsequent visits until 
the study closure will be done as modified follow-up (e.g., less frequent visits, regular 
telephone contacts, a contact at study closure, or other means) in order to ascertain whether 
any endpoints or safety events have occurred.  
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are enrolled patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Screen Failure’ (i.e., patient does not meet the required inclusion/exclusion 
criteria) in the eCRF.  This reason for study withdrawal is only valid for screen failures (not 
randomised patients).
3.10.2
Withdrawal of informed consent
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 does 
not agree to any kind of further assessments or contact whatsoever.  If agreed by the patient, a 
PTDV should be performed.  Discontinuation of IP in itself is not considered withdrawal of 
consent.


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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 consent 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.  Data 
generated to the time of complete withdrawal from the study will not be destroyed.  
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 completely, in compliance with local 
privacy laws/practices.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, patients are placed at undue risk 
because of clinically relevant findings.  The judgment may be based on recommendations 
from the DMC, see DMC Charter for details.  The study can also be stopped based on results 
of the interim analysis (see Section 8.5.6).
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 
The schedule of study visits and assessments is shown in Table 1 and explained further in Sections 4.1 and 4.2.
Table 1
Study plan
Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontin-
uation 
visit 
(PTDV)
Study 
closure 
visit 
(SCV)
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
Day 360 
(±14 and 
every 4th
month)
≤6 weeks 
from SED
Sign Informed Consent 
Form (ICF)
X
4.1.1
Enrolment in IxRS
X
4.1.1
Local laboratory 
assessment of NT-
proBNPa
Xa
4.1.1
Inclusion/exclusion 
criteria
X
X
3.1
Demography 
X
4.1.1
Medical/surgical history
X
4.1.1
General physical 
examination
X
X
X
5.2.2
Targeted physical 
examination
X
X
X
X
X
X
5.2.2


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Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontin-
uation 
visit 
(PTDV)
Study 
closure 
visit 
(SCV)
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
Day 360 
(±14 and 
every 4th
month)
≤6 weeks 
from SED
Assessment of left 
ventricular functionb
X
4.1.1
Echocardiographic 
assessment of cardiac 
structure and functionc
X
X
4.1.1
5.8
NYHA Functional 
Classification
X
X
X
X
X
5.1.6
Electrocardiogram (ECG)
X
5.2.3
Height
X
5.2.4.2
Vital signs (BP, pulse 
and body weight)
X
X
X
X
X
X
X
X
X
5.2.4
Pregnancy testing
X
X
4.1.1
Randomisation in IxRS
X
3.5
Concomitant medication 
and cardiac and HF 
related procedures
X
X
X
X
X
X
X
X
7.7
Central laboratory 
assessmentsd
X
X
X
X
X
X
X
X
X
5.2.1
PK sampling (pre-dose)e
X
5.4


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Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontin-
uation 
visit 
(PTDV)
Study 
closure 
visit 
(SCV)
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
Day 360 
(±14 and 
every 4th
month)
≤6 weeks 
from SED
ePRO questionnairesf
X
X
X
Xf
X
X
5.1.9
Potential endpoint events, 
SAEs, DAEs, AEs of 
interestg       
X
X
X
X
X
X
X
X
X
5.1.1
Dispense IP (including 
kit verification in 
IxRS)/Collect IP
Xh
X
X
X
Xi
Xi
7.2
IP compliance reminder
X
X
X
X
X
X
7.5
Sample for future 
biomarker research, 
optionalj
X
X
5.7
a
Local laboratory assessment is optional and may be used to assess eligibility (according to local routine) of NT-proBNP. If used, the ICF need to be signed before the 
optional assessment starts. 
b
LV assessments should be done if no assessment has been performed within 12 months prior to enrolment, or if the results of prior assessments are unavailable.
c 
Only for patients in the echocardiography substudy: A baseline echocardiographic assessment will occur after eligibility is confirmed and prior to the randomization at 
visit 2. A follow up echocardiogram will occur at visit 6.
d
Central laboratory assessments include alkaline phosphatase (ALP), ALT, AST, bilirubin, blood urea nitrogen (BUN), creatinine (including eGFR assessment), 
haematocrit, haemoglobin (Hb), HbA1c, NT-proBNP, phosphate, potassium, and sodium, as specified in Table 2.
e
PK samples will be collected at visit 7.
f
PGIS, KCCQ, EQ-5D-5L will be filled in at visit 2,5,6,7 and every 12 months after visit 7, and at PTDV and SCV.  PGIC will be filled in at the same visits, with 
exception of visit 2.
g  
SAEs will be collected from the time of informed consent throughout the study until and including the patient’s last visit.  Potential endpoints, DAEs, AEs leading to dose 
reduction and temporary interruptions and AEs of interest will be collected from randomisation throughout the study until and including the patient’s last visit.


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h         IP Dispensation only 
i
IP Collection only. 
j
Blood samples for potential future biomarker research will be collected at visit 2 and visit 7 and may be analysed at the discretion of AstraZeneca.  The biomarker 
sampling is subject to separate approval/consent by the patient and is optional.


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4.1
Enrolment period
4.1.1
Visit 1, Enrolment (Day -14±7)
During enrolment period the following assessments and procedures will be completed:

Patient signs the ICF before any study procedures.

Patients who agree to the optional sampling of blood for potential 
future biomarker research will provide their consent.  The biomarker 
consent is optional and included in the main ICF.  

The patient will be enrolled and assigned an E-code in IxRS.  

Optional local laboratory assessment
Failure to meet the criteria for NT-proBNP is expected to be the main 
reason for screen failure in this study.  Therefore, sites will be allowed to 
perform an optional pre-study assessment, which will comprise of local 
assessment of NT-proBNP.  Investigators will only assess patients who 
are potentially eligible for the study based on their medical conditions 
and existing therapies, and only those who are expected to meet all other 
entry criteria.
Local laboratory assessment of NT-proBNP will be done according to 
local routine.  
When the local results of NT-proBNP are available and indicate that the patient may be 
eligible based on the clinical judgement of the investigator, the patient may proceed to further 
enrolment procedures:

The investigator reviews the inclusion and exclusion criteria.  Patients 
who do not meet these criteria must not be randomised in the study.

Demography (date of birth, sex, race, ethnic group) and relevant 
medical and surgical history, including smoking history, will be 
recorded.

The investigator will perform a general physical examination (see 
Section 5.2.2).

Assessment of left ventricular function will be performed if no 
assessment has been performed within 12 months prior to enrolment 
(preferably by an echocardiogram).

NYHA Functional Classification will be evaluated.


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
ECG will be recorded.

Vital signs (BP, pulse and body weight) and height will be assessed and 
recorded.  

Laboratory samples will be collected and sent to central laboratory as 
specified in Table 2.  

Pregnancy test for women of child-bearing potential will be done locally 
with a dipstick provided by central laboratory.  
4.2
Treatment period
4.2.1
Visit 2, Randomisation (Day 0)
Prior to visit 2, the investigator will review laboratory results received from the central 
laboratory and assess eligibility based on the laboratory results from visit 1.  Patients not 
eligible will be considered screen failures and should not continue to visit 2.
At randomisation, the following assessments and procedures will be done:

PGIS, KCCQ and EQ-5D-5L will be completed by the patient prior to 
any other site activities and before the patient meets the investigator.  

The investigator will re-assess the inclusion and exclusion criteria.

Vital signs will be assessed and recorded.

The investigator will perform a targeted physical examination with 
focus on signs for HF and volume status.

Pregnancy test for women of child-bearing potential will be done locally 
with a dipstick provided by central laboratory.

Randomisation to IP will be done in IxRS.
-
For stratification/capping purposes, the information whether patient 
has T2D or AF, LVEF value and NYHA class will be recorded in 
IxRS (see Section 3.5.1).

Concomitant medications and cardiac and HF related procedures
will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.  


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-
Patients who have consented to sampling for potential future 
biomarker analysis, will provide blood samples for this purpose.

If the patient has experienced any SAEs since last visit, this will be 
recorded in the eCRF.

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.

For patients who are part of the echocardiographic sub-study, a baseline 
echocardiogram will be obtained after eligibility is confirmed and prior to 
initiation of IP.
4.2.2
Visit 3 (Day 14±3) and Visit 4 (Day 60±7)
At visit 3 and visit 4, the following assessments and procedures will be done:

The investigator will perform a targeted physical examination with 
focus on signs for HF and volume status.

Vital signs will be assessed and recorded.  

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded, see Section 7.7.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.  

If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.  

The patient will continue taking the study medication dispensed at the 
last visit.  IP compliance will be discussed.  The patient will be reminded 
to take the IP in accordance with protocol and without interruptions.
4.2.3
Visit 5 (Day 120±7)
At visit 5, the following assessments and procedures will be done:

ePRO questionnaires will be completed by the patient prior to any other 
site activities and before the patient meets the investigator.  

The investigator will perform a targeted physical examination with 
focus on signs for HF and volume status.  


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
NYHA Functional Classification will be evaluated.

Vital signs will be assessed and recorded.  

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.

If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

New IP will be dispensed via IxRS to the patient and drug accountability 
of the returned medication will be checked.  The patient will be reminded 
to take the IP in accordance with protocol and without interruptions.  
4.2.4
Visit 6 (Day 240±14)
At visit 6, the following assessments and procedures will be done:

ePRO questionnaires will be completed by the patient prior to any other 
site activities and before the patient meets the Investigator.  

The investigator will perform a targeted physical examination with 
focus on signs for HF and volume status.  

NYHA Functional Classification will be evaluated.

Vital signs will be assessed and recorded.

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.

If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.  

New IP will be dispensed via IxRS to the patient and drug accountability 
of the returned medication will be checked.  The patient will be reminded 
to take the IP in accordance with protocol and without interruptions.  


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
Remind the patient that at visit 7 there will be pre-dose PK sampling.  
The day of visit 7 the patient must delay the intake of study medication 
until after the visit.

For patients who are part of the echocardiographic sub-study a final 
echocardiogram will be done at visit 6.
4.2.5
Visit 7, 8, 9 etc (Day 360±14; and every 4th month ±14 days)
At visit 7 and all subsequent on-site visits until SCV, the following assessments and 
procedures will be done:

ePRO questionnaires will be completed by the patient prior to any other 
site activities and before the patient meets the investigator, at visit 7 and 
every 12 months thereafter, i.e., visit 10, 13 etc.

The investigator will perform a targeted physical examination with 
focus on signs for HF and volume status.  

Vital signs will be assessed and recorded.  

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.  
-
At visit 7, pre-dose, a PK sample will be collected.  This day the 
patient must delay the intake of IP until after the visit.  The date and 
time of last dose before sampling will be recorded in eCRF.
-
At visit 7, patients who have consented to sampling for potential 
future biomarker analysis, will provide blood samples for this 
purpose.

If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

IP will be dispensed via IxRS to the patient and drug accountability of 
the returned medication will be checked.  The patient will be instructed to 
take the IP in accordance with protocol without interruptions.  
4.2.6
Premature Treatment Discontinuation Visit (PTDV)
Patients who prematurely and permanently discontinue treatment with study medication 
should return for a PTDV, which will be done as soon as possible after last IP dose.


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
ePRO questionnaires will be completed by the patient prior to any other 
site activities and before the patient meets the investigator.  

The investigator will perform a general physical examination.

NYHA Functional Classification will be evaluated.

Vital signs will be assessed and recorded.  

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.

If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.  

Drug accountability of the returned medication will be checked.
Patients who discontinue treatment prematurely should attend all study visits according to 
plan, including the Study Closure Visit (SCV).  
For further details regarding discontinuations from IP, please see Section 3.9.
4.2.7
Study Closure Visit (SCV)
All patients will be asked to return for a SCV when the predetermined number of primary 
endpoint events is anticipated, i.e., SED.  All randomised patients (including any patients who 
have discontinued treatment with IP) should return for their SCV as soon as possible but no 
later than 6 weeks after the SED.  

ePRO questionnaires will be completed by the patient prior to any other 
site activities and before the patient meets the investigator.  

The investigator will perform a general physical examination.

NYHA Functional Classification will be evaluated.

Vital signs will be assessed and recorded.  

Any changes in relevant concomitant medications and cardiac and HF 
related procedures will be recorded.  

Laboratory samples will be collected and sent to the central laboratory 
as specified in Table 2.  


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
If the patient has experienced any potential endpoints, SAEs, DAEs
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.  

The patient will return remaining IP and drug accountability will be 
checked.
After stopping IP the investigator should ensure that the patient is treated according 
to standard clinical practice and ascertain there is a proper medical follow-up plan 
in place
4.2.8
Unscheduled visits
An unscheduled visit may occur in-between scheduled visits e.g., to follow up on potential 
endpoint events such as re-sampling for eGFR (see Section 5.1.4).
4.3
Follow-up period (Not applicable)
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded in the eCRFs in Rave as 
specified in the study protocol and in accordance with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
5.1
Efficacy assessments
5.1.1
Endpoint reporting overview
Potential endpoint events will be identified using laboratory data (refer to Table 2 for 
laboratory assessments and timings), when questioning the patient about his/her overall health, 
or through information received through standard medical practice.  Investigators will be 
encouraged to have a low threshold to submit any potential/possible event that might represent 
an endpoint.
The following potential endpoints will be reported and source documents submitted for central 
adjudication:

All deaths

All HF events (hospitalisations for HF or urgent HF visits)


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
Potential renal endpoints:

Dialysis

Kidney transplantations

Doubling of serum creatinine (since the most recent central laboratory 
measurement) 

Cardiac ischaemic events (MI and unstable angina)

Cerebrovascular events (stroke and TIA)

DKA (not considered an efficacy variable but will be adjudicated as a 
safety variable)
In addition, eGFR declines ≥50% from baseline, eGFR values <15 mL/min/1.73m2, new 
diagnosis of atrial fibrillation and new diagnosis T2D will be recorded in the eCRF but will 
not be adjudicated.  
For each potential endpoint event, the investigator or delegate will record information in the 
eCRF.  If the event is subject to adjudication, relevant source documents will be assembled.  
The source documents and relevant eCRF data will be sent for central adjudication.  
Detailed instructions regarding endpoint reporting will be provided to the study sites.
Additional details about the evaluations of potential endpoint events will be described in the 
CEA charter.
5.1.2
Classification of Death
The CEA committee members will adjudicate and classify all deaths based on definitions 
described in the CEA charter.  For the purpose of the efficacy analysis, deaths will be sub-
classified by CV and non-CV as well as renal primary cause (death due to ESRD when 
dialysis is not given).  The investigator will record the classification of death as CV or Non-
CV death in the eCRF.
5.1.3
Heart failure (HF) events
All potential HF endpoint events (hospitalisations for HF or urgent HF visits) should be 
recorded as an AE and on a separate page in the eCRF and submitted to the CEA for 
adjudication.  The CEA will adjudicate the events as specified in the CEA Charter.  
See for definition of Heart failure event according to CDISC definition (Hicks et al 2014) 
which is currently the latest version.  CDISC may be updated during the course of the study.  
The CEA charter will describe in detail how HF events will be adjudicated in the current 
study.


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5.1.4
Potential renal endpoints
5.1.4.1
Endpoints related to eGFR decline
eGFR baseline is defined as the mean central laboratory value from Visit 1 and Visit 2.  
Laboratory values related to eGFR decline will trigger an action by site in the following 
situations: 

Potential Renal Endpoints Local laboratory values indicate that eGFR 
value has declined ≥50% compared with baseline, or is below 15 
mL/min/1.73m2.  
NB As soon as possible, patient should come to the study site for 
confirmation by a central laboratory testing.
OR

Central laboratory values, collected during a study visit, indicating that 
eGFR value has declined ≥50% compared with baseline, or is below 
15 mL/min/1.73m2.
The central laboratory will notify site if eGFR is <15 mL/min/1.73m2 or if there is ≥50% 
decline in eGFR compared to baseline. A re-sampling should be done after at least 4 weeks, 
and preferably no later than 6 weeks after the first sampling. If the eGFR decline is confirmed, 
it should be recorded in the eCRF.
The central laboratory will calculate eGFR using CKD-EPI equation (Levey at al 2009).
5.1.4.2
Dialysis and renal transplantation  
If a patient starts dialysis and or go through a renal transplantation this will be recorded in the 
eCRF and submitted for adjudication.  
5.1.4.3
Doubling of serum creatinine
Doubling of serum creatinine (compared to the most recent central laboratory measurement) 
will be recorded in the eCRF and submitted for adjudication.  
Recording of doubling of serum creatinine compared to the most recent central laboratory 
result can be triggered by a local laboratory result OR a central laboratory result.
5.1.5
Initiation of new, or increased dose of existing oral treatment for worsening of 
heart failure (HF)
Documented evidence of worsening HF symptoms/signs leading to initiation of a new 
treatment for HF sustained for at least 4 weeks or augmentation of existing oral therapy for 
HF (e.g., increase in dose of diuretic) sustained for at least 4 weeks, will be reported in the 
eCRF.


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5.1.6
New York Heart Association (NYHA) class
The definition of NYHA class is included in Appendix D.  The investigator will evaluate this 
according to the study plan and assessment will be recorded in the eCRF.
5.1.7
New diagnosis of Atrial Fibrillation (AF)
New diagnosis of AF during the study will be defined as proportion of patients, without 
history of AF at baseline, who develop AF during the study.  This will be recorded as an AE 
with additional information on a separate eCRF page.
5.1.8
New diagnosis of type 2 diabetes
ew onset of T2D, post randomisation, defined according to the following criteria:

Reporting of new onset T2D necessitating initiation of anti-diabetic 
medication.
OR

HbA1c >6.5% (48 mmol/mol) measured by central lab at two consecutive 
study visits.
New onset of T2D will be recorded as an AE and on a separate eCRF page.
5.1.9
Cardiac ischaemic events 
Sites should record potential acute coronary syndromes such as MI and unstable angina in the 
eCRF and submit for adjudication.  The CEA committee members will adjudicate all potential 
cardiac ischaemic events to decide if they qualify as MI according to the criteria defined in the 
CEA charter.  
5.1.10
Cerebrovascular (CV) events
Sites should record potential strokes and TIAs in the eCRF and submit to the CEA for 
adjudication.  The CEA committee members will adjudicate all cerebrovascular events to 
decide if they qualify as stroke according to the criteria defined in the CEA charter.  
5.1.11
Patient reported outcomes (PROs)
PROs is an umbrella term referring to all outcomes and symptoms that are directly reported by 
the patient.  PROs have become important endpoints for regulatory and reimbursement 
authorities when evaluating effectiveness of treatments in clinical trials.  The following PROs 
will be administered in the study: PGIS, PGIC, KCCQ, EQ-5D-5L (see Appendix E).  Patients 
will be asked to complete the PROs at the visits as specified in Table 1.
5.1.11.1
Patient global impression of severity (PGIS)
The PGIS question captures patient’s severity of HF symptoms.  It will be used as an anchor 
in the estimation of the minimal important change.  


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5.1.11.2
Patient global impression of change (PGIC)
The PGIC question will be used to capture patients overall change in HF symptoms since start 
of the treatment.  It will also be used as an anchor in the estimation of the minimal important 
change.
5.1.11.3
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ is a self-administered disease specific instrument and has shown to be a valid, 
reliable and responsive measure 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 total symptom score 
incorporates the symptom domains into a single score.  Scores are transformed to a range of 0-
100.  Higher scores represent a better outcome.  
5.1.11.4
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.
5.1.11.5
Administration of patient reported outcomes (PRO)
All PROs will be administered electronically (ePRO).  Patients will complete the PRO 
assessments at the study site using a handheld electronic device (ePRO).  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.
All assessments should be completed as follows:

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.

Before being seen by the investigator.

PRO questionnaires must be completed by the patient in private.

The appointed site personnel should explain to patient the value and 
relevance of ePRO assessments and inform them that these questions are 
being asked to find out, directly from patients, how they feel.  The 
appointed site personnel should also stress that the information is 
confidential.  


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
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 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.
5.2
Safety assessments
5.2.1
Laboratory assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in Table 2.  The date of central laboratory sample 
collection will be recorded in the eCRF.  All laboratory variables will be analysed at the 
central laboratory, except urine human chorionic gonadotropin (hCG) (pregnancy test, using a 
dipstick provided by the central laboratory), and optional local laboratory samples taken at 
enrolment, which will be analysed locally.  
All samples should be taken by adequately trained study personnel and handled in accordance 
with instructions in the Laboratory Manual.  Up to date reference ranges will be provided 
during the study and laboratory results will be compared with the laboratory standard normal 
ranges and reported back to site.  
Samples sent to the central laboratory will be collected, labelled, stored and shipped as 
detailed in the Laboratory Manual.  
The following safety laboratory variables will be measured:
Table 2
Laboratory variables
Haematology
Clinical Chemistry
Haemoglobin (Hb) b
Alanine transaminase (ALT) b
Haematocrit
Alkaline phosphatase (ALP) b
Aspartate transaminase (AST) b
Urinalysis (dipstick)
Bilirubin, totalb
U-hCG (pregnancy test) e
Blood urea nitrogen (BUN) a
  Creatinine (including eGFR assessment) a
  HbA1ca
NT-proBNPc


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Phosphated
Potassiuma
Sodiuma
a
Central laboratory analysis at all on site visits.
b
Central laboratory analysis at visit 1, PTDV and SCV.  
c
Central laboratory analysis at visit 1, 2 and 6.
d         Central laboratory analysis at visit 2, 5, PTDV and SCV.
e
Local dipstick analysis at visit 1 and visit 2.
The investigator should make an assessment of the laboratory results with regards to clinically 
relevant abnormalities.  The laboratory results should be signed, dated and retained at the site 
as source data for laboratory variables.
5.2.1.1
Unscheduled laboratory assessments
Unscheduled laboratory samples will be requested by the central laboratory for follow-up on 
e.g., eGFR values.  Follow-up samples related to eGFR should be collected during an 
unscheduled visit and sent to central laboratory for analysis.
5.2.2
Physical examination
A general physical examination will be performed at the time of randomization and when the 
patient stops IP and include an assessment of the following: general appearance, respiratory 
and cardiovascular systems (including oedema) and abdomen.
A targeted physical examination (including heart, lungs, oedema, dyspnoea, ascites, and 
weight gain) will be performed at onsite visits where no general physical examination is being 
performed, (see Table 1) with focus on signs for HF and volume status.  
The assessment dates will be recorded in the eCRF.
5.2.3
Electrocardiogram (ECG)
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 enrolment (Visit 1) after the patient has been lying down 
to rest for at least 5 minutes.  ECG date, heart rate and heart rhythm will be recorded in the 
eCRF.  The baseline ECG should be made available for CEA upon request, to facilitate 
adjudication of potential cardiac ischaemic events and events with new onset of AF.
5.2.4
Vital signs
Vital signs will be assessed according to the study plan, Table 1.  
5.2.4.1
Pulse and blood pressure (BP)
Pulse and BP will be measured three times at all visits, and all measurements will be recorded 
in the eCRF.  The measurements should be done before any blood sampling using a 


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standardized cuff adapted to the size of the patient’s arm after the patient has been sitting and 
resting for least 5 minutes. Preferably, the same arm should be used at all visits.
5.2.4.2
Body weight and height
The patient’s body weight will be measured with light clothing and no shoes at all visits.  If 
the patient has a prosthetic limb, this should be consistently worn or not 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 eCRF.
5.3
Other assessments (Not applicable)
5.4
Pharmacokinetics (PK)
5.4.1
Collection of samples
One pre-dose blood sample for determination of the dapagliflozin concentration in plasma will 
be taken at visit 7.  Information about last intake of IP and sampling ID, date and time will be 
recorded in the eCRF.
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.  
5.4.2
Determination of drug concentration
Samples for determination of dapagliflozin concentration in plasma will be analysed by the 
bioanalytical laboratory on behalf of AstraZeneca, using an appropriate validated bioanalytical 
method.  Full details of the analytical method used will be described in a separate 
bioanalytical report.
5.4.3
Storage and destruction of pharmacokinetic samples
PK samples will be analysed during the course of the study and disposed of after the 
Bioanalytical Report finalization or six months after issuance of the draft Bioanalytical Report 
(whichever is earlier).  The results of the PK analyses will be kept at the bioanalytical 
laboratory until the end of the study to prevent unblinding.
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method.  Any results from such analyses may be 
reported separately from the clinical study report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.


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5.5
Pharmacodynamics (Not applicable)
5.6
Pharmacogenetics (Not applicable)
5.7
Biomarker analysis 
Serum and plasma will be collected and stored for potential future analysis for exploratory 
biomarkers to assess correlations with the activity of the diseases affecting patients in the 
study, effects of study drug, clinical outcomes and toxicity.
It is mandatory to obtain the patient's consent to the donation and use of biological samples.  
The consent date will be recorded in the eCRF.  Patients not consenting to donate biological 
samples for future biomarker analysis are still able to participate in the study, but without 
providing samples for biomarker analysis.
The biomarkers to be studied will be selected on possible relevance on pathophysiology of the 
studied diseases.
5.7.1
Storage, re-use and destruction of biological samples
Samples will be stored in AZ biobank for a maximum of 15 years from the date of the last 
patient’s last visit, after which they will be destroyed.  The results of this biomarker research 
will be reported either in the CSR itself or as an addendum, or separately in a scientific report 
or publication.  The results of this biomarker research may be pooled with biomarker data 
from other studies with dapagliflozin to generate hypotheses to be tested in future research.  
5.7.2
Labelling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are collected, labelled and shipped in 
accordance with the Laboratory Manual and the Biological Substance, Category B 
Regulations (materials containing or suspected to contain infectious substances that do not 
meet Category A criteria), see Appendix B ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AZ and appropriate labelling, 
shipment and containment provisions are approved.  Samples can be shipped to specialist labs 
around the world and analysed by academic collaborators or commercial partners.
5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The PI at each site keeps full traceability of collected biological samples from the patients 
while in storage at the study site until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival.
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.


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AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AZ Biobank during the entire life cycle.
5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a patient 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.
As collection of donated biological samples is an optional part of the study, the patient may 
continue in the study.  
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified as soon as possible to AZ Ensures that biological 
samples from that patient, if stored at the study site, are identified as soon 
as possible, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent as soon as possible and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site

Ensures that the patient and AstraZeneca are informed about the sample 
disposal
AZ ensures the laboratory(ies), or biobank holding the samples is/are informed about the 
withdrawn consent as soon as possible and that samples are disposed of/destroyed and the 
action documented and returned to the study site.
5.8
Echocardiographic Sub-study 
An echocardiographic sub-study is planned to be conducted in a subset of patients (approx. 
300-400 patients) in the Dapa-HF trial. The sub-study is designed to evaluate the impact of 
dapagliflozin at a dose of 10 mg daily, compared to placebo, in addition to conventional heart 
failure treatment, on changes in cardiac structure and function as determined by 
echocardiography.
Enrolment will be restricted to a subset of sites for the main Dapa-HF trial.  At participating 
sites, eligible patients for the main trial, excluding patients with atrial fibrillation at ECG at 
visit 1, who consent to participation in the sub-study will undergo digitally acquired protocol 
echocardiograms at randomization and at 8 months post-randomization.  


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Echocardiographic images, free of any personal health or patient identifying information 
except study ID, will be transmitted electronically to the study echo core laboratory.  
The results of this echocardiography study will be reported separately.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all personnel involved in the study 
are familiar with the content of this section.
6.1
Definition of adverse events (AEs)
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, ECG).  In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.  The term AE in this 
document refers only to the categories of events described in Section 6.3.
6.2
Definitions of serious adverse event (SAE)
An SAE 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-patient hospitalisation or prolongation of existing
hospitalisation

Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix A.  


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6.3
Recording of adverse events 
6.3.1
Time period for collection of adverse events
AEs will be collected from randomisation (Visit 2) throughout the treatment period until and 
including the patient’s last visit.
SAEs will be recorded from the time of informed consent throughout the treatment period 
until and including the patient's last visit.
AEs should be recorded in the eCRF only if: 

It qualifies as an SAE (as defined in Section 6.2)

The AE is the reason for permanent discontinuation from IP (DAE) 

The AE is the reason for IP interruption or dose reduction

It qualifies as an AE of interest:

Volume depletion

Renal events 

Major hypoglycaemic events

Fractures 

Potential DKAs 

AEs leading to amputation and AEs leading to a risk for lower limb 
amputations (“preceding events”) 

A potential endpoint (see Section 5.1) that fulfils the AE criteria. NB: 
not all potential endpoints are per definition an AE, e.g. a potential 
endpoint solely related to laboratory findings (see Section 6.3.5) 
should not be recorded unless any of the above mentioned criteria is 
met.
An AE/SAE could be associated with more than one potential endpoint.  In such scenario, 
only one AE/SAE should be reported but all potential endpoints should be reported 
individually.  
6.3.2
Adverse events of interest
6.3.2.1
Volume depletion
Events of volume depletion (e.g., dehydration, hypovolemia, or hypotension) will be recorded 
in the eCRF as AEs.


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6.3.2.2
Renal events
Renal events, such as an acute clinically relevant decline in kidney function as judged by the 
investigator, will be recorded in the eCRF as AEs.  If the event also qualifies as a potential 
endpoint as defined in Section 5.1.4, a separate eCRF will also be completed.  
6.3.2.3
Major hypoglycaemic event
A major hypoglycaemic event is defined as an event that requires assistance of another person 
to actively administer carbohydrates, glucagon, or take other corrective actions.  
Plasma glucose concentrations may not be available during an 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.
6.3.2.4
Fractures
All fractures will be recorded in the eCRF as AEs.  
6.3.2.5
Diabetic ketoacidosis (DKA)
All potential events of DKA will be recorded in the eCRF and submitted to an independent 
DKA Adjudication Committee, see Section 6.8.5.
6.3.2.6
Adverse events (AEs) leading to amputation and AEs leading to a risk for 
lower limb amputations (“preceding events”)
To ensure that data on amputations is systematically collected, amputations and underlying 
conditions 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, non-serious and serious AEs putting the patient at risk for a lower limb 
amputation (“preceding events”) should also be recorded in the eCRF as AE/SAE whether or 
not it is leading to an amputation. The lower limb “preceding events” of interest are vascular, 
diabetic foot related, wounds, infections and neuropathies for which additional information 
will be collected (for details see eCRF instruction).
6.3.1
Follow-up of unresolved adverse events
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.
6.3.2
Variables 
The following variables will be collect for each AE:


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
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 IP (yes or no)

Action taken with regard to IP

Outcome
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
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria described in Section 6.2.  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 Section 6.2.  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 Section 6.2.


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6.3.3
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 A.
6.3.4
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 
fulfilling the criteria as specified in Section 6.3.1).  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.
6.3.5
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR. Deterioration as compared with baseline in protocol-mandated laboratory values, 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 investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low Hb value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
6.4
Reporting of serious adverse events (SAEs)
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


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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 AE 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 WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.  If the WBDC 
system is not available, then the investigator or other site personnel reports a SAE to the 
appropriate AstraZeneca representative by telephone in accordance with SAE reporting 
timelines.
The AstraZeneca representative will advise the investigator/site personnel how to proceed.
6.4.1
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 6.4).
In addition, fatal AEs and potential HF endpoints will be centrally adjudicated by an 
independent CEA committee (see Section 5.1.1 and 6.8.4).  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 6.4) 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).
6.5
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 with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose eCRF module


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
An overdose without associated symptoms is only recorded on the 
Overdose eCRF module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AZ representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AZ Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AZ.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel informs the appropriate AZ representatives within 1 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 
relevant information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT paper 
CRF form is used to report the outcome of the pregnancy.


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6.7
Management of IP related toxicities (not applicable)
6.8
Study governance and oversight
6.8.1
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, DMC and DKA committee as needed, development of the statistical 
analysis plan, 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 regard 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 non-
voting members of the Sponsor, and will operate under an Executive Committee charter.
6.8.2
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.
6.8.3
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.
6.8.4
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.


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6.8.5
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.  
6.9
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 study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
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 subject.
Medication error includes situations where an error:

occurred

was identified and intercepted before the subject received the drug

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 subject

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 subject received the medication (excluding IxRS errors)

Wrong drug administered to subject (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 

Subject accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging


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
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.  
If an medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 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 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product
Table 3
Investigational Product
Investigational product
Dosage form and strength
Manufacturer
Dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated tablets 10 mg
AstraZeneca
Matching placebo for 
Dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated tablets placebo
AstraZeneca
Dapagliflozin 5 mg
Green, plain, diamond shaped, 
film coated tablets 5 mg
AstraZeneca
Matching placebo for 
Dapagliflozin 5 mg
Green, plain, diamond shaped, 
film coated tablets placebo
AstraZeneca
Dapagliflozin and its matching placebo tablets will be packed in bottles.  The tablets may 
contain lactose, which may cause discomfort in lactose-intolerant individuals.
7.2
Dose and treatment regimens
At randomisation, Visit 2 (day 0), eligible patients will be randomly assigned to 1 of 2 
treatments:

Dapagliflozin 10 mg, given once daily per oral use

Placebo – one placebo tablet to match dapagliflozin 10 mg, given once 
daily per oral use
Randomisation and treatment pack assignment will be managed via an IxRS at Visit 2.  The IP 
should be taken once daily in the morning and at approximately the same time every day, 
during the study period.  If the patient, for any reason prefers not to administer the IP in the 


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morning, any other time point during the day may be applied, provided the patient routinely
administer the IP in approximate 24 hours intervals.  The IP should not be altered (e.g., 
crushed, put in another vehicle) and should not be given by nasogastric tube or other routes.  
If the preferred 10 mg dose is reduced to dapagliflozin 5 mg or matching placebo (see Section 
3.9.1) or increased back to 10 mg or matching placebo (see Section 3.9.2), this will be done in 
IxRS and the dose change will be recorded in the eCRF.  
Missed doses of dapagliflozin or placebo blinded study medication should not be compensated 
for (i.e., if a dose is missed, the next regularly scheduled dose should be taken and should not 
be doubled).
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
7.4
Storage
All IP should be kept in a secure place under appropriate storage conditions.  The IP label on 
the bottle specifies the appropriate storage.  
7.5
Compliance
The administration of all investigational products should be recorded in the appropriate 
sections of the eCRF.  
7.6
Accountability
The IP provided for this study will be used only as directed in the study protocol.  The site 
personnel will account for all IP dispensed to and returned from the patient.
Patients will be asked to bring all unused study medication and empty packages to the study 
site at each site visit.  The investigator or delegate will enter the amount of returned tablets in 
the eCRF.  Any patient found to be noncompliant would be counselled on the importance of 
taking their study medication as prescribed.  
Any study medication deliberately or accidentally destroyed must be recorded.  Any 
discrepancy between dispensed and returned study medication should be explained.  
The investigator will retain the returned medication until the AZ representative or delegate 
collects it, along with any medication not dispensed.  The AZ representative or delegate is 
responsible for confirming the investigator or delegate has recorded the quantities of returned 
and unused tablets at a patient level before medication is destroyed.  The AZ representative or 
delegate will advise on the appropriate method for destruction of unused study medication.  


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7.7
Concomitant medications and other treatments 
All patients should be treated according to regional standard of care for HF, CV risk factors 
(e.g., blood pressure, lipids, antithrombotic treatment) and diabetes.  Background medication 
will not be provided by the Sponsor.
7.7.1
Prohibited medication
Concomitant treatment (i.e., treatment in combination with IP) with open label SGLT2 
inhibitors eg, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin and 
luseogliflozin and fix dose combinations containing these drugs is prohibited. Also in 
situations when the patient is not on IP, treatment with open label SGLT2 inhibitors during the 
study, could interfere with the interpretation of study results and should therefore not be given 
unless all other possibilities to treat the patient properly has been considered. 
7.7.2
Recording of concomitant treatment
Detailed recording of medications related to HF (see Section 7.7.3), diabetes (see Section 
7.7.4) as well as other relevant cardiovascular medications (e.g., statins, antihypertensive and 
antithrombotic agents) will be made throughout the study. In addition, all concomitant 
medications will be recorded at the time of any SAEs, potential endpoints and AEs of interest 
(as defined in section 6.3.2 and 6.4). Also, cardiac and heart failure related procedures will be 
captured during the study (see Section 7.7.5.1). Recording of other concomitant medications 
will be made at randomisation (visit 2) and at SCV.
7.7.3
Heart failure (HF) medications
To be eligible, the patient should be on background standard of care therapies for HF 
according to local guidelines.  Standard evidence based treatments will include either an ACE 
inhibitor, ARB or sacubitril/valsartan in combination with a beta-blocker, as well as an MRA 
where appropriate unless contraindicated or not tolerated.  If the patient for any reason is not 
on background standard of care medications at baseline, the reason for this will be recorded in 
the eCRF.  
Most patients will also require a diuretic, generally a loop diuretic such as furosemide, to 
control symptoms.  Optimization of volume status, and proactive adjustment of diuretic doses 
may help minimize any deleterious effects on hypovolemia/volume depletion accentuated by 
the diuretic effects of the IP.  
Patients should remain on stable doses of medications which will allow assessment of 
incremental dapagliflozin effect.  Dose reduction or discontinuation of proven effective 
therapies should be avoided unless all other measures fail to improve the patient’s situation.  
In heart failure, use of ACE-I/ARBs, Sacubitril/Valsartan, mineralocorticoids and beta-
blockers is supported by evidence from previous clinical trials.  However, if the patient’s 
condition warrants a change in any of these standard evidence based medications, it will be 
allowed at the discretion of the investigator.  If patients require dose adjustment of 
background therapy to avoid signs/symptoms of volume depletion, diuretics should be 
decreased prior to adjusting other medications.  


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7.7.4
Anti-diabetes treatment
7.7.4.1
Background
More than 40% of patients with established HF are estimated to have T2D (Kristensen et al 
2016) and it is expected that a large proportion of patients in this study will have an 
established diagnosis of T2D when included in this study.  Furthermore it is expected that 
some patients will develop T2D during the course of the study.  Treatment of diabetes should 
follow established guidelines, 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).  In brief, the 
ADA/EASD recommends lowering HbA1c to < 7.0% in most patients.  Less stringent HbA1c 
goals, e.g., 7.5 to 8% or even slightly higher may be appropriate for patients with a history of 
severe hypoglycaemia, advanced complications, extensive comorbid conditions and those in 
whom the target is difficult to attain despite intensive self-management education, repeated 
counselling, and effective doses of multiple glucose-lowering agents, including insulin.  
7.7.4.2
Treatment of patients with established diagnosis of type 2 diabetes
Patients with T2D at randomisation will continue their T2D treatment.  Patients are eligible 
for adjustments in their anti-diabetes treatment at the discretion of their diabetes health care 
provider.  Diabetes medications at baseline and any changes throughout the study, will be 
recorded in the eCRF.
7.7.4.3
Use of medications known to cause hypoglycaemia in type 2 diabetes
Insulin and insulin secretagogues are known to cause hypoglycaemia.  Therefore, patients 
treated with insulin or SU have a higher risk of experiencing hypoglycaemic events compared 
with those treated with other antidiabetic agents.  Therefore a lower dose of insulin or insulin 
secretagogues may be required to minimize the risk of hypoglycemia when used in 
combination with study medication.  
Reduction of insulin by 10-20% (total daily dose) and SU by 25- 50% and increased 
frequency of blood glucose monitoring may be considered in patients receiving insulin and/or 
SU and with baseline HbA1c <7% at randomisation.  
7.7.5
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 and recorded in the 
appropriate sections of the eCRF as applicable.
7.7.5.1
Cardiac and heart failure related procedures
During the course of the study, information will be recorded regarding any cardiac and heart 
failure related procedures in a specific eCRF module. The procedures will be collected from 
time of randomisation to SCV. Procedures include but are not limited to: PCI/CABG, 
pacemaker implantation, mechanical fluid removal etc. 


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7.8
Post Study Access to Study Treatment
Post-study treatment will not be provided by the Sponsor.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violations have been identified and documented.
A comprehensive Statistical Analysis Plan (SAP) will be developed prior to first patient 
randomised and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data.
The results of the key study outcome will be independently validated by an external statistical 
team.
8.2
Sample size estimate
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint.  Assuming a true hazard 
ratio (HR) of 0.80 between dapagliflozin and placebo, using a one-sided alpha of 2.5%, 844 
primary endpoint events will provide a statistical power of 90% for the test of the primary 
composite endpoint.  This is based on an overall 1:1 allocation between dapagliflozin and 
placebo.  The study is event-driven.  The assumed HR of 0.80 is considered as clinically 
relevant and has taken into account the HF outcomes in the EMPA-REG trial.
With an annual event rate of 11% in the placebo treatment group, 4500 patients are estimated 
to provide the required number of primary events, based on an anticipated recruitment period 
of 18 months and an average follow-up period of approximately 24 months.  The assumed 
placebo event rate of 11% is based on a review of recently published clinical studies in the 
HFrEF population, including the PARADIGM-HF trial.  This study is a group sequential 
design study with one interim analysis using Haybittle-Peto boundary (a one-sided 
alpha=0.001), leaving a one-sided alpha of 2.496% for the final analysis.  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.
8.3
Definitions of analysis sets
8.3.1
Full analysis set
All patients who have been randomised to study treatment will be included in the Full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study.  
Patients will be analysed according to their randomised IP assignment, irrespective of the 
treatment actually received.  The FAS will be considered the primary analysis set for the 
primary and secondary variables and for the exploratory efficacy variables.  


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8.3.2
Safety analysis set
All patients who received at least 1 dose of randomised treatment will be included in the 
safety population.  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.
8.4
Outcome measures for analyses
8.4.1
Primary outcome measure
The primary outcome measures are detailed in Section 2.1.
8.4.2
Secondary outcome measure
The secondary outcome measures are detailed in Section 2.2.  
8.4.3
Safety outcome measure
The safety outcome measures are detailed in Section 2.3.
8.4.4
Exploratory outcome measure
The exploratory outcome measures are detailed in Section 2.4.
8.5
Methods for statistical analyses 
8.5.1
Hypotheses
The Type I error rate for the analysis of the primary endpoint will be adjusted for the interim 
analyses performed by the DMC.
For the primary endpoint the following hypothesis will be tested at the 2.496% 1-sided level:
H0: HR [dapagliflozin:placebo] ≥1
Versus
H1: HR [dapagliflozin:placebo] <1
8.5.2
Closed testing procedure
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilized.  The Type I error will be controlled at a one-sided 
0.02496 level for multiplicity across primary and secondary endpoints and in consideration of 
planned interim analyses.  Statistical significance will be assessed in the pre-specified order of 
the endpoints as specified in Section 2.1 and 2.2.  The testing procedure will continue down 
the hierarchy if the preceding endpoint is rejected at a one-sided 0.02496 level and will stop if 
the preceding endpoint is not rejected at a one-sided 0.02496 level.  Exploratory endpoints 
will be tested at a one-sided 0.025 level without adjustment for multiplicity.  


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8.5.3
Analysis of the primary variable(s)
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, using events 
adjudicated and confirmed by CEA.
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, and adjusting for history of hospitalisation for heart 
failure.  In general, the analysis will use each patient's last contact as the censoring date for 
patients without any primary events.  The 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.  Methods similar to those described for the primary 
analysis will be used to separately analyze the time from randomisation to the first occurrence 
of each component of the primary composite endpoint.  Last contact will be treated as the 
censoring date for patients without the endpoint of interest.  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.
8.5.4
Analysis of the secondary variable(s)
The time-to-event secondary variables will be analysed in the similar manner as the primary 
variable, including time to the first occurrence of hospitalisation for HF or CV death, time to 
the first occurrence of any of the components of the renal composite endpoint, and time to 
death from any cause.  
A composite outcome of all HF hospitalisations (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.  Other analysis methods may also be 
considered.
Change from baseline to each visit for KCCQ will be analysed with a repeated measures 
method. This model will be used to assess the time point of 8 months, although summaries at 
all visits will also be presented. A responder analysis, where a response is defined as a 
clinically meaningful change of 5 or more points of the Total Symptom Score, will also be 
performed. 
8.5.5
Subgroup analysis
Subgroup variables for the primary efficacy endpoint and secondary efficacy endpoints
include demography, baseline disease characteristics, baseline concomitant medications and 
others.  Cox proportional hazard model, the semi-parametric proportional rates model, or the 
repeated measures model will be performed to examine treatment effects within relevant 


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subgroups separately.  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.  
8.5.6
Interim analysis
An interim analysis is planned to be performed when 75% of the primary events are 
adjudicated, using a Haybittle-Peto rule.  There will in principle be one planned interim 
analysis, with the possibility of the DMC to do 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 and timing of interim analyses.  The interim analysis will 
assess superiority of dapagliflozin to placebo.  The interim analysis will have a one-sided 
alpha level of 0.001.  At the interim analysis, the primary composite endpoint will be firstly 
tested 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 at a one-sided level of 
0.001.  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.
8.5.7
Sensitivity analysis
Details of the sensitivity analysis will be provided in the SAP.  
8.5.8
Analysis of safety variables
The number and percent of patients with SAEs, DAEs, AEs leading to dose reductions and 
temporary interruptions, and AEs of interest, will be summarized by treatment group.  
Changes in clinical chemistry/haematology parameters will be summarized over time by 
treatment group.  In addition, the number and percent of patients with a marked abnormality in 
clinical laboratory tests will be summarized over time by treatment group.
For safety analyses, summaries will be provided using both on treatment observations and 
using all observations regardless of whether patients are on or of study treatment.
8.5.9
Exploratory analysis
The exploratory variables (excluding PK and biomarkers for future exploratory research) will 
be analysed as specified in the SAP.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the CSP and related documents with the site personnel and also 


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train them in any study specific procedures and the WBDC, ePROs system and other relevant 
systems utilised.
The PI will ensure that appropriate training relevant to the study is given to all site personnel, 
and that any new information relevant to the performance of this study is forwarded to the 
personnel involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other personnel).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s) and site personnel.

Confirm that facilities remain acceptable.

Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the CRFs that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed.

Perform source data verification (a comparison of the data in the CRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients.  This will require direct access to all original 
records for each patient (e.g., medical records).

Perform source data review, i.e., review of source documentation to 
check quality of source, review protocol compliance, ensure critical 
processes and source documentation are adequate.  

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the investigator(s) or other 
personnel at the centre needs information and advice about the study conduct.  
9.2.1
Risk based quality management
Quality by design will be implemented, including a focus on identifying key risks to patient 
safety, data quality, and Good Clinical Practice (GCP)/regulatory compliance, to build quality 
into the design, conduct, analysis and reporting of the study.  


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A risk based monitoring approach will be applied for this study.  A mix of monitoring 
strategies will be implemented: on-site monitoring, remote monitoring (site level monitoring 
activities performed at a location other than the study site) and centralized monitoring 
systems.  Monitoring strategies will be tailored to risks, permit timely oversight (through 
central/remote monitoring and use of technology), and will be focused on critical processes 
and critical data.
Central monitoring will be used to check that data is consistent and complete, identify unusual 
distribution of data, identify higher risk sites to target additional monitoring, and to ensure 
routine review of data is completed in real time.  
9.2.2
Source data
The Clinical Study Agreement (CSA) will specify the location of source data.  The 
investigator must provide direct access to source data/documents for monitoring, audits, 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review, and regulatory 
inspections.  
9.2.3
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this CSP and the CSA, the terms of CSP shall prevail with respect to the conduct of 
the study and the treatment of patients and in all other respects, not relating to study conduct 
or treatment of patients, the terms of the CSA shall prevail.
Agreements between AZ and the PI should be in place before any study-related procedures 
can take place, or patients are enrolled.
9.2.4
Archiving of study documents
The investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q1 2017 and to end by Q4 2019.
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AZ may also terminate the entire 
study prematurely if concerns for safety arise within this study or in any other study with 
dapagliflozin.
9.4
Data management by AstraZeneca
Data management will be performed by AZ Data Management Centre personnel at Cognizant, 
according to the Data Management Plan (DMP).  


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Data entered into the eCRF will be immediately saved to a central database and changes 
tracked to provide an audit trail.  The data will then be reviewed, queried and updated as 
needed.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Medications will be classified according to the WHO Drug Dictionary.  Classification coding 
will be performed by the Medical Coding Team at the AstraZeneca Data Management Centre.  
The data will be validated as defined in the DMP.  Quality control procedures will be applied 
to each stage of data handling to ensure that all data are reliable and have been processed 
correctly.  The DMP will also clarify the roles and responsibilities of the various functions and 
personnel involved in the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
9.5
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation will be done between the study database and safety database.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the AZ policy on Bioethics and Human Biological Samples.
10.2
Patient data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
10.3
Ethics and regulatory review
An Institutional review board/ Independent ethics committee (IRB/IEC) should approve the 
final study protocol, including the final version of the ICF and any other written information 
and/or materials to be provided to the patients.  The investigator will ensure the distribution of 
these documents to the applicable IRB/IEC, and to the study site personnel.
The opinion of the IRB/IEC should be given in writing.  The investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study.  
The IRB/IEC should approve all advertising used to recruit patients for the study.


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AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AZ will handle the distribution of any of these documents to the national regulatory 
authorities.
AZ will provide Regulatory Authorities, IRB/IECs and Principal Investigators with safety 
updates/reports according to local requirements.
10.4
Informed consent
The Principal Investigator(s) at each site will:

Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study

Ensure each patient is notified that they are free to discontinue from the 
study at any time

Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided

Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the 
patient

Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the informed consent form that is approved 
by an Ethics Committee
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.


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If there are any substantial changes to the study protocol, then these changes will be 
implemented in a new version of the protocol.
The new version of the study protocol is to be approved by the relevant IRB/IEC and if 
applicable, also the national regulatory authority, before implementation.  Local requirements 
are to be followed for new version protocols.  
AZ will distribute any subsequent new versions of the protocol to each PI.  For distribution to 
IRB/IEC see Section 10.3.
If a new version of the protocol requires a change to a site’s ICF, AstraZeneca and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used.  
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the site, including source data verification.  The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the 
International Conference on Harmonisation (ICH), and any applicable regulatory 
requirements.  The investigator will contact AstraZeneca immediately if contacted by a 
regulatory agency about an inspection at the study site.
11.
LIST OF REFERENCES
Ambrosy et al 2014
Ambrosy AP, Gheorghiade M, Chioncel O, Mentz R J, Butler J.  Global perspectives in hospitalised 
heart failure: regional and ethnic variation in patient characteristics, management and outcomes.  J Am 
Coll Cardiol 2014; 63:1123-33.
Bays et al 2013
Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese 
subjects without diabetes mellitus.  Obesity (Silver Spring) 2014 Apr; 22(4):1042-9.
Braunwald 2015
Braunwald E.  The war against heart failure: the Lancet lecture.  Lancet 2015; 385:812-24.  
Cook et al 2014
Cook C, Cole G, Asaria P, Jabbour R, Francis DP.  The annual global economic burden of heart 
failure.  Int J Cardiol 2014; 171:368-378.


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Ferrannini et al 2016
Ferrannini E, Mark M, Mayoux E.  CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty 
Substrate" Hypothesis.  Diabetes Care 2016 Jul; 39(7):1108-14.
Fitchett et al 2016
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A et al.  Heart failure outcomes with 
empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG 
OUTCOME® trial.  Eur Heart J 2016 May 14;37(19):1526-34.
Ghosh and Lin 2000
Ghosh D, Lin DY.  Nonparametric analysis of recurrent events and death. Biometrics 2000; 56:554–
562.
Green et al 2000
Green CP, Porter CB, Bresnahan DR, Spertus JA.  Development and Evaluation of the Kansas City 
Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. J Am Coll Cardiol. 
2000 Apr;35(5):1245-55.
Hicks et al 2014
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL et al, on behalf of the 
Standardized Data Collection for Cardiovascular Trials Initiative.  Standardized Definitions for 
Cardiovascular and Stroke Endpoint Events in Clinical Trials.  Draft Definitions for Clinical Data 
Interchange Standard Consortium (CDISC) August 20, 2014.
Inzucchi et al 2012
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al.  Management of
hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American 
Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). 
Diabetes Care. 2012 Jun;35(6):1364-79. 
Inzucchi et al 2015
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck Met al.  Management of 
Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach.  Update to a Position 
Statement of the American Diabetes Association and the European Association for the Study of 
Diabetes.  Diabetes Care. 2015 Jan;38(1):140-9.
Kasichayanula et al 2014
Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW.  Clinical pharmacokinetics and 
pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2.  
Clin Pharmacokinet.  2014 Jan;53(1):17-27.  
Kohan et al 2014
Kohan DE, Fioretto P, Tang W, List JF.  Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin educes weight and blood pressure but does not
improve glycemic control.  Kidney Int. 2014 Apr;85(4):962-71.


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Kosiborod et al 2015
Kosiborod M, Gause-Nilsson I, Xu J, Sonesson C, Johnsson E.  Efficacy and safety of dapagliflozin in 
patients with type 2 diabetes mellitus and Concomitant Heart Failure.  J Diabetes Complications.  
Published online: 2017 Feb 10. doi: 10.1016/j.jdiacomp.2017.02.001.
Kosiborod et al 2016
Kosiborod M, Xu J, Sjostrand M, Sjostrom CD. Safety and Efficacy of Dapagliflozin in Combination 
with Potassium-sparing Agents. American Diabetes Association, June 2016, New Orleans. Abstract 
1094-P.
Kristensen et al 2016
Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, Merkely B et al.  Risk related to pre–diabetes 
mellitus and diabetes mellitus in heart failure with reduced ejection fraction insights from prospective 
comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure 
trial.  Circ Heart Fail. 2016 Jan;9(1).
Levey at al 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al.   A new equation to 
estimate glomerular filtration rate.  Ann Intern Med.  2009 May 5; 150(9):604-12.
Lin et al 2000
Lin DY, Wei LJ, Yang I, Ying Z.  Semiparametric regression for the mean and rate functions of 
recurrent events.  Journal of the Royal Statistical Society: Series B (Statistical Methodology) 2000; 
62(4):711–730.
McMurray et al 2014
McMurray JJ, Packer M, Desai AS, Gong JG, Lefkowitz MP, Rizkala AR et al.  Angiotensin–
Neprilysin Inhibition versus Enalapril in Heart Failure.  N Eng J Med 2014; 371:993-1004.
Okumura et al 2016 
Okumura N, Jhund PS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL et al for the PARADIGM-HF 
Investigators and Committees. Importance of Clinical Worsening of Heart Failure Treated in the 
Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine 
Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) Circulation 
2016;133:2254-62.
Ponikowski et al 2016
Ponikowski P, Voors A, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.  2016 ESC Guidelines for 
the Diagnosis and Treatment of Acute and Chronic Heart Failure.  European Heart Journal 2016:18, 
891–975.
Rajasekeran et al 2016
Rajasekeran H, Lytvyn Y, Cherney DZI.  Sodium–glucose cotransporter 2 inhibition and 
cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis.  Kidney 
International 2016; 89:524–526.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
86 (102)
Rogers et al 2016
Rogers JK, Yaroshinsky A, Pocock SJ, Stokar D, Pogoda J.  Analysis of recurrent events with an 
associated informative dropout time: Application of the joint frailty model.  Stat Med. 2016 Jun 
15;35(13):2195-205.
Sacks et al 2014
Sacks CA, Jarcho JA, Curfman GD.  Paradigm Shifts in Heart-Failure Therapy — A Timeline.  N Engl 
2014; 371:989-991.
Sjöström et al 2015
Sjöström CD, Johansson P, Ptaszynska A, List J, Johnsson E.  Dapagliflozin lowers blood pressure 
inhypertensive and non-hypertensive patients with type 2 diabetes.  Diab Vasc Dis Res.  2015
Sep;12(5):352-8.
Sonesson et al 2016
Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in 
patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol 2016 
Feb 19;15:37.
Spertus et al 2005
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P et al. Monitoring clinical 
changes in patients with heart failure: a comparison of methods. Am Heart J. 2005;150:707-15.
Wanner et al 2016
Wanner Christoph; Inzucchi, Silvio E.; Lachin, John M; Fitchett, David; von Eynatten, Maximilian. 
Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375:323-34. 
Zinman et al 2015
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E et al.  Empagliflozin, cardiovascular 
outcomes, and mortality in type 2 diabetes.  N Engl J Med 2015; 373:2117-2128.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
87 (102)
Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’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).
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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
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 patient or may require 
medical intervention 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 dyscrasia (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
88 (102)

Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca (AZ) 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.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
89 (102)
Appendix B
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.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) 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 (HIV) 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

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 

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.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
90 (102)
Appendix C
Clinical data interchange standards consortium (CDISC) 
definition for Hospitalisation for heart failure (HF) and 
urgent heart failure visit
A Heart Failure Event includes hospitalisation for heart failure and may include urgent 
outpatient visits.  HF hospitalisations should remain delineated from urgent visits.  If urgent 
visits are included in the HF event endpoint, the number of urgent visits needs to be explicitly 
presented separately from the hospitalisations.
Heart Failure Hospitalisation is defined as an event that meets ALL of the following 
criteria:
1.
The patient is admitted to the hospital with a primary diagnosis of HF
2.
The patient's length-of-stay in hospital extends for at least 24 hours (or a change in 
calendar date if the hospital admission and discharge times are unavailable)
3.
The patient exhibits documented new or worsening symptoms due to HF on 
presentation, including at least ONE of the following:
(a)
Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal 
nocturnal dyspnea)
(b)
Decreased exercise tolerance
(c)
Fatigue
4.
The patient has objective evidence of new or worsening HF, consisting of at least
TWO physical examination findings OR one physical examination finding and at 
least ONE laboratory criterion), including:
(a)
Physical examination findings considered to be due to heart failure, 
including new or worsened:
(i)
Peripheral edema
(ii)
Increasing abdominal distention or ascites (in the absence of primary
hepatic disease)
(iii)
Pulmonary rales/crackles/crepitations
(iv)
Increased jugular venous pressure and/or hepatojugular reflux
(v)
S3 gallop
(vi)
Clinically significant or rapid weight gain thought to be related to
fluid retention
(b)
Laboratory evidence of new or worsening HF, if obtained within 24 hours 
of presentation, including:


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
91 (102)
(i)
Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP 
(NT- proBNP) concentrations consistent with decompensation of 
heart failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 
pg/mL).  In patients with chronically elevated natriuretic peptides, a
significant increase should be noted above baseline.
(ii)
Radiological evidence of pulmonary congestion.
(iii)
Non-invasive diagnostic evidence of clinically significant elevated
left- or right-sided ventricular filling pressure or low cardiac output.  
For example, echocardiographic criteria could include: E/e’ > 15 or 
D-dominant pulmonary venous inflow pattern, plethoric inferior vena
cava with minimal collapse on inspiration, or decreased left
ventricular outflow tract (LVOT) minute stroke distance (time
velocity integral (TVI)).
OR
(iv)
Invasive diagnostic evidence with right heart catheterization showing
a pulmonary capillary wedge pressure (pulmonary artery occlusion
pressure) ≥18 mmHg, central venous pressure ≥12 mmHg, or a
cardiac index < 2.2 L/min/m2 
Note: All results from diagnostic tests should be reported, if available, even if 
they do not meet the above criteria, because they provide important 
information for the adjudication of these events.
5.
The patient receives initiation or intensification of treatment specifically for HF, 
including at least ONE of the following:
(a)
Augmentation in oral diuretic therapy
(b)
Intravenous diuretic or vasoactive agent (e.g., inotrope, vasopressor, or 
vasodilator)
(c)
Mechanical or surgical intervention, including:
(v)
Mechanical circulatory support (e.g., intra-aortic balloon pump,
ventricular assist device, extracorporeal membrane oxygenation, total
artificial heart)
(vi)
Mechanical fluid removal (e.g., ultrafiltration, hemofiltration,
dialysis)
An Urgent Heart Failure Visit is defined as an event that meets all of the following:
1.
The patient has an urgent, unscheduled office/practice or emergency department
visit for a primary diagnosis of HF, but not meeting the criteria for a HF
hospitalisation.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
92 (102)
2.
All signs and symptoms for HF hospitalisation (i.e., 3) symptoms, 4) physical 
examination findings/laboratory evidence of new or worsening HF, as indicated
above) must be met.
3.
The patient receives initiation or intensification of treatment specifically for HF, as 
detailed in the above section with the exception of oral diuretic therapy, which will
not be sufficient.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
93 (102)
Appendix D
New York Heart Association (NYHA) Functional 
Classification
NYHA Functional Classification
Class
Patient symptoms
I
No limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea (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.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
94 (102)
Appendix E
Patient Reported Outcome (PRO) questionnaires
E1
Patient Global Impression of Severity (PGIS) for Heart Failure Symptoms
Study Number: D1699C00001
Site Number:
Subject Number:
Visit Number:
Assessment Date:
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


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1699C00001
Version 2.0
Date 26 October 2017
95 (102)
E2
Patient Global Impression of Change (PGIC) for Heart Failure Symptoms
Patient Global Impression of Change for Heart Failure Symptoms
Overall, how would you rate the change in your heart failure symptoms since starting this study?
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse


Copyright ¤1992 –2005 John Spertus, MD, MPH
E3
Kansas City Cardiomyopathy Questionnaire (KCCQ)
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
Activity
Extremely 
Limited
Quite a bit 
Limited
Moderately 
Limited
Slightly 
Limited
Not at all 
Limited
Limited for 
other reasons or
did not do the 
activity
Dressing yourself
□
□
□
□
□
□
Showering/Bathing
□
□
□
□
□
□
Walking 1 block on 
level ground
□
□
□
□
□
□
Doing yardwork, 
housework or 
carrying groceries
□
□
□
□
□
□
Climbing a flight of 
stairs without
□
□
□
□
□
□
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 
worse
Slightly 
worse
Not changed
Slightly 
better
Much 
better
I’ve had no symptoms 
over the last 2 weeks
□
□
□
□
□
□


Copyright ¤1992 –2005 John Spertus, MD, MPH
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?
Every morning
3 or more times a 
week, but not 
every day
1-2 times a week
Less than once a 
week
Never over the 
past 2 weeks
□
□
□
□
□
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
□
□
□
□
□
□
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you 
want?
All of the 
time
Several 
times per day
At least 
once a day
3 or more times 
per week but not 
every day
1-2 times 
per week
Less than once 
a week
Never over 
the past 2 
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
bothersome
bothersome
bothersome
bothersome
bothersome
no 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 
every day
1-2 times 
per week
Less than 
once a week
Never over 
the past 2 
weeks
□
□
□
□
□
□
□


Copyright ¤1992 –2005 John Spertus, MD, MPH
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
□
□
□
□
□
□
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 night
3 or more times a 
week, but not every day
1-2 times a week
Less than once a 
week
Never over the 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 all sure
Not very sure
Somewhat sure
Mostly sure
Completely 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 understand at 
all
Do not understand 
very well
Somewhat 
understand
Mostly understand
Completely 
understand
□
□
□
□
□
12. Over the past 2 weeks, how much has your heart failure limited you enjoyment of life?
It has extremely 
limited my 
enjoyment of life
It has limited my 
enjoyment of life 
quite a bit
It has 
moderately limited 
my enjoyment of 
life
It has slightly limited 
my enjoyment of life
It has not limited 
my 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?
Not at all 
satisfied
Mostly dissatisfied
Somewhat 
satisfied
Mostly 
satisfied
Completely satisfied
□
□
□
□
□


Copyright ¤1992 –2005 John Spertus, MD, MPH
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 of the time
I felt that way 
most of the time
I occasionally 
felt that way
I rarely felt that 
way
I never felt that 
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 week?
Place an X in one box on each line
Activity
Severely 
Limited
Limited 
quite a bit 
Moderately 
Limited
Slightly 
Limited
Did not 
limit at all
Does not apply 
or did not do 
for other 
reasons
Hobbies, 
recreational 
activities
□
□
□
□
□
□
Working or 
doing household 
chores
□
□
□
□
□
□
Visiting family or 
friends out of  
your home
□
□
□
□
□
□
Intimate 
relationship with 
loved ones
□
□
□
□
□
□


UK (English) © 2009EuroQol Group EQ-5D™is a trade mark of the EuroQol Group
E4
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L)
Health Questionnaire
English version for the UK


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


UK (English) © 2009EuroQol Group EQ-5D™is a trade mark of the EuroQol Group

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.


Document Name: 
                                                                    
 
Document Title: 
                                                                                                    
                                                                                                                                      
                                                                                                                                 
                                                                                                                                             
                                                                                                                  
 
Document ID: 
                                                                                           
 
Version Label: 
 
                  
 
 
 
 
 
 
 
     
            
                                          
              
 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
Signed By 
Meaning of Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
Clinical Study Protocol HF
D1699C00001 Clinical Study Protocol Version 1
Doc ID-003203568
3.0
Approved
CURRENT
LATEST
26-Oct-2017 16:15 GMT+0100
Clinical Approval
26-Oct-2017 20:14 GMT+0100
Biostatistics Approval
26-Oct-2017 22:46 GMT+0100
Clinical Operations
Approval
27-Oct-2017 07:16 GMT+0100
Clinical Development
Approval

SAP_001.pdf: 


Statistical Analysis Plan  
Study Code D1699C00001 
Edition Number 3.0  
Date 23/July/2019 
2 
 
 
 
 
 
 
 
 
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening 
Heart Failure or Cardiovascular Death in Patients with Chronic Heart 
Failure with Reduced Ejection Fraction 
Study Statistician 
 
Date 
 




Statistical Analysis Plan  
Study Code D1699C00001 
Edition Number 3.0  
Date 23/July/2019 
4 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
SIGNATURE OF STUDY STATISTICIAN .......................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................... 3 
TABLE OF CONTENTS ......................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................. 6 
AMENDMENT HISTORY ..................................................................................... 8 
1. 
STUDY DETAILS ................................................................................................. 11 
1.1 
Study objectives ..................................................................................................... 11 
1.1.1 
Primary objective ................................................................................................... 11 
1.1.2 
Secondary objectives ............................................................................................. 11 
1.1.3 
Safety objectives .................................................................................................... 12 
1.1.4 
Explorative objectives ............................................................................................ 13 
1.2 
Definitions .............................................................................................................. 14 
1.2.1 
Primary analysis censoring date ............................................................................. 14 
1.2.2 
Withdrawal of informed consent ........................................................................... 15 
1.2.3 
Discontinuation from study drug ........................................................................... 15 
1.2.4 
Vital status ............................................................................................................. 15 
1.2.5 
Lost to follow-up .................................................................................................... 15 
1.3 
Study design ........................................................................................................... 15 
1.3.1 
Randomization ....................................................................................................... 16 
1.4 
Number of patients ................................................................................................. 17 
2. 
ANALYSIS SETS ................................................................................................. 17 
2.1 
Definition of analysis sets ...................................................................................... 17 
2.1.1 
Full analysis set ...................................................................................................... 17 
2.1.2 
Safety analysis set .................................................................................................. 17 
2.2 
Violations and deviations ....................................................................................... 18 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 18 
3.1 
Primary variable ..................................................................................................... 19 
3.2 
Secondary variables ............................................................................................... 19 
3.2.1 
The composite of CV death and hospitalization for HF ........................................ 19 
3.2.2 
Total number of (first and recurrent) hospitalizations for HF and CV death ........ 19 
3.2.3 
Change from baseline at 8 months in the KCCQ total symptom score ................. 20 


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3.2.4 
The composite of  ≥50% sustained decline in eGFR, end stage renal 
disease and renal death ........................................................................................... 20 
3.2.5 
Death from any cause ............................................................................................. 21 
3.3 
Safety variables ...................................................................................................... 21 
4. 
ANALYSIS METHODS ....................................................................................... 22 
4.1 
General principles .................................................................................................. 22 
4.1.1 
Estimand for primary and secondary outcomes ..................................................... 23 
4.1.2 
Hypotheses ............................................................................................................. 23 
4.1.3 
Confirmatory testing procedure ............................................................................. 24 
4.1.4 
Presentation of time-to-event analyses .................................................................. 24 
4.1.5 
Vital status and follow-up of endpoints ................................................................. 24 
4.2 
Analysis methods ................................................................................................... 25 
4.2.1 
Demographics and baseline characteristics............................................................ 25 
4.2.2 
Concomitant and baseline medication ................................................................... 25 
4.2.3 
Analysis of the primary efficacy variable .............................................................. 26 
4.2.3.1 
Subgroup analysis of the primary endpoint ........................................................... 26 
4.2.3.2 
Sensitivity analysis of the primary endpoint .......................................................... 28 
4.2.4 
Analysis of the secondary efficacy variables ......................................................... 28 
4.2.4.1 
Analysis of recurrent HF events and CV death ..................................................... 28 
4.2.4.2 
Analysis of change from baseline at 8 months in the KCCQ total symptom 
score ....................................................................................................................... 30 
4.2.5 
Analysis of safety variables ................................................................................... 34 
4.2.5.1 
Adverse events ....................................................................................................... 34 
4.2.5.2 
Serious adverse events ........................................................................................... 35 
4.2.5.3 
Adverse events leading to discontinuation, interruption or dose reduction ........... 35 
4.2.5.4 
Adverse events of interest ...................................................................................... 35 
4.2.5.5 
Laboratory Evaluation............................................................................................ 36 
4.2.5.6 
Marked laboratory abnormalities ........................................................................... 36 
4.2.6 
Analysis of exploratory objectives ......................................................................... 36 
5. 
INTERIM ANALYSES ......................................................................................... 37 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 38 
7. 
REFERENCES ...................................................................................................... 38 
8. 
APPENDIX ............................................................................................................ 41 
8.1 
Appendix A Laboratory Abnormality Criteria....................................................... 41 
8.2 
Appendix B Estimation of clinically meaningful thresholds for KCCQ total 
symptom score ....................................................................................................... 43 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
AF 
Atrial fibrillation 
ATC 
Anatomical Therapeutic Chemical 
CEA 
Clinical event adjudication 
CKD-EPI  
Chronic kidney disease epidemiology collaboration equation 
CMH 
Cochran-Mantel-Haenszel 
CMWPC 
Clinically meaningful within-patient change 
CSP 
Clinical study protocol 
CSS 
KCCQ clinical summary score 
CV 
Cardiovascular 
DAE 
Adverse event leading to discontinuation of investigational product 
DMC 
Data monitoring committee 
eCDF 
Empirical cumulative distribution function  
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End stage renal disease 
FAS 
Full analysis set 
HbA1c 
Glycosylated haemoglobin 
HF 
Heart failure 
HFrEF 
Heart failure with reduced 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 
MA 
Marked abnormality 
MAR 
Missing at random 


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Abbreviation or 
special term 
Explanation 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
MMRM 
Mixed model repeated measures 
MRA 
Mineralocorticoid antagonist 
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 
ROC 
Receiver operating characteristic 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCV 
Study closure visit 
SED 
Study end date 
SD 
Standard deviation 
T2D 
Type 2 diabetes 
TSS 
KCCQ total symptom score 
WoC 
Withdrawal of consent 
 


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AMENDMENT HISTORY 
Date /Version 
Brief description of change 
1 Feb 2017 / 
Version 1.0 
 Version 1.0 signed 
19 Feb 2019 
/Version 2.0 
Secondary objective for KCCQ changed from clinical summary score to total 
symptom score, following protocol update (protocol version 2.0, 26 October 
2017) [Section 1.1.2, 3.2.3, 4.2.4.2] 
 
AEs leading to a risk for lower limb amputations added to safety objective, 
following protocol update [section 1.1.3, 3.3] 
 
Echocardiography substudy added to exploratory objective, following protocol 
update [section 1.1.4] 
 
Clarification of prohibited concomitant medication added [section 2.2, 4.2.2] 
 
The analysis of the KCCQ endpoint changed to a composite rank-based method, 
following FDA feedback regarding the initially proposed mixed model repeated 
measures approach. [Section 3.2.3, 4.1.1, 4.2.4.2] 
 
Adjudication requirement for potential events related to eGFR decline was 
removed, following protocol update [Section 3, 3.2.4, 4.2] 
 
Event types that are being withheld from reporting to health authorities limited 
to HF events and death (Renal events will not be withheld). [Section 3.3] 
 
Definition of baseline diabetic status for subgroup analysis added [Section 4.1] 
 
eGFR will be calculated from central laboratory creatinine values, rather than 
using eGFR calculated by central laboratory. [Section 4.1] 
 
Clarification that the significance level will be determined based on the exact 
actual proportion of primary endpoints included in the interim analysis [Section 
4.2] 
 
Updates to the list of subgroups [Section 4.2.3.1, Table 1] 
• 
Diuretics removed due to small group of patients not on diuretics. 
• 
History of hypertension replaced by etiology of HF (Ischemic vs Non-
ischemic/unknown). 
• 
Clarification that atrial fibrillation group will include patients with atrial 
flutter and be based on enrolment ECG 
• 
Definition of T2D subgroup clarified 
 
In consideration of large variability associated with few events, it has been 
specified that HRs with confidence intervals will not be presented if less than 15 
events in asubgroup [Section 4.2.3.1] 
 
Specification that ‘on+off’ treatment will be considered the primary analysis 
approach for fractures and amputations [section 4.2.5] 
 
 


Statistical Analysis Plan  
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Date /Version 
Brief description of change 
 
Statement about urinalysis data removed. This was included by mistake in 
version 1.0. No central laboratory measurements are collected in this study 
[Section 4.2.5.5] 
 
Statement about presentation of potential events of Fournier’s gangrene  added 
[Section 4.2.5.4] 
 
Clarification that presentation of DKA will primarily be based on adjudicated 
DKA 
 
Statement about a primary analysis censoring date to be applied after a decision 
to stop the trial after interim analysis added [Section 5] 
23 July 2019 / 
Version 3.0 
Details of statistical methods, assumptions and references for the joint frailty 
model of recurrent HF events and CV death added based on FDA request. 
Details about Ghosh and Lin plot added. [section 3.2.2 and 4.2.4.1] 
 
Removed reference to the R package Sanon (Kawaguchi et al 2011) for 
derivation of the adjusted win ratio as the Mann-Whitney odds estimate and 
removed the intermediate step to explicitly calculate the standard error of the 
Mann-Whitney odds. The same statistic will be derived using SAS as described 
in Koch et al 1998 (reference added) [section 4.2.4.2, Estimation of treatment 
effect]   
 
Additional details regarding responder analysis of KCCQ TSS added [section 
4.2.4.2, Estimation of treatment effect]. 
• 
Handling of patients whose baseline value is too high/low to make it 
possible to achieve the threshold for improvement/deterioration. 
• 
Details of logistic regression of the proportion of patients achieving the 
responder thresholds added. 
• 
Responder analysis by thresholds derived from anchor-based analysis 
added. 
 
Clarification added regarding the variable representing the number of HF events 
in multiple imputation of missing TSS values. [section 4.2.4.2, Handling of 
missing data] 
 
Clarification of use of imputed TSS values in responder analysis [section 
4.2.4.2, Handling of missing data] 
 
Correction: Descriptive statistics for KCCQ scores will be presented at 4 and 8 
months [section 4.2.4.2, Supportive and sensitivity analyses] 
 
Correction to clarify how the sensitivity analysis of change from baseline TSS is 
different from the main analysis in terms of handling patients who died. 
[section 4.2.4.2, Supportive and sensitivity analyses] 
 
Correction: Removed creatinine clearance from laboratory variables to be 
summarized. Assessment of creatinine clearance is not defined in the study 
protocol. [section 4.2.5.5] 


Statistical Analysis Plan  
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Date /Version 
Brief description of change 
 
Marked lab abnormality criteria for creatinine clearance < 45 mL/min and eGFR 
< 45 mL/min/1.73m2 were removed since not considered appropriate criteria for 
abnormality in the enrolled study population and had been included by mistake. 
[Appendix A]. 
The criterion serum creatinine ≥1.5xbaseline was retained and serum creatinine 
≥2xbaseline was added. 
 
Added Appendix B describing the estimation of clinically meaningful thresholds 
for KCCQ TSS. 


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1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
 
Primary Objective: 
Outcome Measure: 
To determine whether dapagliflozin is superior 
to placebo, when added to standard of care, in 
reducing the incidence of CV death or a HF 
event (hospitalization for HF or equivalent HF 
event, ie an urgent HF visit).   
Time to the first occurrence of any of the components 
of this composite:  
1. 
CV death 
2. 
Hospitalization for HF 
3. 
An urgent HF visit  
 
1.1.2 
Secondary objectives  
Secondary Objective: 
Outcome Measure : 
To compare the effect of dapagliflozin versus 
placebo on CV death or hospitalization for HF. 
Time to the first occurrence of either of the 
components of this composite:  
1. 
CV death  
2. 
Hospitalization for HF 
To compare the effect of dapagliflozin versus 
placebo on total number of recurrent HF 
hospitalizations and CV death.   
Total number of (first and recurrent) HF 
hospitalizations and CV death.   
To compare the effect of treatment with 
dapagliflozin versus placebo on the Kansas 
City Cardiomyopathy Questionnaire (KCCQ)  
total symptom score for HF symptoms. 
Change from baseline measured at 8 months in the 
total symptom score of the KCCQ, a specific HF 
patient reported outcome questionnaire. 
 


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To determine if dapagliflozin compared with 
placebo reduces the incidence of a composite 
endpoint of worsening renal function.   
Time to the first occurrence of any of the components 
of this composite: 
1. 
≥50% sustained decline in eGFR 
2. 
Reaching End Stage Renal Disease 
(ESRD)  
− 
Sustained eGFR 
<15 ml/min/1.73m2 or, 
− 
Chronic dialysis treatment or,  
− 
Receiving a renal transplant 
3. 
Renal death  
To determine whether dapagliflozin, compared 
with placebo, reduces the incidence of all-
cause mortality.   
Time to death from any cause. 
 
1.1.3 
Safety objectives 
Safety Objective: 
Outcome Measure : 
To evaluate the safety and tolerability of 
dapagliflozin in this patient population.   
1. 
Serious Adverse Events (SAEs) 
2. 
Discontinuation of IP due to Adverse 
Events (DAEs) 
3. 
Changes in clinical 
chemistry/haematology parameters  
4. 
Adverse events of interest (volume 
depletion, renal events, major 
hypoglycaemic events, fractures, diabetic 
ketoacidosis (DKA), AEs leading to 
amputation and AEs leading to a risk for 
lower limb amputations [“preceding 
events”])  
 


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1.1.4 
Explorative objectives 
Exploratory Objective: 
Outcome Measure : 
To compare the effect of dapagliflozin versus 
placebo on an expanded composite outcome 
reflecting worsening of HF.   
Time to the first occurrence of any of the components 
of the expanded composite worsening HF outcome:  
4. 
CV death 
5. 
Hospitalization for HF 
6. 
An urgent HF visit 
7. 
Documented evidence of worsening HF 
symptoms/signs leading to initiation of a 
new treatment for HF sustained for at least 
4 weeks or augmentation of existing oral 
therapy for HF (eg, increase in dose of 
diuretic) sustained for at least 4 weeks.   
To determine whether dapagliflozin compared 
with placebo will have effect on New York 
Heart Association (NYHA) class. 
Change in NYHA class from baseline. 
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of 
diagnosis of AF in patients without history of 
AF at baseline. 
Proportion of patients without history of AF at 
baseline with a new diagnosis of AF during the study. 
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of hyper – and hypokalaemia.   
Time to the first occurrence of each of any of the 
following central lab levels of serum potassium: 
• >6.0 mmol/L 
• >5.5 mmol/L 
• <3.5 mmol/L 
• <3.0 mmol/L 
 
To determine whether dapagliflozin compared 
with placebo will affect the number of events 
of doubling of serum creatinine. 
Number of events with doubling of serum creatinine 
(compared with the most recent laboratory 
measurement). 
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of 
diagnosis of T2D in patients without diabetes 
at baseline.   
Proportion of patients without T2D at baseline with a 
new diagnosis of T2D during the study.   
To determine whether dapagliflozin compared 
with placebo will have effect on HbA1c in 
T2D subgroup. 
Changes in HbA1c from baseline.   


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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 reduce the incidence of 
myocardial infarction (MI). 
Time to first fatal or non-fatal MI. 
To determine whether dapagliflozin compared 
with placebo will reduce the incidence of any 
stroke (ischemic, hemorrhagic, or 
undetermined). 
Time to first fatal or non-fatal stroke of any cause. 
To compare the effect of dapagliflozin versus 
placebo on health status assessed by Patient 
Global Impression of Change (PGIC) and 
Patient global impression of severity (PGIS) 
questionnaires. 
Changes in health status measured by PGIC and 
PGIS. 
To compare the effect of dapagliflozin versus 
placebo on health status assessed by EuroQol 
five-dimensional five-level questionnaire (EQ-
5D-5L) to support health economic analysis 
and health technology assessment. 
Changes in health status measured by EQ-5D-5L. 
To collect and analyse pharmacokinetic (PK) 
samples for dapagliflozin concentration. 
Not applicable.  Results will be reported separately. 
To assess cardiac structure and function with 
echocardiography at baseline and 8 months 
follow-up. 
Not applicable.  Results will be reported separately. 
To collect and store samples of plasma and 
serum for future exploratory biomarker 
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 primary analysis censoring date (PACD) at which time at least 
the pre-defined target number of 844 events for the primary composite endpoint is expected to 
have occurred. The study sites will be instructed to plan for study closure visits to be 
performed after PACD. 
 
The analyses of the 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 


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Section 3.1 and 3.2) will be censored at PACD. Endpoint events with onset after PACD will 
also be adjudicated. 
 
1.2.2 
Withdrawal of informed consent 
Withdrawal of consent (WoC) means withdrawal from study and should only occur if the 
patient does not agree to any kind of further assessment at all. No data after date of WoC 
should be collected, with the exception of vital status (dead or alive) at the end of the study 
collected from public sources, which will be included in the analysis of death from any cause 
as a sole outcome and in patient disposition summaries. Data collected on or prior to date of 
WoC will be included in analyses.  
 
1.2.3 
Discontinuation from study drug 
Discontinuation from study drug does not mean WoC. Optimally, patients who discontinue 
from study drug should continue study visits according to plan until study closure. 
Alternatively, if the patient does not agree to this approach, modified follow-up should be 
arranged. Data from patients who did not withdraw consent will be included in the intention to 
treat (ITT) analyses irrespective of whether the event occurred before or following 
discontinuation of study drug.  
 
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 lost to follow-up (LTFU) will be limited to patients with unknown vital status at the 
end of the study as defined in Section 1.2.4. Other measures will be used to describe 
incomplete follow-up of the primary endpoint (Section 4.1.5) 
1.3 
Study design 
This is an international, multicentre, parallel group, event-driven, randomized, double-blind, 
placebo-controlled study in patients with chronic heart failure with reduced ejection fraction 
(HFrEF), evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in 
addition to background regional standard of care therapy, for the prevention of cardiovascular 
(CV) death or reduction of heart failure (HF) events. 
It is estimated that approximately 7000 patients at approximately 500-600 sites in 20-25 
countries will be enrolled to reach the target of approximately 4500 randomized patients.  The 
investigational product (IP) will be added to the prescribed background therapy for HF (and 


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background therapy for T2D when applicable) as considered appropriate by the investigator 
and in accordance with regional standards of care. 
The anticipated duration of the study is approximately 33 months.  The study closure 
procedures will be initiated when the predetermined number of adjudicated primary endpoints 
is predicted to have occurred (844). This date, which in the clinical study protocol (CSP) is 
termed study end date (SED) will be the common censoring date for efficacy time-to-event 
analyses. Thus, it will in this SAP be termed the primary analysis censoring date (PACD, 
Figure 1).   
 
Figure 1 Study flow chart 
 
1.3.1 
Randomization 
Patients will be randomized 1:1 to either dapagliflozin 10 mg or placebo. Randomization will 
be stratified by type 2 diabetes (T2D) status at randomization (2 levels: with T2D; without 
T2D). T2D for stratified randomization is defined as established diagnosis of T2D or HbA1c 
more or equal to 6.5% (48 mmol/mol) shown at central laboratory test at enrolment (visit 1). 
See section 4.1 for definition of baseline diabetic status for analysis. 
Randomization will be performed in balanced blocks of fixed size. The randomization codes 
will be computer generated and loaded into the IxRS (Interactive Voice/Web Response 
System) database.   
The number of randomized patients with and without T2D will be monitored in order to 
ensure a minimum of 30% in each sub-population. Randomization may be capped (ie, no 
more patients can be randomized in a specific sub-population) if the pre-determined limit is 
reached.  


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Randomization of patients based on geographic region will be monitored to ensure global 
representation.  LVEF category, NYHA class and atrial fibrillation status may be capped in 
IxRS to avoid over- or under-representation of these patient subgroups. 
1.4 
Number of patients 
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint.  Assuming a true hazard 
ratio (HR) of 0.80 between dapagliflozin and placebo, using a one-sided alpha of 2.5%, 844 
primary endpoint events will provide a statistical power of 90% for the test of the primary 
composite endpoint.  This is based on an overall 1:1 allocation between dapagliflozin and 
placebo.  The study is event-driven.  The assumed HR of 0.80 is considered as clinically 
relevant and has taken into account the HF outcomes in the EMPA-REG trial (Fitchett et al 
2016). 
With an annual event rate of 11% in the placebo treatment group, 4500 patients are estimated 
to provide the required number of primary events, based on an anticipated recruitment period 
of 18 months and an average follow-up period of approximately 24 months.  The assumed 
placebo event rate of 11% is based on a review of recently published clinical studies in the 
HFrEF population, including the PARADIGM-HF trial (McMurray et al 2014).  The number 
of patients with incomplete follow-up of endpoints is expected to be small; hence, these are 
not considered in the determination of the sample size. 
This study is a group sequential design study with one interim analysis at 75% of the 
adjudicated target number of events using Haybittle-Peto boundary (a one-sided alpha=0.001), 
leaving a one-sided alpha of 2.496% for the final analysis.   
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
2.1.1 
Full analysis set 
All patients who have been randomized to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study.  
Patients will be analysed according to their randomized IP assignment, irrespective of the 
treatment actually received.  The FAS will be considered the primary analysis set for the 
primary and secondary variables and for the exploratory efficacy variables.   
2.1.2 
Safety analysis set 
All randomized patients who received at least 1 dose of randomized treatment will be included 
in the safety population.  Patients will be analysed according to the treatment actually 
received. For any patients given incorrect treatment, ie randomized 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 analyzed according to their 


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randomized treatment. Patients who got only the incorrect treatment will be analyzed 
according to that treatment. 
The safety analysis set 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 randomized treatment 
group 
• Patients who were randomised but did not meet inclusion and exclusion criteria 
• Patients who received the wrong study treatment at any time during the study. 
• Patients who received prohibited concomitant medication, which for this study is 
limited to open label SGLT2 inhibitors taken in combination with IP.  
 
As the primary analysis is intention-to-treat analysis, protocol deviation will not imply 
exclusion from the primary analysis. 
3. 
PRIMARY AND SECONDARY VARIABLES 
Potential endpoint events and event dates will be adjudicated by an independent clinical event 
adjudication (CEA) committee. The 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. 
The primary and secondary efficacy variables and their components will only include HF  
events confirmed by the CEA. Deaths adjudicated as ‘cause undetermined’ with regard to CV 
death or non-CV death will be included as CV death in the primary efficacy analyses.  
All adjudicated events from randomization until WoC or PACD will be included in the 
analysis of primary and secondary endpoints, except for the analysis of all-cause death as a 
sole outcome, which also will include deaths (not adjudicated) after WoC, but on or before 
PACD. 
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 randomization to the first occurrence 
of an event (start date of the event – randomization date + 1), or for event free patients, 
from randomization to censoring (censoring date – randomization date + 1). 


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Event free patients will be censored as described below for each respective endpoint. 
3.1 
Primary variable 
The primary efficacy variable is time from randomization to the first occurrence of any event in the 
composite of CV Death, hospitalization for HF or an urgent HF visit.  
The three components of the endpoint will be individually adjudicated by the CEA committee. 
Patients who did not have an endpoint event will be censored at the earliest of date of WoC or 
non-CV death when applicable, and otherwise at the earliest of date of last clinical event 
assessment or PACD. Last clinical event assessment is defined as the last date when the event 
assessment question for a potential heart failure event was completed on the eCRF event 
assessment page. It is expected that patients alive and under study follow-up will have a 
clinical event assessment at their SCV after PACD 
In analysis of hospitalization for HF and urgent HF visit to examine the contribution of each 
component of the composite endpoint, date of death from any cause will be an additional point 
of censoring. 
3.2 
Secondary variables 
The secondary endpoints are included in a hierarchical testing sequence following the primary 
endpoint as ordered in Section 3.2.1 - 3.2.5. 
3.2.1 
The composite of CV death and hospitalization for HF 
The efficacy variable is time from randomization to the first occurrence of any event in the 
composite of CV death and hospitalization for HF. Patients who did not have the endpoint will 
be censored by the same rule as for the primary endpoint. 
3.2.2 
Total number of (first and recurrent) hospitalizations for HF and CV death 
The efficacy variable is the total number of first and recurrent hospitalizations for HF and CV 
death, not including urgent HF visit. 
For the analysis of recurrent heart failure hospitalization 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. 
The time from randomization 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. Recurrent HF 
hospitalizations, CV death and censoring processes all have continuous distributions so that 
HF hospitalization and death cannot happen at the same time. If HF hospitalization and CV 
death occurred at the same day, then only the CV death will be counted.  
Patients who did not have the endpoint will be censored by the same rule as for the primary 
endpoint. 


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3.2.3 
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 Kansas City 
Cardiomyopathy Questionnaire (KCCQ) total symptom score (TSS). By the ITT principle, the 
analysis will include all data irrespective of whether the patient has discontinued study drug. 
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 0-100. Higher scores represent a better outcome. 
Baseline is defined as the value at randomization 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 score is assessed by the 
patient at randomization, 4, 8, 12 months following randomization, thereafter every 12 
months, and at the premature treatment discontinuation visit (PTDV) and the study closure 
visit (SCV).  
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 to 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 (i.e., lower ranks corresponding to negative or smaller values of change from 
baseline). Patients who die prior to the 8-month assessment will be assigned the worst rank, 
i.e., 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.   
3.2.4 
The composite of  ≥50% sustained decline in eGFR, end stage renal disease and 
renal death 
The efficacy variable is time from randomization to the first occurrence of any event in the 
composite of ≥50% sustained decline in eGFR, reaching end stage renal disease (ESRD) and 
renal death.  
 
ESRD is defined as any of  
• Sustained eGFR <15 ml/min/1.73m2 
• Chronic dialysis treatment 
• Receiving a renal transplant 
All components of the composite endpoint will be defined and described in detail in the CEA 
charter.  The components sustained eGFR decline of ≥50% from baseline and sustained eGFR 
<15 ml/min/1.73m2 will however not be adjudicated by the CEA. 


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Sustained eGFR decline of ≥50% from baseline and sustained eGFR <15 ml/min/1.73m2 will 
be based on two consecutive central laboratory values at least 28 days apart below the 
respective limit. The start date of the event is the date of the first of the two qualifying 
consecutive central laboratory values. Thus, the analysis will include eGFR events with onset 
prior to PACD that are confirmed after PACD, in addition to those eGFR events confirmed 
prior to PACD.  
Chronic dialysis will be adjudicated as treatment ongoing for at least 28 days, or when the 
ESRD is deemed irreversible and the dialysis treatment was stopped before day 28. Similar to 
the eGFR events, the onset date of chronic dialysis will be the date when the qualifying 
dialysis treatment started.  Chronic dialysis, renal transplant and renal death will be 
independently adjudicated as defined in the CEA charter. Deaths adjudicated with 
‘undetermined’ cause will not be considered as renal death. 
Patients who do not have an endpoint event will be censored at the earliest of date of WoC 
and non-renal death when applicable, and otherwise at the earliest of date of last clinical event 
assessment and PACD. Clinical event assessment will be captured by the question for 
potential renal events on the eCRF event assessment page. The earliest assessment date among 
components will be used as the censoring date. For example, for the last clinical event 
assessment, if the central laboratory eGFR assessment is not done in conjunction with the 
assessment of dialysis and renal transplant, the date of last available central laboratory eGFR 
measurement will be used as the censoring date.    
3.2.5 
Death from any cause 
The efficacy variable is time to from randomization to death from any cause. All deaths on or 
prior to PACD, including death after WoC will be included. Patients who are alive will be 
censored at the earliest of date last known alive and PACD. 
Deaths occurring after WoC will not be adjudicated. For such events, the date of death will be 
collected only in eCRF. 
3.3 
Safety variables 
The safety and tolerability of dapagliflozin will be evaluated from serious adverse events 
(SAEs), adverse events leading discontinuation (DAEs) of study drug, changes in 
clinical/haematology parameter and adverse events (AEs) of interest (volume depletion, renal 
events, major hypoglycaemic events, fractures, diabetic ketoacidosis, AEs leading to 
amputation and AEs leading to a risk for lower limb amputations [“preceding events”]). 
SAEs will be collected from time of informed consent until and including the patent’s last 
visit. 
Non-serious AEs will be collected from randomization until and including the patient’s last 
visit, only if it is a DAE, an AE of interest, an AE leading to a potential endpoint or the AE is 
the reason for interruption of study drug or dose reduction. 


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Deaths and HF events will be recorded as SAEs in the database, but will not be reported to 
health authorities to avoid unnecessary unblinding of efficacy endpoints that are fulfilling the 
SAE criteria. If it is determined by the CEA committee that a potential endpoint does not meet 
the endpoint criteria, but is judged by investigators to fulfil the SAE criteria, then the event 
will be reported to AZ patient safety data entry site and if applicable to the health authorities. 
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. 
The primary and secondary analyses 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 randomization assignment.  
Baseline diabetic status 
T2D at baseline will be defined as established diagnosis of T2D (recorded in eCRF medical 
history) or central laboratory HbA1c ≥6.5% at both visit 1 (enrollment) and visit 2 
(randomisation). 
Exploratory analyses may include “pre-diabetic” subjects not categorized as T2D above and 
having central laboratory HbA1c ≥5.7% at visit 1 and/or visit 2. Other subjects will be 
categorized to a third group, here denoted “normo-glycaemic” 
In consideration of missing data, subjects without medical history of T2D and a single HbA1c 
≥5.7% (including ≥6.5%) from visit 1 or visit 2 will be categorized as pre-diabetic. Subjects 
without medical history of T2D and no HbA1c measurement or a single measurement < 5.7% 
will be included in the normo-glycaemic group (thus non-diabetic). 
 
Incomplete dates 
All efforts should be made to obtain complete dates of clinical assessments and events. For 
analyses requiring complete dates, partially missing dates will be imputed based on available 
corroborating information. Absent of any additional corroborating information, partially 
missing dates will be imputed as follows: if only the year part of a date is available (YY), then 
the date will be set to YY0701. If only the year and month is available (YYMM), then the date 
will be set to YYMM15. Additional imputation rules will be defined as appropriate to ensure 
that eg, dates will not be imputed as prior to randomization, after death or end date before start 
date. 


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Baseline laboratory value 
For all laboratory variables, with the exception of eGFR, the baseline value is defined as the 
last value on or prior to date of first dose of randomized study drug, or for patients who did 
not receive treatment, the last value on or prior to date of randomization. 
eGFR 
The eGFR values will be calculated (in mL/min/1.73 m2)  from the central laboratory 
creatinine measurements using the CKD-EPI formula (Levey at al 2009). Descriptive statistics 
will be presented based on laboratory data. 
Baseline eGFR will be calculate as mean of visit 1 and visit 2 values. In case of re-screening, 
the mean of latest values at each of visit 1 and visit 2 on or prior to date of randomization will 
be used. 
Study drug compliance 
The percentage of study drug 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. 
 
Study drug compliance will be presented descriptively, including mean, median, quartiles and 
5% and 95% percentiles. 
4.1.1 
Estimand for primary and secondary outcomes 
The primary and secondary event based objectives will be evaluated under the treatment 
policy estimand to reflect the effect of the initially assigned randomized study drug, 
irrespective of adherence to randomized study treatment. Specifically, the analysis will be 
performed for the full analysis set including all events that occurred on or prior to PACD, 
including events following premature discontinuation of study drug.  
The estimand for the change from baseline in  KCCQ total symptom score 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 3.2.3. For all 
other types of intercurrent events, including but not limited to a premature discontinuation of 
randomized treatment, a treatment policy strategy will be used.  
4.1.2 
Hypotheses 
To control the overall type I error rate at 2.5% one-sided, the significance level will be 
adjusted for one interim analysis of efficacy performed by the DMC (Section 5).  For the 


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primary endpoint the following null hypothesis will be tested at the 2.496% one-sided 
significance level 
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 one-sided alternative hypotheses for the 
respective treatment difference. The significance level will be re-calculated based on the exact 
proportion of primary endpoints included in the interim analysis and may be marginally 
adjusted (Section 5).   
4.1.3 
Confirmatory testing procedure 
A closed testing procedure including a pre-specified hierarchical order of the primary and 
secondary endpoints will be utilized. The Type I error will be controlled at a one-sided 
0.02496 level for multiplicity across primary and secondary endpoints and in consideration of 
the planned interim analysis. Statistical significance will be assessed in the pre-specified order 
of the endpoints as specified in Section 1.1.1 and 1.1.2. The testing procedure will continue 
down the hierarchy if the preceding endpoint is rejected at a one-sided 0.02496 level and will 
stop if the null hypothesis for the preceding endpoint is not rejected at a one-sided 0.02496 
level. 
If the study is stopped in the efficacy interim analysis (Section 5), testing of secondary 
endpoints will continue down the hierarchy at one-sided significance level 0.001. 
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, hazard ratio 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 a given group, presented as patients with 
event per 100 patient years. 
 
Kaplan- Meier (KM) estimates of the cumulative proportion of patients with events will be 
calculated and plotted per treatment group, with the number of patients at risk indicated below 
the plot at specific time points. The KM plots will be presented for all time to event analyses, 
including the individual components of the composite endpoints. 
 
4.1.5 
Vital status and follow-up of endpoints 
Potential endpoints will be collected and adjudicated from randomization 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 


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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 (derived from the eCRF final status form) 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 lost to follow-up 
(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 as the patient had a primary 
endpoint event, died from non-CV death or had complete event assessment on or after the 
PACD. 
 
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 randomization until the 
earliest of first primary endpoint event, death, WoC, censoring due to incomplete event 
assessment (in cases where last complete event assessment is prior to PACD) or PACD. The 
denominator, representing maximum complete follow-up, will be the time to 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 data set, for each 
treatment group as well as for all patients combined.  No statistical test will be performed for 
comparison of any baseline measurement among treatment groups.  
4.2.2 
Concomitant and baseline medication 
Baseline medication is defined as medication with at least one dose taken before date of 
randomization and with no stop date before date of randomization.  
Concomitant medication is defined as medications taken post randomization, irrespective of 
study drug.  
The frequency of baseline and concomitant medication will be presented for the FAS per ATC 
class and treatment group. 


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Summaries of prohibited medication (as defined in CSP Section 7.7.1) will be presented. In 
this study prohibited medication is limited to open label SGLT2 inhibitors taken in 
combination with IP. 
4.2.3 
Analysis of the primary efficacy variable 
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 randomization, and adjusting for history of hospitalization for heart 
failure.  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 score statistic will be used. The 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 events in the component 
analysis will be larger than the number of patients with composite events. Methods similar to 
those described for the primary analysis will be used to separately analyze the time from 
randomization 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 1. A test of interaction between randomized treatment group and 
the subgroup variable will be performed in each Cox model, stratified by T2D and including 
as covariates history of hospitalization for HF, the relevant subgroup variable and the 
interaction between treatment and the subgroup variable.  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. HRs with confidence 
interval will be presented in a forest plot, also including the event rate 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.   
 
 
 


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Table 1 Characteristics and categories for sub group analysis of the primary endpoint 
Characteristic 
Categories 
Age (years) 
<= 65, >65 
Sex 
Male, female 
Race 
White, Black or African, Asian, Other 
Geographic region 
Asia (China, India, Japan, Taiwan, Vietnam) 
Europe (Bulgaria, Czech Republic, Denmark,  
              Germany, Hungary, Netherlands, 
              Poland, Russia, Slovakia, Sweden, 
              UK) 
North America (Canada, US) 
South America (Argentina, Brazil) 
NYHA class at enrollment 
II, III/IV 
LVEF at enrollment 
<= median, > median 
NT-proBNP at enrollment 
<= median, > median 
Prior Hospitalization for HF 
Yes, No 
MRAs at baseline 
Yes, No 
Type 2 diabetes at baseline * 
Yes, No 
Atrial fibrillation or flutter at enrolment ECG 
Yes, No 
Etiology of HF 
Ischemic, Non-ischemic/unknown 
BMI (kg/m2) at enrollment 
<30, ≥30 
Baseline eGFR (ml/min/1.73m2 ) 
<60, ≥60 
* Defined as history of T2D or HbA1c ≥6.5% at both visit 1 and visit 2 (Section 4.1) The subgroup analysis by 
T2D status will exclude T2D as a stratification factor from the model. 
The subgroup analyses will be repeated for the CV death component of the primary composite 
endpoint and the secondary composite endpoint of CV death or HF hospitalization. 
No hazard ratio estimates with confidence interval and p-values will be given for subgroups 
with less than 15 events in total, both treatment groups combined. 


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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 not included as endpoint events, but treated as censoring events, will be performed. 
Missing data and informative censoring 
The time-to-event analysis using the Cox regression depends on the assumption of non-
informative or ignorable censoring, corresponding to the missing-at-random assumption.  The 
missing data in this context are patients who are prematurely censored due to WoC, LTFU or 
otherwise incomplete follow-up of endpoints. The amount of missing data 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 impact of missing data 
and the robustness of the results with regard to the assumption of non-informative censoring, 
sensitivity analysis will be planned based on the evaluation of the missing follow-up and 
discussed in relation to the observed efficacy signal.  This may include analysis where 
scenarios in terms of increased risk in censored patients are explored to identify a ‘tipping 
point’ where statistical significance would be lost. 
4.2.4 
Analysis of the secondary efficacy variables 
The time-to-event secondary variables include  
• time to the first occurrence of hospitalization for HF or CV death  
• time to the first occurrence of any of the components of the renal composite endpoint  
• time to death from any cause.  
These endpoints will be analysed in the same manner as the primary variable, including 
stratification by T2D status at randomization. The composite of hospitalization for HF or CV 
death will be adjusted for history of hospitalization for heart failure. The renal composite 
endpoint will be adjusted for baseline eGFR. Censoring is described in Section 3.2 for each 
endpoint. 
Additionally, exploratory subgroup analysis will be conducted for the secondary composite 
endpoint of CV death or HF hospitalization in the same way as the subgroup analysis for the 
primary endpoint. 
4.2.4.1 
Analysis of recurrent HF events and CV death 
The composite outcome of recurrent HF hospitalizations or CV death will be analysed by the 
semi-parametric proportional rates model (Lin et al 2000)  known as the LWYY (Lin-Wei-
Yang-Ying) method, to test the treatment effect and to quantify the treatment difference in 


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terms of the rate ratio with 95% confidence interval and p-value. Recurrent HF 
hospitalizations, CV death and censoring processes all have continuous distributions so that 
HF hospitalization and death cannot happen at the same time. If a HF hospitalization and CV 
death occurred at the same day, then only CV death will be counted. Moreover, CV death is a 
terminating event which, unlike censoring, prevents the occurrence of new HF 
hospitalizations. 
In addition, the two components in the composite endpoint (total HF hospitalizations 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 HF 
hospitalizations 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 
hospitalizations (dilution of effect size if the drug has a positive effect on both components). 
In order 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.  
For joint frailty analysis the following assumptions are made: (Liu et al 2004) 
• As noted above, HF hospitalization and death cannot happen at the same day (only the 
CV death will be counted) and CV death is a terminating event which prevents the 
occurrence of new HF hospitalizations. 
• The hazard function of CV death (the instantaneous risk of death given that the subject 
is still alive) follows a proportional hazards model with constant baseline hazard, 
stratified by T2D status at randomization with treatment and history of hospitalization 
for heart failure as covariates.  
• The hazard function of recurrent HF hospitalizations (the instantaneous risk of having 
another HF hospitalization given that the subject is still alive) follows a proportional 
hazards model as well, with constant baseline hazard, stratified by T2D status at 
randomization with treatment and history of hospitalization for heart failure as 
covariates.  
• Within subject recurrent HF hospitalizations and CV death are correlated events. This 
correlation varies from subject to subject. To account for this correlation, the hazard 
function of recurrent HF hospitalizations and hazard function of CV death are modeled 
by a joint a subject specific random frailty term which follows a gamma distribution 
with unit mean and unknown variance. 
• Censoring (including non-CV death) is noninformative, in particular it does not 
depend on random frailty. 
 
Estimation in the frailty proportional hazards model will be done using Gaussian quadrature 
approach (Liu and Huang 2008, Lu and Liu 2014, SAS Institute Inc. 2018 ). Since SAS PROC 
NLMIXED supports only normal distributions, a probability integral transformation to 
generate numbers from a gamma distribution will be used (Nelson et al 2006) following Liu 
and Huang 2008. 


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Additionally, non-parametric estimates of  the marginal mean of the cumulative number of 
recurrent HF hospitalization rates over time will be calculated allowing for death as terminal 
event, and the estimates will be plotted (Ghosh and Lin 2000). The estimation will be done in 
SAS using the PROC PHREG and by treating the situation as competing risks with several 
records per subject (Andersen et al 2019) 
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 to 8 months in TSS in surviving patients, as defined in Section 3.2.3, 
will be analysed using the rank ANCOVA method (Stokes et al 2012) to test the null 
hypothesis of no differences 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 TSS value as follows.  
First the change from baseline to 8 months in TSS and vital status at 8 months, as well as 
values of the baseline TSS covariate will be transformed to standardized ranks, 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 TSS while alive before deriving fractional ranks. Then, separate 
regression models will be fit to the ranked data for each randomization 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 further 
testing of differences between treatment groups. The Cochran-Mantel-Haenszel (CMH) test, 
stratified for the T2D status at randomization, using the values of the residuals as scores will 
be used to compare treatment groups. 
Responses missing for reasons other than death will be imputed as described in section 
‘Handling of missing data”. 
The p-value from the CMH test of treatment effect at 8 months will be used for the 
confirmatory statistical testing of the 3rd secondary endpoint in the multiple testing procedure 
described in section 4.1.3 
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 win ratio (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, e.g. on rare occasions, the confidence interval for WR could exclude unity while the 
pre-planned hypothesis test could be non-significant, or the hypothesis test could be 


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significant with the confidence interval for WR including unity. Formal inference for the 
superiority of the treatment over control will be made only from the preplanned hypothesis 
test. 
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 estimated to be in favour of dapagliflozin. 
The win ratio statistic adjusted for the randomization stratification factor and baseline 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 randomization-based covariance adjustment. The win ratio 
statistic will be calculated as Mann-Whitney odds, i.e., 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 summarized across the 
following categories:    
5 point improvement from baseline to 8 months in TSS vs no significant improvement: 
- Change from baseline in TSS ≥ 5 points, vs 
- Death prior to the 8 months assessment or change from baseline in TSS < 5 points.  
5 point deterioration from baseline to 8 months in TSS vs no significant deterioration: 
- Death prior to the 8 months assessment or change from baseline in TSS ≤ -5 points, vs 
- Change from baseline to 8 months in TSS > -5 points. 
If a patient had a baseline value of TSS ≥ 95 points, ie near the “ceiling”, they will be defined 
as having a 5 point improvement only if they had TSS ≥ 95 points at 8 months. Similarly, if a 
patient had a baseline value of TSS ≤ 5 points, ie near the “floor”, they will be defined as 
having a 5 point deterioration only if they had TSS ≤ 5 points at 8 months. 


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The proportion of TSS responder categories will be compared between treatment groups using 
a logistic regression model including treatment group, stratification variable (T2D at 
randomisation) and baseline TSS value. The observed number of and proportion of TSS 
responders, odds ratio between treatment groups and its 95% confidence interval and 
corresponding 2-sided 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 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 (10 point improvement, 10 
point deterioration, 15 point improvement; Appendix B Section 8.2), with “ceiling” and 
“floor” values handled consistently.  
Empirical cumulative distribution function (eCDF) plots will be presented by treatment group 
to summarize the distribution of change from baseline to 8 months in 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). 
Handling of missing data 
The number of patients with missing vital status at 8 months is expected to be negligible. If 
some patients are LTFU or patients who withdrew consent have unknown vital status, the 
main analysis will be done with these patients assigned the worst ranks (same as deaths). 
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, 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 TSS imputed 
using the multiple imputation (MI) methodology as follows. 
Missing TSS values at baseline or at 8 months will be imputed under the Missing at Random 
(MAR) 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 TSS values. The imputation model will 
include the treatment group, T2D randomization stratum, TSS at baseline, month 4, and 8, and 
a categorical variable representing the number of HF events (0, 1, ≥2 events) in the interval 
from randomization to 4 month and in the interval from 4 to 8 months. Occurrences of HF 
events will be determined based on the investigator-reported potential HF events. The 
auxiliary variable related to HF events is included in the imputation model to improve the 
imputation accuracy, because the occurrence of HF events is associated with quality of life 
assessed by KCCQ. 


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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 test 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 
normalizing Wilson-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: 
 
where 
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 to 1). 
The transformed statistics are approximately normally distributed with a 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, as discussed in the 
“Estimation of treatment effect” sub-section above, the average number and percent of 
subjects in each category across all multiple imputed datasets will be reported. The 
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 TSS values for the patients who have missing TSS 
due to reasons other than death. 
Supportive analyses and sensitivity analyses 
The number and percent of patients who die prior to the 8-month assessment will be 
summarized by treatment group. 


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Descriptive statistics of scores and change from baseline at 4, and 8 months will be presented 
for total symptom score, 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 TSS, will be 
repeated in an exploratory fashion for change from baseline in TSS at 4 months, and for the 
overall summary score and clinical summary scores at 4 and 8 months. 
To assess the impact on TSS change from baseline of a treatment effect on mortality, an 
alternative ranking will  be applied, where patients deceased prior to the 8-month assessment 
will be assigned the same worst rank regardless of their last value while alive . This is done to 
reduce the impact of treatment differences in time to CV death on the assessment of this 
KCCQ secondary endpoint. 
4.2.5 
Analysis of safety variables 
Analysis set 
For safety analyses, all summaries will be based on the safety analysis set (Section 2.1.2). 
Exposure 
The total exposure to study drug will be defined as the length of period on study drug, 
calculated for each patient as date of last dose – date of first dose +1. 
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 randomized study drug and on or before 30 days after last dose of study drug. 
Additional presentations will include all events with onset on or after first dose of study drug 
regardless of whether patients are on or off study treatment at the time of the event (the ‘on 
+off ‘ treatment period).  
All summaries of AEs and safety lab data described in Section 4.2.5.1 to 4.2.5.6 below will be 
presented for the on-treatment period. Additional summaries based on the on+off treatment 
period will be presented for SAEs and AEs of special interest. For fractures and amputations 
on+off treatment will be considered the primary analysis approach, while the on-treatment 
period will be the primary analysis approach for other AEs of special interest. 
4.2.5.1 
Adverse events  
Summaries of AEs will primarily be based on the on-treatment period, except for fractures and 
amputations as described in section 4.2.5   


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In addition to SAEs, the collection of AEs that are not serious is limited to DAEs, AEs leading 
to interruption of IP or dose reduction and AEs of interest. Thus, summaries of AEs will be 
limited to these categories and general summaries of all AEs are not planned. 
AEs will be classified according to MedDRA by the medical coding team at AstraZeneca data 
management centre, using the most current version of  MedDRA possible. 
Summaries by system organ class (SOC) and preferred term (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 will be 
performed. 
A summary table of the total number and percent of patients with SAE, DAE, AE leading to 
dose reduction and temporary interruption, and for each category of AE of interest per 
treatment group will be provided. 
4.2.5.2 
Serious adverse events 
SAEs will be presented as described below both on treatment and on+off treatment. 
The number and percent of patients with SAEs will be presented by SOC, PT and treatment 
group. The most common SAEs will also be presented by PT and treatment group only.  
AEs with outcome death will be presented separately by SOC and PT. 
4.2.5.3 
Adverse events leading to discontinuation, interruption or dose reduction  
The number and percent of patients will be presented by SOC and PT for AEs leading 
discontinuation, AEs leading to temporary interruption and dose reduction (separately for each 
of the three categories based action taken “Drug Permanently Discontinued”, “Drug 
Interrupted” and “Drug Reduced” respectively). 
4.2.5.4 
Adverse events of interest 
Each category of AEs of interest will be presented separately.   AEs of interest fall in the 
categories volume depletion, renal events, major hypoglycaemic events, fractures, diabetic 
ketoacidosis (DKA), AEs leading to amputation and AEs leading to a risk for lower limb 
amputations [“preceding events”].  
 
In addition to the pre-specified events of interest, analysis and presentation of potential events 
of Fournier’s gangrene will also be included. 
Potential DKA events will be adjudicated. The adjudicated outcome will be considered the 
main analysis for DKA. 


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For each AE of interest, a summary table including the number and percent of patients with 
any event in the AE category, SAE, DAE, AE leading to interruption and dose reduction. Each 
AE of interest category will also be 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 patient will be presented for AE of special interest, where 
relevant eg for major hypoglycaemic events and amputation. 
 
In addition to the presentation of on-treatment events, on+off presentations will be provided 
for all AEs of interest. 
 
 
4.2.5.5 
Laboratory Evaluation 
All summaries of clinical chemistry/haematology parameters will be based on samples 
analyzed at the central laboratory, and presented in SI units. 
 
The result and the change from baseline of each clinical chemistry/haematology tests, 
including estimated GFR , will be summarized by treatment group at each scheduled visit 
using descriptive statistics, including n, mean, SD, median and quartiles. 
 
 
4.2.5.6 
Marked laboratory abnormalities 
The number and percent of patients with a marked abnormality in clinical laboratory tests will 
be summarized over time by treatment group. 
 
Laboratory abnormalities will be evaluated based on marked abnormality (MA) criteria. The 
list of MAs is provided in Appendix A (Section 8.1 ) 
 
An on-treatment value will be considered an MA if either 
• the on-treatment value is beyond an MA limit AND the baseline value is not beyond 
the same limit, 
OR 
• both the baseline and on-treatment value are beyond the same MA limit AND the on-
treatment values is more extreme (farther from the limit) than was the baseline 
 
Laboratory MAs occurring during the on-treatment period will be summarized by treatment 
group. The directions of changes (high or low) in MAs will be indicated in the tables. 
Additionally, for each patient with a MA for a parameter, all the patient’s values of that 
parameter over the treatment period will be listed. 
 
4.2.6 
Analysis of exploratory objectives 
The analysis of the exploratory variables will in the same fashion as the primary and 
secondary efficacy variables be based on the ITT principle, including data irrespective of 
whether the patient has discontinued study drug. 


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The time to event endpoints including  
• MI 
• stroke 
• first occurrences of serum potassium falling above/below defined thresholds 
• the wider composite reflecting worsening HF (CV death, hospitalization for HF, urgent 
HF visit or worsening HF symptoms/signs leading to initiation of new treatment or 
augmentation of existing oral treatment) 
will be analysed with the same methods as the primary endpoint. 
Change from baseline to each visit for HbA1c, body weight, blood pressure and EQ-5D will 
be analysed with a repeated measures method. The analysis of HbA1c will be limited to 
patients with T2D at baseline as defined in Section 4.1. All non-missing visit data will be 
used, including measurements after discontinuation of study drug.  The model will include 
terms for treatment group, visit, visit*treatment group and baseline measurement as a 
covariate.  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.  The missing 
data will not be imputed. 
The proportion of patients with no worsening NYHA classification will be analyzed by a 
logistic regression by visit with treatment group, baseline NYHA and T2D at randomization.  
The odds ratio between treatment groups and its 95% confidence interval and corresponding 
two-sided p-value will be presented.   
The proportion of patients with new diagnosis of T2D in non-diabetic patients (as defined in 
Section 4.1) will be analyzed by a logistic regression with treatment group and baseline 
HbA1c.  The odds ratio between treatment groups and its 95% confidence interval and 
corresponding two-sided p-value will be presented.  In addition to analysing patients who are 
non-diabetic at baseline, the subgroup of pre-diabetic patients as defined in Section 4.1 will be 
analysed. 
The proportion of patients with new diagnosis of AF in patients without history of AF at 
baseline will be analysed with logistic regression with treatment group and T2D at 
randomization. 
5. 
INTERIM ANALYSES 
An interim analysis is planned to be performed when approximately 75% of the primary 
events have been  adjudicated, using a Haybittle-Peto rule.  There will in principle be one 
planned interim analysis, with the possibility for the DMC to do subsequent interim analysis if 


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they deem necessary. The significance level for the final analysis will be determined by the 
Haybittle-Peto function based on the actual number and timing of interim analyses. 
The interim analysis will assess superiority of dapagliflozin to placebo.  The interim analysis 
will use a one-sided alpha level of 0.001.  At the interim analysis, the primary composite 
endpoint will be first tested at the specified alpha level.  If superiority is achieved for the 
primary endpoint, then the superiority of dapagliflozin to placebo on CV death will be tested 
at a one-sided alpha level of 0.001. If CV death is significant, then an action is triggered 
whereby the DMC will evaluate the totality of the available efficacy data and safety data, to 
determine if benefit is unequivocal and overwhelming such that the DMC recommends ending 
the study. 
If the interim analysis leads to a decision to terminate the study early based on the pre-defined 
stopping guidelines for superiority, the executive committee will define a PACD, on or after 
which study closure visits will commence. The study report will be based on all events 
occurring on prior to the PACD. 
If the study is stopped for superiority at an interim analysis, then testing of secondary 
endpoints will continue down the hierarchy at a one-sided alpha  level 0.001. 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
The analysis of the KCCQ total symptom score was in the protocol (section 8.5.4) based on a 
repeated measures analysis. This endpoint will be analysed as a composite rank-based 
endpoint as described in section 3.2.3 and 4.2.4.2.  
7. 
REFERENCES 
Andersen et al 2019 
Andersen PK, Angst J, Ravn H. Modeling marginal features in studies of recurrent events in 
the presence of a terminal event. Lifetime data anal 2019 Jan: 1-15. 
Coon and Cook 2018 
Coon CD, Cook KF. Moving from significance to real-world meaning: methods for 
interpreting change in clinical outcome assessment scores. Qual Life Res 2018 Jan; 27(1):33-
40. 
De Vet et al 2010  
De Vet HC, Terluin B, Knol DL, Roorda LD, Mokkink LB, Ostelo RW, Hendriks EJ, Tertwee 
CB. Three ways to quantify uncertainty in individually applied "minimally important change" 
values. J Clin Epidemiol 2010 Jan; 63(1):37-45. 


Statistical Analysis Plan  
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Edition Number 3.0  
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39 
Fitchett et al 2016 
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S et al. Heart failure outcomes with 
empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the 
EMPA-REG OUTCOME® trial. Eur Heart J 2016; 37 (19): 1526-1534 
Froud and Abel 2014 
Froud R, Abel G. Using ROC curves to choose minimally important change thresholds when 
sensitivity and specificity are valued equally: the forgotten lesson of pythagoras. Theoretical 
considerations and an example application of change in health status. 2014 PloS ONE 9(12): 
e114468. 
Ghosh and Lin 2000 
Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics 2000; 
56:554–562. 
Green et al 2000 
C. Patrick Green, MD, Charles B. Porter, MD, FACC, Dennis R. Bresnahan, MD, FACC, 
John A.Spertus, MD, MPH, FACC Development and Evaluation of the Kansas City 
Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. JACC, 
Vol.35 No 5, April 2000:1245-55 
Kawaguchi  et al 2011 
Kawaguchi A, Koch G, Wang X. Stratified Multivariate Mann-Whitney Estimators for the 
Comparison of Two Treatments with Randomization Based Covariance Adjustment. Statistics 
in Biopharmaceutical Research, 2011;3(2), 217–231. 
 
Koch et al 1998 
Koch GG, Tangen CM, Jung JW, Amara  IA. Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non‐parametric strategies for 
addressing them. Statist. Med 1998; 17(15‐16), 1863-1892. 
Levey at al 2009 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, 
Eggers P, VanLente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 
May 5; 150(9):604-12 
Lin et al 2000 
Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate functions 
of recurrent events. Journal of the Royal Statistical Society: Series B (Statistical 
Methodology) 2000; 62(4):711–730. 
Liu et al 2004 
Liu L, Wolfe RA, Huang X. Shared Frailty Models for Recurrent Events and a Terminal 
Event. Biometrics, 2004;60(3);747-756  


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Liu and Huang 2008 
Liu L, Huang X. The use of Gaussian quadrature for estimation in frailty proportional hazards 
models. Statist. Med. 2008; 27(14):2665–2683 
Lu and Liu 2014 
Lu L, Liu C. Analysis of Correlated Recurrent and Terminal Events Data in SAS. Proceedings 
of the Northeast SAS Users Group Conference 2008 
McMurray et al 2014 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, 
Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. 
Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371 
(11):993-1004 
Nelson et al 2006 
Nelson KP, Lipsitz SR, Fitzmaurice GM, Ibrahim J, Parzen M, Strawderman R. Use of the 
probability integral transformation to fit nonlinear mixed-effects models with nonnormal 
random effects. J Comp Graph Stat 2006; 15 39-57 
Ratitch et al 2013 
Ratitch B,  Lipkovich I, O’Kelly M. Combining Analysis Results from Multiply Imputed 
Categorical Data.  PharmaSUG 2013 - Paper SP03 
Rogers et al 2016 
Jennifer K Rogers, Alex Yaroshinsky, Stuart J Pocock, David Stokar and Janice Pogoda. 
Analysis of recurrent events with an associated informative dropout time: Application of the 
joint frailty model. Statist. Med. 2016, 35 2195–2205 
SAS Institute Inc. 2018 
SAS/STAT® 15.1 User’s Guide. Cary, NC: SAS Institute Inc. 2018. Example 86.5: Failure 
Time and Frailty Model, page 7097 
Spertus et al 2005 
Spertus J Am Heart J 2005. Monitoring clinical changes in patients with heart failure: A 
comparison of methods. Multicenter Study 
Stokes et al 2012 
Stokes ME, Davis CS, Koch GG.Categorical Data Analysis Using the SAS System. Carry, 
NC: SAS Institute Inc. 
Wang and Pocock 2016 
Wang D, Pocock S. A win ratio approach to comparing continuous non-normal outcomes in 
clinical trials. Pharmaceut. Statist. 2016, 15 238–245 


Statistical Analysis Plan  
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8. 
APPENDIX 
8.1 
Appendix A Laboratory Abnormality Criteria 
Table 2 provides the criteria for assessing marked abnormalities in safety laboratory 
parameters.  When there is more than one limit for a variable, summaries will be provided for 
each limit. 
If both the baseline and on-treatment values of a parameter are beyond the same MA limit for 
that parameter, then the on-treatment value will be considered a MA only if it is more extreme 
(farther from the limit) than was the baseline value.  
The following three criteria will also be summarized by treatment group in examination of the 
elevated AT (ALT and/or AST) and total bilirubin: 
• 
(AST or ALT > 3XULN) and (Total Bilirubin > 1.5XULN within 14 days on or 
after AT elevation) 
• 
(AST or ALT > 3XULN) and (Total Bilirubin > 2XULN within 14 days on or after 
AT elevation) 
(AST or ALT > 3XULN) and {(Total Bilirubin > 2XULN and no ALP ≥ 2XULN) within 14 
days on or after AT elevation} 
Table 2 Marked abnormality criteria for safety laboratory variables and elevated AT (ALT and/or AST) 
and total bilirubin 
 
 
Marked Abnormality Criteria 
Clinical laboratory variables 
Units 
Low 
High 
Hematology 
HCT  
vol 
< 0.20 
> 0.55 
HCT  
vol 
 
> 0.60 
Hemoglobin  
g/L 
< 60 g/L 
> 180 g/L 
Hemoglobin  
g/L 
 
> 200 g/L 
Blood Chemistry 
ALP 
U/L 
 
> 1.5X ULN 
ALP 
U/L 
 
> 3X ULN 
ALT 
U/L 
 
> 3X ULN 
AST 
U/L 
 
> 3X ULN 


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Marked Abnormality Criteria 
Clinical laboratory variables 
Units 
Low 
High 
AST or ALT 
U/L 
 
> 3X ULN 
ALT 
U/L 
 
> 5X ULN 
AST 
U/L 
 
> 5X ULN 
AST or ALT 
U/L 
 
> 5X ULN 
ALT 
U/L 
 
> 10X ULN 
AST 
U/L 
 
> 10X ULN 
AST or ALT 
U/L 
 
> 10X ULN 
ALT 
U/L 
 
> 20X ULN 
AST 
U/L 
 
> 20X ULN 
AST or ALT 
U/L 
 
> 20X ULN 
Total Bilirubin 
µmol/L 
 
> 1.5X ULN  
> 2X ULN 
Na (Sodium) 
mmol/L 
< 130 mmol/L 
> 150 mmol/L 
Na (Sodium) 
mmol/L 
< 120 mmol/L 
 
K (Potassium) 
mmol/L 
 2.5 mmol/L 
 6.0 mmol/L 
Creatinine 
µmol/L 
 
1.5X BL CREAT 
Creatinine 
µmol/L 
 
2X BL CREAT 
BL is the baseline measurement 
 
 
 
 


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8.2 
Appendix B Estimation of clinically meaningful thresholds for 
KCCQ total symptom score 
B1 Methods 
Thresholds for clinically meaningful within-patient change (CMWPC) will be estimated 
according to predefined algorithms using an anchor-based approach, supplemented with 
graphical visualizations of the distribution across anchor categories. Clinically meaningful 
thresholds will be estimated for change from baseline TSS at 8 months. 
Section B1 describes the methods which were applied to blinded study data, with results and 
derived thresholds described in section  B2 below. The analysis was performed on the FAS 
population, 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 patient 
global impression of severity (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. 
 
Categorization 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 3. 


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Table 3 Categories of change from baseline PGIS at 8 months 
 
PGIS at baseline 
PGIS at 8 months 
No 
symp-
toms 
Very 
mild 
Mild 
Mode-
rate 
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. MD Moderate deterioration.  SD Small deterioration.  SI Small improvement. Moderate 
improvement. LI Large improvement. 
 
The categories in Table 3 will be further collapsed as  
• ‘moderate or large deterioration’ in the categorization with 5 categories (version A) 
• ‘small or moderate deterioration’ in the categorization with 5 categories (version B) 
• ‘small or moderate improvement’ in the categorization with 5 categories (version B) 
• ‘moderate or large improvement’ in the categorization with 5 categories (version A) 
The change from baseline TSS at 8 months, will be used repeatedly in the anchor-based 
analyses. To explore the adequateness of each anchor categorization, the Spearman correlation 
coefficient between change from baseline 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). 


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Descriptive statistics (mean, SD, median, quartiles, minimum and maximum), empirical 
cumulative distribution function (eCDF) will be presented for each categorization. The eCDF 
curves display a continuous plot 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 categorization. 
Additionally, to better characterize the association between change from baseline in each 
endpoint, and CMWPC according to the anchors, the sensitivity and specificity will be 
calculated based on receiver operating characteristic (ROC) curve analysis using logistic 
regression analyses for each cut-off in change from baseline TSS. The following categories 
will be examined: 
• Large improvement 
• Moderate or large improvement 
• Moderate or large deterioration 
• Large deterioration 
 
The CMWPC thresholds derived from analysis of ROC curves, for each anchor category, will 
be defined by the change value corresponding to the cut-point in the ROC space which 
minimizes the sum of squares of 1-sensitivity and 1-specificity, ie, which is closest to the top-
left corner in the ROC space (Froud and Abel 2014). The certainty with which an estimated 
threshold can be used will depend on its corresponding sensitivity and specificity values. It is 
commonly not recommended to apply thresholds to individual patients when sensitivity and 1-
specificity are lower than 75% (De Vet et al 2010). 
Establishing the clinically meaningful threshold 
The various estimates from the different streams of evidence (tables and plots of the 
distribution, ROC curve analyses) 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 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 TSS by 
treatment, in the unblinded results, and responder analysis will be performed for the 
thresholds. 


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B2 Summary of results of anchor-based analysis on blinded study data 
The descriptive statistics for change from baseline KCCQ-TSS at 8 months in different 
categories of change from baseline PGIS at 8 months in Table 4 suggest that a large 
improvement in PGIS corresponds to a median increase in TSS of 15 points. A moderate or 
large improvement in PGIS (5 categories, version A) corresponds to a median increase in 
KCCQ-TSS of about 10 points, whereas a small or moderate improvement (5 categories, 
version B) corresponds to a median increase in KCCQ-TSS of about 8 points. Similarly, a 
moderate or large deterioration in PGIS corresponds to a median decrease in KCCQ-TSS of 
about 6 points, whereas a small or moderate deterioration corresponds to a median decrease in 
KCCQ-TSS of about 2 points. The mean values are generally more extreme, as would be 
expected, but as this is a complete-case analysis (excluding deaths and not accounting for 
baseline values which are near the “ceiling” and “floor” of the KCCQ-TSS scale) the median 
values represent more reliable estimates of average change. 
Table 4 Distribution of change from baseline KCCQ-TSS at 8 months by change from baseline PGIS at 8 
months 
 
N 
(%) 
Mean 
SD 
Min 
Q1 
Median 
Q3 
Max 
Correlation* 
PGIS at 8 Months: 7 Categories 
 
 
 
 
 
 
 
 
 
0.35 
Large Improvement 
255 
(7) 
20.0 
22.7 
-22.9 
2.1 
15.6 
34.4 
90.6 
 
Moderate Improvement 
402 
(10) 
11.9 
18.7 
-35.4 
0.0 
9.4 
20.8 
72.9 
 
Small Improvement 
831 
(21) 
9.6 
17.4 
-49.0 
0.0 
8.3 
17.7 
80.2 
 
Stable 
1522 
(39) 
3.2 
15.5 
-63.5 
-4.2 
1.0 
10.4 
82.3 
 
Small Deterioration 
561 
(14) 
-3.0 
18.2 
-71.9 
-11.5 
-2.1 
7.3 
50.0 
 
Moderate Deterioration 
223 
(6) 
-6.9 
20.8 
-100.0 
-17.7 
-4.2 
6.3 
43.7 
 
Large Deterioration 
89 
(2) 
-11.9 
21.6 
-65.6 
-25.0 
-8.3 
0.0 
54.2 
 
PGIS at 8 Months: 5 Categories 
(Version A) 
 
 
 
 
 
 
 
 
 
0.34 
Moderate or Large Improvement 
657 
(17) 
15.0 
20.7 
-35.4 
0.0 
10.4 
26.0 
90.6 
 
Small Improvement 
831 
(21) 
9.6 
17.4 
-49.0 
0.0 
8.3 
17.7 
80.2 
 
Stable 
1522 
(39) 
3.2 
15.5 
-63.5 
-4.2 
1.0 
10.4 
82.3 
 
Small Deterioration 
561 
(14) 
-3.0 
18.2 
-71.9 
-11.5 
-2.1 
7.3 
50.0 
 
Moderate or Large Deterioration 
312 
(8) 
-8.4 
21.1 
-100.0 
-19.3 
-6.3 
4.2 
54.2 
 
PGIS at 8 Months: 5 Categories 
(Version B) 
 
 
 
 
 
 
 
 
 
0.34 
Large Improvement 
255 
(7) 
20.0 
22.7 
-22.9 
2.1 
15.6 
34.4 
90.6 
 
Small or Moderate Improvement 
1233 
(32) 
10.3 
17.9 
-49.0 
0.0 
8.3 
19.8 
80.2 
 
Stable 
1522 
(39) 
3.2 
15.5 
-63.5 
-4.2 
1.0 
10.4 
82.3 
 
Small or Moderate Deterioration 
784 
(20) 
-4.1 
19.0 
-100.0 
-12.5 
-2.1 
6.8 
50.0 
 


Statistical Analysis Plan  
Study Code D1699C00001 
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Large Deterioration 
89 
(2) 
-11.9 
21.6 
-65.6 
-25.0 
-8.3 
0.0 
54.2 
 
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 categorization 
Categories of change from baseline PGIS at 8 months as defined in Table 3 
The eCDF curves in Figure 2 demonstrate a clear separation between all categories of deterioration and 
the no change category, in the interval between 5 and 20 points decrease in KCCQ-TSS at 8 months. 
For improvement, the separation is clear between improvement and no change in the interval between 
5 and 20 points increase in KCCQ-TSS at 8 months, but the distinction is not as clear between small 
and moderate improvement. From  


Statistical Analysis Plan  
Study Code D1699C00001 
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48 
 
Figure 3 it’s evident that the combined moderate or large categories of deterioration and improvement 
are clearly separated from the no change category. This is also observed for combined small or 
moderate categories of deterioration and improvement in Figure 4. 
Figure 2 Empirical cumulative distribution function for change from baseline KCCQ-TSS at 8 months 
versus change from baseline PGIS at 8 months with 7 categories 
 
 


Statistical Analysis Plan  
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Figure 3 Empirical cumulative distribution function for change from baseline KCCQ-TSS at 8 months 
versus change from baseline PGIS at 8 months with 5 categories (version A) 
 
 


Statistical Analysis Plan  
Study Code D1699C00001 
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Figure 4 Empirical cumulative distribution function for change from baseline KCCQ-TSS at 8 months 
versus change from baseline PGIS at 8 months with 5 categories (version B) 
 


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The thresholds from analysis of ROC curves, in   
Table 5 suggest that an increase in KCCQ-TSS at 8 months of 9 points may be a sufficient 
cut-off to identify a moderate or large improvement, or even a large improvement, based on 
ROC curve analysis. For deterioration, the suggested cut-off for a large deterioration is a 
decrease in KCCQ-TSS at 8 months of 2 points. The sensitivity and specificity of these cut-
offs are not very high. 
Table 5 Characteristics of thresholds for change from baseline in KCCQ-TSS at 8 months as assessed by 
PGIS at 8 months based on ROC analysis 
 
Estimated 
thresholda 
Sensitivityb 
Specificityc 
Change from baseline PGIS at 8 months 
         
         
         
  Large improvement 
     9.4 
    0.62 
    0.68 
  Moderate or large improvement 
     7.3 
    0.60 
    0.65 
  Moderate or large deterioration 
    -1.0 
    0.62 
    0.69 
  Large deterioration 
    -2.1 
    0.72 
    0.69 
a Anchor-based threshold for clinically meaningful within-patient change is defined as the point on the ROC curve which 
minimizes the sum of squares of (1-sensitivity) and (1-specificity). 
b Sensitivity is defined as the true positive rate for each response threshold, i.e. the number identified as responders by both 
KCCQ-TSS and change from baseline PGIS at 8 months divided by the total number identified as responders by change from 
baseline PGIS at 8 months. 
c Specificity is defined as the true negative rate for each response threshold, i.e. the number identified as non-responders by 
both KCCQ-TSS and change from baseline PGIS at 8 months divided by the total number identified as non-responders by 
change from baseline PGIS at 8 months. 
Selection of thresholds for supportive responder analysis 
Based on the results of the threshold analysis summarized in this appendix and clinical 
discussions regarding CMWPC it was decided that a clinically relevant and achievable 
threshold for improvement, in the study population, is estimated to correspond to an increase 
in KCCQ-TSS at 8 months of between 5 and 10 points, with a large improvement possibly 
corresponding to an increase of 15 points. A clinically relevant deterioration is estimated to 
correspond to a decrease in KCCQ-TSS at 8 months of between 5 and 10 points. 
In the analyses (see section 4.2.4.2) of the third secondary efficacy endpoint, change from 
baseline measured at 8 months in the total symptom score of the KCCQ, decreases in KCCQ-
TSS at 8 months of 5 and 10 points and increases of 5, 10 and 15 points will be indicated in 
the eCDF for change from baseline TSS by treatment. In addition to the responder analyses of 


Statistical Analysis Plan  
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5 points improvement and deterioration, further supportive analyses will be performed for the 
10 point deterioration, 10 point improvement and 15 point improvement CMWPC thresholds.