International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, Phase III Study Evaluating the Effect of Dapagliflozin on Exercise Capacity in Heart Failure Patients With Preserved Ejection Fraction
Phase: PHASE3
Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Dapagliflozin
Study Code
D169EC00001
Version
3.0
Date
4 March 2020
An International, Multicentre, Parallel-group, Randomised, Double-blind, 
Placebo-controlled, Phase III Study Evaluating the effect of Dapagliflozin on 
Exercise Capacity in Heart Failure Patients with Preserved Ejection 
Fraction (HFpEF)
Short Title: DETERMINE-preserved – Dapagliflozin EffecT on ExeRcise 
capacity using a 6-MINutE walk test in patients with heart failure with 
preserved ejection fraction
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): EudraCT 2018-003441-42

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VERSION HISTORY
Version 1.0
15 January 2019
Initial creation
Version 2.0
7 November 2019
Section 1.1 (Schedule of activities): Table 1 was changed to reflect 
changes in the CSP text. 
Section 1.2 (Synopsis): Updated to reflect changes in the CSP text, 
including the study period changed due to prolonged recruitment, and 
the exact aligning of the endpoint wording with the one in Section 3. 
Section 3 (OBJECTIVES AND ENDPOINTS): Primary and key 
secondary objectives were combined into dual primary objectives and 
sample size was increased to 500, to increase the power in evaluating 
the effect of dapagliflozin on KCCQ in HFpEF subjects. Exploratory 
objectives were reordered and rephrased. 
Section 4.1 (Overall design): The target of having approximately 400 
patients randomized was changed to 500. 
Section 4.2 (Scientific rationale for the study): Explanation of using 
pre-specified 5-point threshold in KCCQ was added. 
Section 5.1 and 5.2 (Inclusion criteria and Exclusion criteria) were 
clarified. 
Section 6.3.1.2 (Capping) was updated to allow it on a level lower 
than the whole study.
Section 7.1.1.1 (Unexpected acute declines in eGFR): a clarification 
note added.
Section 7.4 (Discontinuation of the study): Reasons for the early 
closure of the study site were added as per more recent protocol 
template. 
Section 8 (STUDY ASSESSMENT AND PROCEDURES): 
Additional information was added to Visit 4 description. This visit is 
now allowed to be performed in-clinic. 

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Also, subsections revised for consistency with the changes introduced 
in the objectives and sample size.
Section 9 (STATISTICAL CONSIDERATIONS) revised for 
consistency with the changes introduced in the objectives and sample 
size. 
General: minor editing corrections for consistency in minor sections.
Version 3.0
4 March 2020
The main purpose of this amendment was to add a primary objective 
to the study (ie, effect on physical limitation). The primary objectives 
are now to determine whether dapagliflozin is superior to placebo in 
reducing heart failure symptoms, reducing physical limitation, or 
improving exercise capacity in patients with chronic heart failure. The 
family of primary endpoints are KCCQ-TSS, KCCQ-PLS, and 
6MWD. Most amendments were consequential to the change in 
primary objectives/endpoints.
The secondary objective/endpoint was switched with one of the 
exploratory objectives/endpoints and exploratory endpoints were 
revised. The remaining amendments were intended to add clarity and 
correct minor errors. The following details the key changes:
Section 1.2 (Synopsis): Updated to reflect changes in the CSP text, 
including the changes to the objectives/endpoints as detailed in 
Section 3. 
Section 2: (INTRODUCTION) Updated to reflect changes in the 
objectives/endpoints as detailed in Section 3.
Section 3 (OBJECTIVES AND ENDPOINTS): A third primary 
efficacy objective/endpoint was added (ie, KCCQ-PLS). The 
secondary objective/endpoint (now ‘total time spent in light to 
vigorous physical activity’) was switched with an exploratory 
objective/endpoint (now ‘movement intensity during walking’). 
The exploratory KCCQ endpoints and the description of the subset 
of patients to be assessed for certain exploratory measures were 
revised.
Section 4 (STUDY DESIGN): Updated to reflect changes in the 
objectives/endpoints as detailed in Section 3. Further 

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explanation/clarification was added for the choice of primary 
endpoints.
Section 8.1 (Efficacy assessments): Updated to reflect changes in 
the objectives/endpoints as detailed in Section 3. 
Section 9 (STATISTICAL CONSIDERATIONS): Updated to 
reflect changes in the objectives/endpoints as detailed in Section 3, 
including updated power calculations and methodology for type I 
error control.
General: Minor editing corrections to improve clarity and 
consistency.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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TABLE OF CONTENTS
1
PROTOCOL SUMMARY.................................................................................. 9
1.1
Schedule of Activities......................................................................................... 9
1.2
Synopsis ........................................................................................................... 16
1.3
Schema............................................................................................................. 22
2
INTRODUCTION............................................................................................ 23
2.1
Study rationale.................................................................................................. 23
2.2
Background ...................................................................................................... 24
2.3
Benefit/risk assessment..................................................................................... 25
2.3.1
Potential risks to patients .................................................................................. 25
2.3.1.1
Protection against risks ..................................................................................... 26
2.3.2
Potential benefits to patients ............................................................................. 27
2.3.3
Conclusion........................................................................................................ 27
3
OBJECTIVES AND ENDPOINTS................................................................... 27
4
STUDY DESIGN ............................................................................................. 29
4.1
Overall design................................................................................................... 29
4.2
Scientific rationale for study design .................................................................. 30
4.3
Justification for dose......................................................................................... 31
4.4
End of study definition...................................................................................... 32
5
STUDY POPULATION ................................................................................... 33
5.1
Inclusion criteria............................................................................................... 33
5.2
Exclusion criteria.............................................................................................. 36
5.3
Lifestyle restrictions (not applicable) ................................................................ 38
5.4
Screen failures .................................................................................................. 38
6
STUDY TREATMENTS.................................................................................. 38
6.1
Treatments administered................................................................................... 39
6.1.1
Investigational products.................................................................................... 39
6.2
Preparation/handling/storage/accountability...................................................... 39
6.3
Measures to minimise bias: randomisation and blinding.................................... 40
6.3.1
Stratification and capping ................................................................................. 41
6.3.1.1
Stratification..................................................................................................... 41
6.3.1.2
Capping ............................................................................................................ 41
6.4
Treatment compliance....................................................................................... 41
6.5
Concomitant therapy......................................................................................... 42
6.5.1
Prohibited medications...................................................................................... 42
6.5.2
Background medication .................................................................................... 43
6.5.2.1
Heart failure background standard of care......................................................... 43
6.5.2.2
Anti-diabetes background treatment for patients with T2DM ............................ 43
6.5.3
Other concomitant treatment............................................................................. 43

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6.6
Dose modification (not applicable) ................................................................... 43
6.7
Treatment after the end of the study.................................................................. 43
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 44
7.1
Discontinuation of investigational product........................................................ 44
7.1.1
Temporary discontinuation ............................................................................... 44
7.1.1.1
Unexpected acute declines in eGFR.................................................................. 44
7.1.1.2
Volume depletion/hypotension.......................................................................... 45
7.1.1.3
Patients at risk of volume depletion................................................................... 45
7.1.2
Rechallenge ...................................................................................................... 45
7.1.3
Procedures for discontinuation of investigational product ................................. 45
7.2
Lost to follow-up .............................................................................................. 46
7.3
Withdrawal from the study................................................................................ 46
7.4
Discontinuation of the study ............................................................................. 47
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 48
8.1
Efficacy assessments......................................................................................... 56
8.1.1
Clinical outcome assessment............................................................................. 56
8.1.1.1
6MWD ............................................................................................................. 57
8.1.1.2
Patient-reported outcomes................................................................................. 58
8.1.2
Oxygen saturation............................................................................................. 60
8.1.3
Physical activity measured at home (accelerometer, Monitor B)........................ 61
8.1.4
Serum NT-proBNP........................................................................................... 61
8.1.5
New York Heart Association Functional Classification..................................... 61
8.2
Safety assessments............................................................................................ 62
8.2.1
Physical examination ........................................................................................ 62
8.2.2
Electrocardiograms........................................................................................... 62
8.2.3
Vital signs......................................................................................................... 62
8.2.4
Body weight, height and waist circumference ................................................... 63
8.2.5
Clinical safety laboratory assessments............................................................... 63
8.2.6
Other safety assessments................................................................................... 64
8.3
Collection of adverse events ............................................................................. 64
8.3.1
Method of detecting AEs and SAEs .................................................................. 64
8.3.1.1
AEs leading to amputation, and potential risk-factor AEs for amputations 
affecting lower limbs (‘preceding events’) ........................................................ 65
8.3.1.2
DKA events...................................................................................................... 65
8.3.1.3
Capture of additional laboratory values............................................................. 65
8.3.2
Time period and frequency for collecting AE and SAE information.................. 66
8.3.3
Follow-up of AEs and SAEs ............................................................................. 66
8.3.4
AE data collection............................................................................................. 66
8.3.5
Causality collection........................................................................................... 67
8.3.6
AEs based on signs and symptoms.................................................................... 67
8.3.7
AEs based on examinations and tests ................................................................ 67
8.3.8
Hy’s Law.......................................................................................................... 68
8.3.9
Disease-under study (not applicable)................................................................. 68
8.3.10
Disease progression (not applicable) ................................................................. 68

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8.4
Safety reporting and medical management........................................................ 68
8.4.1
Reporting of SAEs............................................................................................ 68
8.4.2
Pregnancy and maternal exposure ..................................................................... 69
8.4.3
Overdose .......................................................................................................... 69
8.4.4
Medication error ............................................................................................... 70
8.5
Pharmacokinetics.............................................................................................. 70
8.5.1
Determination of drug concentration................................................................. 71
8.5.2
Storage and destruction of pharmacokinetic samples......................................... 71
8.6
Pharmacodynamics (not applicable).................................................................. 71
8.7
Genetics............................................................................................................ 71
8.7.1
Collection of mandatory genetic samples (not applicable)................................. 71
8.7.2
Optional exploratory genetic sample ................................................................. 71
8.7.3
Storage and destruction of genetic samples ....................................................... 72
8.8
Biomarkers (not applicable).............................................................................. 72
8.9
Health economics (not applicable) .................................................................... 72
9
STATISTICAL CONSIDERATIONS............................................................... 72
9.1
Statistical hypotheses........................................................................................ 72
9.2
Sample size determination ................................................................................ 73
9.3
Populations for analyses.................................................................................... 73
9.3.1
Enrolled............................................................................................................ 73
9.3.2
Full analysis set ................................................................................................ 73
9.3.3
Safety analysis set............................................................................................. 73
9.4
Statistical analyses............................................................................................ 74
9.4.1
Efficacy analyses .............................................................................................. 74
9.4.1.1
Analysis of the primary efficacy variables......................................................... 74
9.4.1.2
Analysis of the secondary efficacy variable....................................................... 75
9.4.2
Safety analyses ................................................................................................. 76
9.4.3
Other analyses .................................................................................................. 76
9.4.4
Methods for multiplicity control ....................................................................... 76
9.5
Interim analyses................................................................................................ 76
9.5.1
Data monitoring committee............................................................................... 76
10
REFERENCES................................................................................................. 77
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 81
LIST OF TABLES
Table 1
Schedule of activities............................................................................... 10
Table 2
Study objectives....................................................................................... 27
Table 3
Study treatments ...................................................................................... 39

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LIST OF FIGURES
Figure 1
Study design............................................................................................ 22
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................. 82
Appendix B
Adverse event definitions and additional safety information .................... 86
Appendix C
Handling of human biological samples .................................................... 90
Appendix D
Genetics................................................................................................... 92
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 96
Appendix F
Medical device incidents: definition and procedures for recording, 
evaluating, follow-up, and reporting (not applicable) ............................... 99
Appendix G
Abbreviations ........................................................................................ 100
Appendix H
The Kansas City Cardiomyopathy Questionnaire ................................... 102
Appendix I
Patient Global Impression of Severity in Heart Failure Symptoms ......... 107
Appendix J
Patient Global Impression of Change in Heart Failure Symptoms .......... 108
Appendix K
Patient Global Impression of Change in Walking Ability....................... 109
Appendix L
Patient Rating of Dyspnoea.................................................................... 110
Appendix M
Patient Rating of Fatigue........................................................................ 111
Appendix N
European Quality of Life EQ-5D-5L Questionnaire ............................... 112
Appendix O
Patient Overall Treatment Benefit.......................................................... 115
Appendix P
The Borg CR10 Scale® ......................................................................... 116
Appendix Q
New York Heart Association Functional Classification.......................... 119

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1
PROTOCOL SUMMARY
1.1
Schedule of Activities

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Table 1
Schedule of activities
Visit
1
Enrolment
2
Randomisation
3
4 b
Telephone 
call
5
Final visit
Early 
Withdrawal 
Visit OR Early 
Treatment 
Discontinuation 
Visit c
Details in CSP 
section or 
Appendix
2a
Randomisation 
A
2b a
Randomisation 
B
Week
-2 (±1)
0
0
8 (±1)
14 (±1)
16 (±1)
Day (visit window [±days])
-14 (±7)
1
1
56 (±7)
98 (±7)
112 (±7)
Informed consent 
X
Section 5.1
Inclusion/exclusion criteria
X
X
X
Sections 5.1 and 
5.2
Demography
X
Section 5.1
Medical and surgical history
X
X
X
Section 5.1
Concomitant medications
X
X
X
X
X
X
X
Section 6.5
Kansas City Cardiomyopathy 
Questionnaire d
X
X
X
X
X
X
Section 8.1.1.2
Patient global impression of 
severity in HF symptoms d
X
X
X
X
X
X
Section 8.1.1.2
Patient global impression of 
change in HF symptoms d
X
X
X
Section 8.1.1.2
Patient global impression of 
change in walking ability d
X
X
X
Section 8.1.1.2
Dyspnoea, fatigue d
X
X
X
X
X
X
Section 8.1.1.2
EQ-5D-5L d
X
X
X
X
X
Section 8.1.1.2
Overall treatment benefit d
X
X
X
Section 8.1.1.2
Physical examination
X
X
X
X
X
X
Section 8.2.1
NYHA functional classification
X
X
X
X
X
X
Section 8.1.5
12-lead ECG 
X
Section 8.2.2

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Table 1
Schedule of activities
Visit
1
Enrolment
2
Randomisation
3
4 b
Telephone 
call
5
Final visit
Early 
Withdrawal 
Visit OR Early 
Treatment 
Discontinuation 
Visit c
Details in CSP 
section or 
Appendix
2a
Randomisation 
A
2b a
Randomisation 
B
Week
-2 (±1)
0
0
8 (±1)
14 (±1)
16 (±1)
Day (visit window [±days])
-14 (±7)
1
1
56 (±7)
98 (±7)
112 (±7)
Vital signs: Systolic and 
diastolic blood pressure
X
X
X
X
X
X
Section 8.2.3
Vital signs: Pulse rate
X
X
X
X
X
X
Section 8.2.3
Body weight
X
X
X
X
X
X
Section 8.2.4
Height
X
Section 8.2.4
Waist circumference
X
X
X
X
X
X
Section 8.2.4
6-minute walking test e, f, g
X h
X i
X j
X
X
X
Section 8.1.1.1
Central laboratory NT-proBNP, 
sodium, potassium, 
creatinine/eGFR, haematocrit, 
HbA1c
X
X
X
X
X
X
Sections 8.1.2 & 
8.2.5
Sample for genetic research (if 
consented)
X
X
Section 8.7; 
Appendix D
Local pregnancy test using 
urine β-hCG (female patients of 
child-bearing potential only)
X
X
X
Section 8.2.5
Randomisation
X
X
Dispense IP
X
X
Administer IP dose in clinic for 
PK assessment
X
X
X
X k

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Table 1
Schedule of activities
Visit
1
Enrolment
2
Randomisation
3
4 b
Telephone 
call
5
Final visit
Early 
Withdrawal 
Visit OR Early 
Treatment 
Discontinuation 
Visit c
Details in CSP 
section or 
Appendix
2a
Randomisation 
A
2b a
Randomisation 
B
Week
-2 (±1)
0
0
8 (±1)
14 (±1)
16 (±1)
Day (visit window [±days])
-14 (±7)
1
1
56 (±7)
98 (±7)
112 (±7)
PK blood sampling l
X
X
X
X k
Section 8.5
Wearable activity monitor 
dispensed, if applicable m
X (Monitor 
B #1 
dispensed for 
immediate 
use)
X (Monitor 
B #2 
dispensed 
for 
immediate 
use; Monitor 
B #3 
dispensed 
for delayed 
use at Week 
14)
Section 8.1.3
Collect wearable activity 
monitor, if applicable m
X
(Monitor B #1)
X
(Monitors 
B #2 & 
#3)
X
(any monitors)
Section 8.1.3
Telephone callb reminding 
patient to wear activity monitor 
B #3 and return it at Visit 5 
(Final Visit); and to hold IP in 
the morning of visit 5 (Final 
visit). IP at visit 5 (Final visit) 
will be taken at clinic.
X

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Table 1
Schedule of activities
Visit
1
Enrolment
2
Randomisation
3
4 b
Telephone 
call
5
Final visit
Early 
Withdrawal 
Visit OR Early 
Treatment 
Discontinuation 
Visit c
Details in CSP 
section or 
Appendix
2a
Randomisation 
A
2b a
Randomisation 
B
Week
-2 (±1)
0
0
8 (±1)
14 (±1)
16 (±1)
Day (visit window [±days])
-14 (±7)
1
1
56 (±7)
98 (±7)
112 (±7)
Check IP compliance
X
X
X
Collect unused IP
X
X
AEs n
X
X
X
X
X
X
X
Sections 8.3 & 
8.4
a
Only patients with a difference in 6MWD not within ±15% between Visit 1(Enrolment) and Visit 2a (Randomisation A) need to repeat the assessments at 
Visit 2b (Randomisation B). The result from the final randomisation visit will be used as the baseline value. See footnote i for calculation example.
b
Visits 1, 2, 3 and 5 are all clinical visits that are conducted at the study site, while Visit 4 is conducted by telephone with the patient not at the study site. In 
exceptional cases, for the patient’s convenience, it is allowed to conduct this visit on-site.
c
Patients may withdraw from participating in the study, or they may discontinue taking study medication early but remain in the study (ie, continue attending 
study visits and completing study assessments). As far as possible, all assessments planned for Visit 5 (Final visit) should be also performed at an Early 
Withdrawal Visit and at an Early Treatment Discontinuation Visit. At a minimum, safety assessments, PROs, and the 6MWT (if the patient is able) should 
be performed. Patients who discontinue treatment early but remain in the study may resume taking study medication again as soon as they are able to and 
wish to. An Unscheduled Visit may be performed at any time after randomisation, if required in the opinion of the Investigator, with the assessments 
required given in Section 8.
d
All PROs will be administered using a site-based electronic tablet, except for the patient global impression of change in walking ability and the Borg CR10 
Scale® score, which will both be administered on paper. To avoid bias in patient responses, all PRO questionnaires must be completed prior to any other 
study procedures, following informed consent, except for the Borg CR10 Scale® score, which forms part of the 6MWT. Patients will first complete the 
patient global impression of change in walking ability followed by the PROs on the site-based electronic tablet, which should all be completed before the 
6MWT.
e
The 6MWT consists of a suite of assessments that are carried out before and after the 6MWT itself: seated pulse rate, blood pressure, oxygen saturation and 
the Borg CR10 Scale® score for dyspnoea and fatigue.
f
The 6MWD for each patient, determined from the 6MWT, will first be recorded on paper before being transferred to the eCRF by the Investigator or site 
staff later.

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g
A number of measures have been introduced to minimise variability in patient performance of the 6MWT. Prior to initiating testing, every effort should be 
made by the Investigator to establish that the patient is in their “usual” state of health: meaning that the patient has no concurrent medical issues (eg, upper 
respiratory tract infection, COPD/chronic heart failure exacerbation, exacerbation of musculoskeletal difficulties, etc) that might adversely affect his or her 
performance of the 6MWT. In the event that such conditions are present, the test should be aborted and rescheduled within a 14 day window, to allow time 
for the resolution of the acute medical issue and the patient to return to his or her “usual” state of health.
h
At Visit 1 (Enrolment), if the 6MWD is outside the range of ≥100 metres and ≤425 metres the patient is NOT eligible for inclusion OR rescreening in the 
study, and will, thus, be considered a screen failure.
i
At Visit 2a (Randomisation A), if the 6MWD is outside the range of ≥100 metres and ≤425 metres the patient is NOT eligible for inclusion OR rescreening 
in the study, and will, thus, be considered a screen failure. If the 6MWD at Visit 2a (Randomisation A) is within the range of ≥100 metres and ≤425 metres, 
but the 6MWD recorded at Visit 1 (Enrolment) is not within ±15% of the 6MWD recorded at Visit 2a (Randomisation A), the patient must stop Visit 2a 
(Randomisation A) immediately; if the difference is within ±15%, the patient can be randomised into the study, with remaining assessments at Visit 2a 
being completed and does not need to perform Visit 2b (Randomisation B). (Inclusion criterion #7).
Calculation: 
Let E be the 6MWD at Visit 1 (Enrolment), let Ra be the 6MWD at Visit 2a (Randomisation A) and let Rb be the 6MWD at Visit 2b (Randomisation B).
The 15% variability criterion at Visit 2a (Randomisation A) is fulfilled if E ≥ Ra*0.85 and E ≤ Ra*1.15.
The 15% variability criterion at Visit 2b (Randomisation B) is fulfilled if Ra ≥ Rb*0.85 and Ra ≤ Rb*1.15.
Example 1: 
If a subject has 6MWD at Visit 1 (Enrolment) equal to 170 metres and 6MWD at Visit 2a (Randomisation A) equal to 200 metres, then the variability is 
(170-200)/200 which is within ±15% and the subject fulfils the variability requirement in inclusion criterion #7.
Example 2: 
If a subject has 6MWD at Visit 1 (Enrolment) equal to 200 metres and 6MWD at Visit 2a (Randomisation A) equal to 170 metres, then the variability is 
(200-170)/170 which is not within ±15% and the subject does not fulfil the variability requirement in inclusion criterion #7.
Example 3:
If a subject has 6MWD at Visit 2a (Randomisation A) equal to 340 metres and 6MWD at Visit 2b (Randomisation B) equal to 400 metres, then the 
variability is (340-400)/400 which is within ±15% and the subject fulfils the variability requirement in inclusion criterion #7.
j
If a patient fails the 6MWD variability, described in inclusion criterion #7, at Visit 2a (Randomisation A) he/she can repeat the 6MWT within 1 week at 
Visit 2b (Randomisation B). At Visit 2b (Randomisation B), if the 6MWD is outside the range of ≥100 metres and ≤425 metres the patient is NOT eligible
for inclusion OR rescreening in the study, and will, thus, be considered a screen failure. If the 6MWD at Visit 2b (Randomisation B) is within the range 
≥100 metres and ≤425 metres, but the 6MWD recorded at Visit 2a (Randomisation A) is not within ±15% of the 6MWD recorded at Visit 2b 
(Randomisation B) the patient is excluded from the study and considered a screening failure; if the difference is within ±15% the patient can be randomised 
into the study with the remaining assessments at Visit 2b (Randomisation B) being completed. The result from the final randomisation visit will be used as 
the baseline value. See the above footnote i for the calculation example.
k
Applicable only for the early withdrawal visit.
l
Patients will be reminded not to take IP at home on the days they attend the clinic for Visit 5 (Final visit).
m
Two distinct types of wearable activity monitor will be used in this study. At a subset of study sites, patients will wear an activity monitor during the 
6MWT; this one is for use in the clinic only (wearable activity monitor A), and it is different to the activity monitor that will be dispensed for use at home 
(wearable activity monitor B). At a subset of study sites, some patients will be dispensed an activity monitor to wear at home.
n
SAEs will be collected from the time of providing informed consent, and non-serious AEs will be collected from the time of randomisation.

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6MWD  6-minute walk distance; 6MWT  6-minute walk test; AEs  adverse events; β-hCG  beta human chorionic gonadotropin; COPD  chronic obstructive 
pulmonary disease; CSP  Clinical Study Protocol; ECG  electrocardiogram; eCRF  electronic case report form; eGFR  estimated glomerular filtration rate; 
EQ-5D-5L  European Quality of Life 5-dimension 5-level questionnaire; HbA1c  glycated haemoglobin; HF  heart failure; IP  investigational product; 
NT-proBNP  N-terminal pro b-type natriuretic peptide; NYHA  New York Heart Association; PK  pharmacokinetic; PRO  patient-reported outcome

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1.2
Synopsis
International co-ordinating investigator
USA
Protocol Title:
An International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, 
Phase III Study Evaluating the effect of Dapagliflozin on Exercise Capacity in Heart Failure 
Patients with Preserved Ejection Fraction (HFpEF)
Short Title:
DETERMINE-preserved - Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE 
walk test in patients with heart failure with preserved ejection fraction
Rationale:
The prevalence of chronic heart failure continues to increase globally, and the annual global 
economic burden (several hundred billion dollars in 2012) will increase as the population 
ages. Recent data from cardiovascular outcome studies of sodium-glucose co-transporter-2 
inhibitors (empagliflozin and canagliflozin) and real world studies (including patients treated 
with dapagliflozin) indicate that treatment with sodium-glucose co-transporter-2 inhibitors can 
reduce the risk of cardiovascular death and hospitalisation due to heart failure in patients with 
Type 2 diabetes mellitus (T2DM) overall and in patients with T2DM and concomitant heart 
failure. Additional important endpoints in heart failure patients include assessment of change 
in heart failure symptoms, physical limitation, and exercise capacity. This study will test 
whether dapagliflozin is superior to placebo for change in any of the family of 3 primary 
endpoints: Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS); 
Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ-PLS); or, 6-
minute walk distance (6MWD) from baseline at Week 16, in patients with chronic heart 
failure (New York Heart Association [NYHA] Functional Class II-IV) and preserved left 
ventricular ejection fraction (>40%), with or without T2DM.

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Objectives and Endpoints
Primary Objectives:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in patients with chronic HF NYHA 
Functional Class II-IV and preserved ejection fraction 
(LVEF>40%) [HFpEF] in: 
•
reducing patient-reported HF symptoms
•
reducing patient-reported physical limitation
•
improving exercise capacity
Family of primary endpoints:
•
Change from baseline in the KCCQ-TSS at 
Week 16.
•
Change from baseline in the KCCQ-PLS at 
Week 16.
•
Change from baseline in 6MWD at Week 16.
Secondary Objective:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in increasing time spent non-sedentary, 
evaluated in a subset of at least 100 patients 
Change from baseline at the end of the study in total 
time spent in light to vigorous physical activity, as 
assessed using a wearable activity monitor 
(accelerometer).
Safety objective:
Variables:
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients with 
HFpEF
•
AEs
•
SAEs
•
DAEs
•
AEs leading to amputation
•
Potential risk factor AEs for amputations 
affecting lower limbs
•
Laboratory tests
•
Vital signs
Exploratory Objectives:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in increasing total physical activity, 
evaluated in a subset of at least 100 patients 
Change from baseline at end of study in total activity 
measured by vector magnitude units per minute, as 
assessed using a wearable activity monitor 
(accelerometer).
To determine whether dapagliflozin is superior to 
placebo in reducing serum NT-proBNP
Change from baseline in serum NT-proBNP at 
Week 16.
To determine whether dapagliflozin is superior to 
placebo in increasing the exercise capacity during 
daily life, evaluated in a subset of at least 100 patients 
Change from baseline at end of study in movement 
intensity during walking, as assessed using a 
wearable activity monitor (accelerometer).
To determine whether dapagliflozin is superior to 
placebo in reducing the proportion of patients with 
worsened NYHA Functional Classification
Proportion of patients with worsened NYHA 
Functional Classification at Week 16.
To compare the effect of dapagliflozin versus placebo 
on physical activity, evaluated in a subset of at least 
100 patients 
Change from baseline at end of study for exploratory 
endpoints assessed using wearable activity monitors 
(accelerometers), in amount, duration and intensity.
To compare the effect of dapagliflozin versus placebo 
on health status as assessed by EQ-5D-5L
Change from baseline in health status utilities as 
measured by EQ-5D-5L at Week 16.
To compare the effect of dapagliflozin versus placebo 
on patient reported dyspnoea and fatigue
Change from baseline in dyspnoea at Week 16.
Change from baseline in fatigue at Week 16.

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Objectives and Endpoints
To assess the patients’ overall evaluation of net 
treatment benefit
Distribution of patients’ assessment of benefit of IP.
To explore whether dapagliflozin compared to 
placebo improves symptom frequency, symptom 
burden, symptom stability, social limitation, and QoL
Changes from baseline in the following KCCQ
domains at Week 16:
•
TSS domains: symptom burden and symptom 
frequency
•
Overall summary score
•
Symptom stability domain
•
Self-efficacy domain
•
Social limitation domain
•
QoL domain
To assess change in oxygen saturation after 6MWT
Change from baseline in oxygen saturation difference 
after 6MWT at Week 16.
To determine whether dapagliflozin compared with 
placebo has an effect on systolic BP
Change from baseline in systolic BP at Week 16.
To determine whether dapagliflozin compared with 
placebo has an effect on body weight
Change from baseline in body weight at Week 16.
To determine whether dapagliflozin compared with 
placebo has an effect on eGFR.
Change from baseline in eGFR at Week 16.
To collect and store blood samples for PK assessment
Explore dapagliflozin exposure-response relationship 
for efficacy and safety endpoints. The results will be 
analysed and reported in a separate report.
To collect and store blood samples for future 
exploratory genetic samples
Not applicable. Results will be analysed and reported 
separately.
6MWD  6-minute walk distance; 6MWT  6-minute walk test; AE  adverse event; BP  blood pressure; DAE  
adverse event leading to discontinuation of investigational product; eGFR  estimated glomerular filtration rate; 
EQ-5D-5L  European Quality of Life 5-dimensional 5-level health status questionnaire; HF  heart failure; HFpEF  
heart failure with preserved ejection fraction; IP  investigational product; KCCQ  Kansas City Cardiomyopathy 
Questionnaire; LVEF  left-ventricular ejection fraction; NT-proBNP  N-terminal pro b-type natriuretic peptide; 
NYHA  New York Heart Association; PK  pharmacokinetic; PLS  Physical Limitation Score; QoL  Quality of 
Life; SAE  serious adverse event; TSS  total symptom score 
Overall design
This is an international, multi-centre, parallel-group, randomised, double-blind, 
placebo-controlled, phase III study in heart failure patients with preserved left ventricular 
ejection fraction, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily 
in addition to background local standard of care therapy, including treatments to control 
co-morbidities, on change in heart failure symptoms as measured by the KCCQ-TSS, physical 
limitation as measured by the KCCQ-PLS, and exercise capacity as measured by 6MWD. 
Adult patients aged ≥40 years with chronic heart failure with preserved left ventricular 
ejection fraction (>40% and evidence of structural heart disease) and NYHA Functional 

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Class II-IV, who meet all of the inclusion criteria and none of the exclusion criteria, will be 
randomised 1:1 to receive either dapagliflozin 10 mg or matching placebo. Randomisation 
will be stratified by the presence or absence of T2DM. It is estimated that approximately 
1000 patients will need to be enrolled to reach the target of approximately 500 randomised 
patients.
Study period
Estimated date of first patient enrolled Q1 2019.
Estimated date of last patient completed Q3 2020.
Number of patients
Approximately 1000 patients will be enrolled to reach a target of approximately 
500 randomised patients, assuming a screening failure rate of 50%.
Treatments and treatment duration
Patients who meet all of the inclusion criteria and none of the exclusion criteria, will be 
randomised 1:1 to receive either once daily dapagliflozin 10 mg or matching placebo. 
Treatment should start within 24 hours after randomisation and the anticipated average 
treatment duration is 16 weeks.
Data Monitoring Committee
Due to the short duration of the study and the accumulated safety profile of dapagliflozin, a 
separate independent data monitoring committee will not be necessary to assess patient safety 
during this study. However, 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, with all reviewers blinded to the study 
treatments.
Statistical methods
The primary objectives of the study are to determine whether dapagliflozin is superior to 
placebo in reducing heart failure symptoms, reducing physical limitation, or improving 
exercise capacity in patients with chronic heart failure. The study will randomise 
approximately 500 patients (approximately 250 patients per treatment group). This sample 
size estimate is based on the primary efficacy endpoints (change from baseline in KCCQ-TSS, 
KCCQ-PLS, and 6MWD at Week 16). Randomisation will be stratified by presence or 
absence of T2DM.
Efficacy analysis
The primary and secondary efficacy endpoints will be evaluated under a combined treatment 
policy (intent-to-treat) and composite variable strategy estimand, including differences in the 

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outcome variable at the end of the 16-week treatment period. The intent-to-treat approach is 
employed to reflect the effect of the initially assigned randomised study drug, irrespective of 
exposure to study drug and concomitant treatment as well as subsequent treatment after 
discontinuation of study drug. A composite variable strategy approach is employed to account 
for deaths occurring during the follow-up period.
The family of primary efficacy endpoints (KCCQ-TSS, KCCQ-PLS, and 6MWD) will be 
analysed based on a rank analysis of covariance model with rank-based change from baseline 
at Week 16 as the dependent variable. Rank-based baseline value will be included as a 
covariate along with the stratification factor used in the randomisation. Ties will be assigned 
the mean of the corresponding ranks. In this analysis, data that are missing due to death will 
be ranked “worse” than observed data and data missing for reasons other than death, and the 
ranking amongst the deceased patients will be based on the last value while alive. Missing 
data due to reasons other than death (eg, missing visits, early withdrawal from the study, 
including lost to follow-up) will be replaced by multiple imputation with predictive mean 
matching. Rank analysis of covariance will then be applied to each imputation dataset and 
results will be pooled across datasets.
The magnitude of treatment effect in each of the KCCQ-TSS and KCCQ-PLS will also be 
presented as the number and percentage of patients by treatment group across the following 
categories of change from baseline: 

Death

Deterioration from baseline (change from baseline ≤-5)

Stable (-5< change from baseline <5)

Improvement (change from baseline ≥5)
The magnitude of treatment effect in 6-minute walk distance will also be presented as the 
number and percentage of patients by treatment group across the following categories of 
change from baseline:

Death

No improvement from baseline (change from baseline ≤0 metres)

Minimal improvement (0< change from baseline <30 metres)

Improvement (change from baseline ≥30 metres)
Clinical meaningfulness has not been demonstrated for the pre-specified categories. 
Therefore, thresholds for clinically meaningful within-patient change for KCCQ-TSS, KCCQ-
PLS, and 6MWD will be assessed using pre-specified methods described in the Statistical 
Analysis Plan and the derived thresholds will be the main categories used to assess the 
magnitude of treatment effect.

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To provide a visual display of the relative benefit of dapagliflozin over placebo across 
different ranges of response at Week 16, empirical cumulative distribution functions for each 
treatment group will be presented.
The type I error rate will be controlled to support superiority claims for dapagliflozin 
compared with placebo. The overall type I error (alpha) will initially be split between the 
KCCQ-TSS, KCCQ-PLS, and 6MWD. Testing will proceed to the secondary endpoint if 
statistical significance is demonstrated for at least 1 endpoint in the primary endpoint family. 
The testing procedure will be described in detail in the Statistical Analysis Plan.
Safety analysis
Safety analyses will be performed using the Safety Analysis Set, consisting of all patients who 
received one dose of investigational product. Safety data will be summarised descriptively by 
actual treatment received and will not be formally tested.
Sample size estimate
Enrolment in this study is intended to yield approximately 500 patients randomised to 
treatment. This sample size estimate is based on the primary endpoints of KCCQ-TSS, 
KCCQ-PLS, and 6MWD, as well as the assumption that mortality over the entire 16-week 
treatment period is about 5% in each treatment arm. 
 
 
 
 
 
 
 
 
 
 

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1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design
Visit
E
RA
RB a
T
FV
1
2a
2b a
3
4
5
Week
-2 ±1
0
0 a
8 ±1
14 ±1
16 ±1
Day
-14 ±7
1
1 a
56 ±7
98 ±7
112 ±7
a
Visit 2b occurs within 7 days of Visit 2a and constitutes Week 0 and Day 1 for patients who qualify for 
Randomisation B.
E  Enrolment; FV  Final visit; RA  Randomisation A; RB  Randomisation B; SOC  Standard of care; T  telephone 
call

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2
INTRODUCTION
2.1
Study rationale
Chronic heart failure (HF) continues to be a major cause of mortality, hospitalisations and 
suboptimal quality of life. Even with the best possible treatment, the five-year survival rate for 
HF patients is worse than for most cancers (Braunwald 2015). Moreover, the prevalence of
chronic HF continues to increase globally. An estimated 38 million people are affected 
worldwide (Braunwald 2015), with over 1 million hospitalisations annually in both the United 
States and Europe (Ambrosy et al 2014). The annual global economic burden in 2012 was 
estimated to be $108 billion (Cook et al 2014); this will increase dramatically as the 
population ages.
HF is a complex syndrome caused by structural and/or functional abnormalities. It is 
characterised by dyspnoea, fatigue, and pulmonary congestion and/or peripheral oedema due 
to fluid retention. Patients with signs and symptoms of HF are categorised, based on 
measurement of left-ventricular ejection fraction (LVEF), as having HF with reduced LVEF 
(HFrEF) or HF with preserved LVEF (HFpEF); this study investigates patients with the latter. 
For the purposes of this study, HFpEF is defined as LVEF >40% (HFrEF is usually defined as 
LVEF ≤40%). It should be noted that HF patients with a LVEF value of 40% to 50% often 
represent a separate population (Ponikowski et al 2016). Therefore, in this study, patients with 
a LVEF value above 40% and below 50% will be evaluated as a subgroup in supportive 
analyses. The proportion of patients in the study with a LVEF value above 40% and below 
50% at baseline will be monitored to ensure that the majority of patients have an LVEF value 
above 50%.
Approximately half of all HF patients have HFpEF (Oktay et al 2013). Risk of death for 
HFpEF patients is high, with annualised mortality rate up to 15% in community settings (Lam 
et al 2011). Patients with HFpEF have a particularly significant unmet medical need given that 
outcome studies hitherto performed have not resulted in any approved pharmacotherapy 
specifically for this condition. Conversely, outcome studies have provided evidence for 
treatments for HFrEF that can improve symptoms and haemodynamics as well as reduce 
hospitalisations for HF and mortality. These treatments include diuretics, angiotensin 
converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin II receptor blocker 
neprilysin inhibitors, mineralocorticoid receptor antagonists, and beta-blockers (Iwaz et al 
2016).
Recent data from cardiovascular outcome studies of sodium-glucose co-transporter-2 
(SGLT2) inhibitors (empagliflozin and canagliflozin) indicate that treatment with SGLT2 
inhibitors can reduce the risk of cardiovascular death and hospitalisation due to HF in patients 
with Type 2 diabetes mellitus (T2DM) overall, and in patients with T2DM and concomitant 

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HF (Zinman et al 2015; Ferreira et al 2016; Fitchett et al 2016; Neal et al 2017; Rådholm et al 
2018).
In this study, patients will be treated with the SGLT2 inhibitor, dapagliflozin, or matching 
placebo and their changes in HF symptoms, physical limitation, and exercise capacity over 16 
weeks will be assessed. Patients’ HF symptoms and physical limitation will be measured 
using the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) 
and Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ-PLS), 
respectively. Patients’ exercise capacity will be measured using the 6-minute walk test 
(6MWT; the distance a patient can walk in a 6-minute period, the 6MWD). The 6MWT is a 
standard method (Holland et al 2014, American Thoracic Society 2002) for measuring the 
exercise response to medical interventions in patients with moderate to severe heart or lung 
disease, having already been used to give pre-treatment and post-treatment comparisons for 
patients with HF (DeBock et al 1994, O’Keeffe et al 1998). In addition, patient health-related 
quality of life will be assessed using various patient-reported outcome (PRO) measures. The 
intention is to determine whether, with once daily administration over a 16-week period, 
10 mg dapagliflozin is superior to placebo for reducing HF symptoms, reducing physical 
limitation, or improving exercise capacity in patients with HFpEF.
2.2
Background
Dapagliflozin is a potent, highly selective and orally active inhibitor of human renal SGLT2. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of dapagliflozin is 
provided in the Investigator’s Brochure. Observations from the overall dapagliflozin clinical 
development programme suggest that dapagliflozin may increase exercise capacity in HFpEF 
patients (as a surrogate measure of daily activity) irrespective of diabetes status. Dapagliflozin 
lowers glycated haemoglobin (HbA1c) with a low risk of inducing hypoglycaemia. In 
addition, dapagliflozin treatment has also been shown to reduce weight and systolic blood 
pressure, and to have favourable effect on increased blood uric acid, albuminuria, and arterial 
elasticity, conditions which are associated with increased cardiovascular and renal risk 
(Shigiyama et al 2017). Dapagliflozin is believed to be nephroprotective through 
non-glycaemic mechanisms (Wanner et al 2016).
In combination, the identified blood pressure- and body weight-lowering effects of 
dapagliflozin, may help to increase the exercise capacity in the HFpEF population, a 
population with a high prevalence of hypertension and obesity. The findings from 
EMPA-REG OUTCOME study (Fitchett et al 2016), with a similar SGLT2 inhibitor 
compound, suggests that kidney function is preserved, or improved, in this diabetic study 
population. Furthermore, HFpEF patients are characterised by fluid retention and a change in 
cardiac metabolism favouring glucose as substrate, both of which have been hypothesised to 
be affected positively by SGLT2 inhibitor treatment. Moreover, arterial stiffness, and 

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abnormal ventriculo-arterial coupling, are common in patients with HFpEF, and may be 
modified by SGLT2 inhibitor treatments (Borlaug and Paulus 2011).
The clinical studies in healthy subjects at high multiple doses also show that, due to the 
mechanism of action, dapagliflozin does not induce hypoglycaemia in non-diabetic subjects; 
however, pharmacodynamic effects on glucose, sodium, and urinary volume are observed. 
Therefore, the changes in these diabetes-independent mechanisms and intra-renal physiology 
are expected to be similar, regardless of underlying disease.
This is an international, multi-centre, parallel-group, randomised, double-blind, 
placebo-controlled, phase III study in HFpEF patients, evaluating the effect of dapagliflozin 
10 mg versus placebo (given once daily in addition to background local standard of care 
therapy, including treatments to control co-morbidities) on change in HF symptoms as 
measured by KCCQ-TSS, physical limitation as measured by KCCQ-PLS, and exercise 
capacity as measured by 6MWD.
2.3
Benefit/risk assessment
Dapagliflozin has global marketing approval in more than 90 countries. More detailed 
information about the known and expected benefits and risks and reasonably expected adverse 
events (AEs) of dapagliflozin may be found in the Investigator’s Brochure. The following is a 
summary of benefit-risk considerations relevant to the HFpEF target population.
2.3.1
Potential risks to patients
The safety profile of dapagliflozin is already well established from clinical studies for T2DM 
and type 1 diabetes mellitus and is generally safe and well-tolerated.
Dapagliflozin, as an inhibitor of SGLT2, increases urinary glucose excretions, which is 
commonly believed to increase the risk of urinary tract infections. Urinary tract infections 
have been reported in dapagliflozin-treated patients in a slightly higher proportion than in 
placebo-treated patients in some global phase III studies. Increased urinary glucose excretion 
may also lead to an increased risk of developing genital infections. Urinary tract infections are 
considered a common side effect (in ≥1/100 to <1/10 patients).
Dapagliflozin reduces blood volume and blood pressure from its diuretic effect, which could 
be a concern in patients with HFpEF, but also be important mechanisms of a potential
treatment effect. However, in the dapagliflozin T2DM programme, the rate of events related 
to volume depletion and impaired renal function have been similar between dapagliflozin and 
placebo. Loop-diuretics are widely used in the target patient population and are also allowed 
in this study. A pooled analysis of patients with T2DM and HF in the dapagliflozin 
development programme, showed no increase of volume depletion events, but an increase in 
renal events, mainly creatinine increases, in patients treated with dapagliflozin (n=171) 

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compared with patients treated with placebo (n=149). About half of the patients were on loop 
diuretics (Kosiborod et al 2017). 
An increase in amputations, mostly affecting toes, was observed in a clinical trial (Neal et al 
2017) with another SGLT2 inhibitor. There is no indication from the clinical development 
programme that dapagliflozin is associated with an increased risk of amputation (further 
information provided in Section 8.3.1.1 for the detection and capture of events leading to 
amputation).
Dapagliflozin has not been shown to induce hypoglycaemia in non-diabetic patients. In 
clinical pharmacology studies, healthy subjects have been treated with single oral doses of up 
to 500 mg and multiple oral doses of 100 mg up to 14 days without any hypoglycaemic 
events.
There have been post-marketing reports of ketoacidosis, including diabetic ketoacidosis, in 
patients with T2DM taking dapagliflozin and other SGLT2 inhibitors. Diabetic ketoacidosis is 
considered a rare (in ≥1/10000 to <1/1000 patients) adverse drug reaction for dapagliflozin in 
patients with T2DM.
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, 
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L 
(250 mg/dL). If ketoacidosis is suspected, interruption of dapagliflozin treatment should be 
considered, and the patient should be evaluated promptly.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (eg, type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin 
dose reduction, reduced caloric intake, or increased insulin requirements caused by infections, 
illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in patients in 
these circumstances. Dapagliflozin is currently not indicated for the treatment of patients with 
type-1 diabetes mellitus; these patients are excluded from this study.
2.3.1.1
Protection against risks
This study has been designed with appropriate measures in place to monitor and minimise any 
potential risks to participating patients. Data regarding amputations and AEs potentially 
placing the patient at risk of a lower limb amputation will be collected (Section 8.3.1.1). To 
ensure the safety of all patients participating in AstraZeneca-sponsored studies, reviews of all 
safety information from all ongoing clinical dapagliflozin studies are conducted as they 
become available. Because of the short duration of the study and the accumulated safety 
profile of dapagliflozin, an independent Data Monitoring Committee will not be used in this 
study.

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2.3.2
Potential benefits to patients
All patients in the study are expected to be treated optimally according to background local 
standard of care therapy, including treatments to control co-morbidities. Dapagliflozin or 
matching placebo will be administered on top of these treatments.
All patients participating in clinical studies, irrespective of whether treated with active 
treatment or not, generally receive closer medical attention than those in ordinary clinical 
practice which may be to their advantage.
2.3.3
Conclusion
Considering the nonclinical and clinical experience with dapagliflozin and the precautions 
included in the study protocol, participation in this study should present a minimal and thus 
acceptable risk to eligible patients. Although hypothesis-generating data suggest beneficial 
effects of SGLT2 inhibitors in patients with T2DM with HF, no available SGLT2 inhibitor has 
a treatment indication for patients with HFpEF. This clinical study will test the hypothesis that 
dapagliflozin is superior to placebo in reducing patient-reported HF symptoms, reducing 
physical limitation, or improving exercise capacity in patients with HFpEF, with or without 
T2DM, in a rigorous fashion. The results could offer substantial benefit to patients with 
HFpEF, a patient population with a large medical need for effective treatments.
3
OBJECTIVES AND ENDPOINTS
Table 2
Study objectives
Primary Objectives:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in patients with chronic HF NYHA 
Functional Class II-IV and preserved ejection 
fraction (LVEF>40%) [HFpEF] in: 
•
reducing patient-reported HF symptoms
•
reducing patient-reported physical limitation
•
improving exercise capacity
Family of primary endpoints:
•
Change from baseline in the KCCQ-TSS at 
Week 16.
•
Change from baseline in the KCCQ-PLS at 
Week 16.
•
Change from baseline in 6MWD at Week 16.
Secondary Objective:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in increasing time spent non-sedentary, 
evaluated in a subset of at least 100 patients 
Change from baseline at the end of the study in total 
time spent in light to vigorous physical activity, as 
assessed using a wearable activity monitor 
(accelerometer).

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Table 2
Study objectives
Safety objective:
Variables:
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients with 
HFpEF
•
AEs
•
SAEs
•
DAEs
•
AEs leading to amputation
•
Potential risk factor AEs for amputations 
affecting lower limbs
•
Laboratory tests
•
Vital signs
Exploratory Objectives:
Endpoint/variable:
To determine whether dapagliflozin is superior to 
placebo in increasing total physical activity, 
evaluated in a subset of at least 100 patients 
Change from baseline at end of study in total activity 
measured by vector magnitude units per minute, as 
assessed using a wearable activity monitor 
(accelerometer).
To determine whether dapagliflozin is superior to 
placebo in reducing serum NT-proBNP
Change from baseline in serum NT-proBNP at 
Week 16.
To determine whether dapagliflozin is superior to 
placebo in increasing the exercise capacity during 
daily life, evaluated in a subset of at least 100 
patients 
Change from baseline at end of study in movement 
intensity during walking, as assessed using a wearable 
activity monitor (accelerometer).
To determine whether dapagliflozin is superior to 
placebo in reducing the proportion of patients with 
worsened NYHA Functional Classification
Proportion of patients with worsened NYHA 
Functional Classification at Week 16.
To compare the effect of dapagliflozin versus placebo 
on physical activity, evaluated in a subset of at least 
100 patients 
Change from baseline at end of study for exploratory 
endpoints assessed using wearable activity monitors 
(accelerometers), in amount, duration and intensity.
To compare the effect of dapagliflozin versus placebo 
on health status as assessed by EQ-5D-5L
Change from baseline in health status utilities as 
measured by EQ-5D-5L at Week 16.
To compare the effect of dapagliflozin versus placebo 
on patient reported dyspnoea and fatigue
Change from baseline in dyspnoea at Week 16.
Change from baseline in fatigue at Week 16.
To assess the patients’ overall evaluation of net 
treatment benefit
Distribution of patients’ assessment of benefit of IP.
To explore whether dapagliflozin compared to 
placebo improves symptom frequency, symptom 
burden, symptom stability, social limitation, and QoL
Changes from baseline in the following KCCQ 
domains at Week 16:
•
TSS domains: symptom burden and symptom 
frequency
•
Overall summary score
•
Symptom stability domain
•
Self-efficacy domain
•
Social limitation domain
•
QoL domain
To assess change in oxygen saturation after 6MWT
Change from baseline in oxygen saturation difference 
after 6MWT at Week 16.

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Table 2
Study objectives
To determine whether dapagliflozin compared with 
placebo has an effect on systolic BP
Change from baseline in systolic BP at Week 16.
To determine whether dapagliflozin compared with 
placebo has an effect on body weight
Change from baseline in body weight at Week 16.
To determine whether dapagliflozin compared with 
placebo has an effect on eGFR.
Change from baseline in eGFR at Week 16.
To collect and store blood samples for PK assessment
Explore dapagliflozin exposure-response relationship 
for efficacy and safety endpoints. The results will be 
analysed and reported in a separate report.
To collect and store blood samples for future 
exploratory genetic samples
Not applicable. Results will be analysed and reported 
separately.
6MWD  6-minute walk distance; 6MWT  6-minute walk test; AE  adverse event; BP  blood pressure; DAE  
adverse event leading to discontinuation of investigational product; eGFR  estimated glomerular filtration rate; 
EQ-5D-5L  European Quality of Life 5-dimensional 5-level health status questionnaire; HF  heart failure; HFpEF  
heart failure with preserved ejection fraction; IP  investigational product; KCCQ  Kansas City Cardiomyopathy 
Questionnaire; LVEF  left ventricular ejection fraction; NT-proBNP  N-terminal pro b-type natriuretic peptide; 
NYHA  New York Heart Association; PK  pharmacokinetic; PLS  Physical Limitation Score; QoL  Quality of 
Life; SAE serious adverse event; TSS  total symptom score 
4
STUDY DESIGN
4.1
Overall design
This is an international, multi-centre, parallel-group, randomised, double-blind, 
placebo-controlled, phase III study in HFpEF patients, evaluating the effect of dapagliflozin 
10 mg versus placebo, given once daily in addition to background local standard of care 
therapy, including treatments to control co-morbidities, on change in HF symptoms as 
measured by KCCQ-TSS, physical limitation as measured by KCCQ-PLS, and exercise 
capacity as measured by 6MWD.
An overview of the study design is provided in Figure 1, Section 1.3. Details on treatments 
given during the study are provided in Section 6.1.
Details on what is included in the efficacy and safety endpoints are provided in Section 3.
Adult patients with chronic HFpEF (defined for the purposes of this study as LVEF >40% and 
evidence of structural heart disease, ie, left atrial enlargement and or left ventricular 
hypertrophy) and New York Heart Association (NYHA) Functional Class II-IV, aged 
≥40 years who meet the all of the inclusion criteria and none of the exclusion criteria, will be 
randomised 1:1 to receive either dapagliflozin 10 mg or matching placebo. Randomised
treatment should be started as soon as possible. It is estimated that approximately 
1000 patients will need to be enrolled to reach the target of approximately 500 randomised 

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patients, assuming a screening failure rate of 50%. The rationale for the sample size 
determination is given in Section 9.2.
In this study the recruitment of patients between sites will be competitive. Data on baseline 
characteristics, endpoints and AEs will be collected through a validated web-based data 
capture system.
4.2
Scientific rationale for study design
This is a randomised, multi-centre, double-blind, placebo-controlled, parallel-group, phase III 
study. Randomisation and double-blinding will minimise potential bias. 
The study population will include patients both with and without T2DM, as the beneficial 
haemodynamic effects of dapagliflozin appear to be independent of the glycaemic effect and 
can therefore be expected in both groups. Enrolment in the study will be capped on a study 
level based on the proportion of patients with and without T2DM and the proportion of 
patients with an LVEF value above 40% and below 50%, and atrial fibrillation/flutter status 
will be monitored to ensure they are representative.
The control group will receive matching placebo; there are no approved pharmacological 
treatments for HFpEF that could be used as a comparator. All patients will be treated 
according to local guidelines on standard of care treatment for patients with HFpEF, focusing 
on treatment of HF symptoms (eg, diuretics) and co-morbidities (including treatment for high 
blood pressure, ischaemic heart disease, and atrial fibrillation/flutter). Each patient is to be 
treated with a diuretic regimen aimed at achieving optimal fluid/volume status for that 
individual (with respect to HF symptoms, renal function, blood pressure, and electrolyte 
status).
The study population will include patients with eGFR ≥25 mL/min/1.73m2. Patients with 
reduced renal function usually present a clinical profile of increased intra-glomerular pressure, 
hypertension, proteinuria and fluid/sodium overload. Through metabolic-independent 
mechanisms, SGLT2 inhibition can improve all these abnormalities. Thus, patients with HF 
and reduced renal function could be expected to benefit from treatment with dapagliflozin.
The primary efficacy endpoints of the study are change from baseline in each of KCCQ-TSS, 
KCCQ-PLS, and 6MWD at Week 16. The KCCQ is a disease-specific PRO measure 
developed for patients with chronic HF. The KCCQ has shown to be a valid, reliable and 
responsive measure of HF symptoms (as measured by KCCQ-TSS) and physical limitation (as 
measured by KCCQ-PLS) (Greene et al 2018, Spertus et al 2005). Such measures have been 
shown to be clinically meaningful endpoints in patients with HF (Ferreira et al 2016).
Although the 5-point threshold for clinically meaningful within-patient change has not been 
demonstrated specifically for the KCCQ-TSS or KCCQ-PLS in published clinical trials, the 

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use of this pre-specified threshold in the DETERMINE studies is supported by its extensive 
use in other KCCQ scales, including the KCCQ-OSS of which the KCCQ-TSS is a part 
(Filippatos et al 2017, Comin-Colet et al 2013). Furthermore, its use for KCCQ-TSS and 
KCCQ-PLS is supported by other studies (Spertus et al 2005, Dreyer et al 2016). Appropriate 
thresholds for clinically meaningful within-patient change will be evaluated using anchor-
based methods, which are described in the Statistical Analysis Plan (SAP).
The rationale for assessing change in 6MWD is that the 6MWT (the test used to determine the 
6MWD) can act as a surrogate of normal daily activity. The 6MWT is a standard method for 
measuring exercise response (Holland et al 2014, American Thoracic Society 2002) to 
medical interventions in patients with moderate to severe heart or lung disease, giving 
clinically meaningful change (Shoemaker et al 2012), having already been used to give 
pre-treatment and post-treatment comparisons for patients with HF (DeBock et al 1994, 
O’Keeffe et al 1998).
Reviews of the literature for clinically relevant thresholds for 6MWT in HF support a 30 m 
threshold for clinically important difference (Shoemaker et al 2013). An older study of 45 
patients (O’Keeffe et al 1998) reported that patients who reported feeling “a bit better” had a 
mean within-patient change in 6MWD of 24 m, and patients who reported “much better” had 
a mean within-patient change of 47 m. Data from chronic respiratory disease studies provides 
the most comprehensive evidence base for clinically relevant 6MWT change thresholds. The 
most recent European Respiratory Society/American Thoracic Society Technical Standard 
(Holland et al 2014) states that the minimal important difference lies between 25 and 33 
metres. This is also consistent with a recent review (Ferreira et al 2016) by leading experts in 
HF. However, these are based on group-level estimates and not within-patient change. 
Appropriate thresholds for clinically meaningful within-patient change in the target population 
will be evaluated using anchor-based methods, with patient global impression of severity 
(PGIS) and patient global impression of change (PGIC) instruments, which are described in 
the SAP.
Finally, patients will also complete a suite of PRO measures (eg, rating of dyspnoea and 
fatigue, and overall treatment benefit [OTB]), to help support the primary endpoints.
4.3
Justification for dose
The 10 mg dose of dapagliflozin has a well-characterised efficacy and safety profile in the 
T2DM clinical development programme and is the recommended dose in the majority of 
countries worldwide.
From a pharmacokinetic (PK) perspective, the currently approved dapagliflozin dose of 10 mg 
once daily is appropriate for use in patients with HFpEF. Slightly higher systemic exposure to 
dapagliflozin is expected in HFpEF patients when symptomatic, based on the dual renal and 

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hepatic metabolism of dapagliflozin and the lower perfusion of these organs in this patient 
group. However, the increase in systemic exposure of 10 mg dapagliflozin is not anticipated to 
warrant dose adjustment in HF patients. Moreover, the anticipated slightly higher systemic 
exposure to dapagliflozin is likely to be beneficial in HF patients, by compensating for the 
reduced renal perfusion and consequently lower renal glucose and sodium filtered loads in 
these patients. Doses lower than 10 mg are therefore unlikely to provide as much benefit to 
patients with HF as the 10-mg dose. Lastly, no changes in dose of concomitant medications in 
the HFpEF population are needed because there is no evidence of clinically meaningful 
drug-drug interactions for dapagliflozin with current medications used for treatment of 
patients with HFpEF, including standard of care medications used to control co-morbidities.
In the dapagliflozin clinical programme, there are no dose-related serious adverse events 
(SAEs) that preclude the use of 10 mg as a preferred dose. Additionally, in a post-hoc analysis 
of data from 320 patients with a documented history of HF and concomitant T2DM in 
placebo-controlled clinical studies, dapagliflozin 10 mg was found to be well-tolerated 
(Kosiborod et al 2017).
There are mechanistic reasons for choosing the 10-mg dose as well. One hypothesis of 
underlying pathophysiology in HFpEF is abnormal pressure coupling between the left 
ventricle and aorta, and drugs that reduce aortic stiffness may have beneficial effects in 
patients with HFpEF (Borlaug and Paulus 2011). Studies examining the highest approved dose 
for empagliflozin have reported improvements in aortic elasticity (Chilton et al 2015, Cherney 
et al 2014); similar studies are ongoing with dapagliflozin. In a completed placebo-controlled 
study, treatment with 10 mg dapagliflozin resulted in improvements in parameters associated 
with arterial remodelling in addition to lowering blood pressure in patients with T2DM (Ott et 
al 2017). This work suggests that selecting the 10-mg dose of dapagliflozin is reasonable from 
a mechanistic perspective to demonstrate a clinical effect.
4.4
End of study definition
The end of study is defined as the last visit/contact of the last patient participating in the study.
A patient is considered to have completed the study when he/she has completed Visit 5 (Final 
visit) even if the patient discontinues treatment during the study, but remains in the study until 
Visit 5 (Final visit). By contrast, patients who prematurely withdraw, or who are prematurely 
withdrawn, from the study, are considered as non-completers.
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if no patients are recruited. Patients from terminated sites will 
have the opportunity to be transferred to another site to continue the study. AstraZeneca may 
also terminate the entire study prematurely if concerns for safety arise within this study or in 
any other study with dapagliflozin. Regardless of the reason for termination, all data required 

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by the protocol at the time of discontinuation of follow-up will be collected. In terminating the 
study, the Sponsor will ensure that adequate consideration is given to the protection of the 
patients’ interests.
Guidelines for the dissemination of study results are given in Appendix A 6.
5
STUDY POPULATION
In this study, patients will usually be recruited from sites involved in routine cardiology 
clinical practice.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be randomised to investigational product (IP). Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures (Section 5.4).
In this protocol, “enrolled” patients are defined as those who sign the informed consent form 
(ICF). “Randomised” patients are defined as those who undergo randomisation and receive a
randomisation number.
Procedures for withdrawal of incorrectly enrolled patients are given in Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
1
Provision of signed informed consent (including genetic sampling if applicable) prior to 
any study specific procedures are performed. The ICF process is described in 
Appendix A 3.
2
Male or female patients aged ≥40 years on the day consent given.
3
Documented diagnosis of symptomatic HF (NYHA Functional Class II-IV) at enrolment, 
and a medical history of typical symptoms/signs of HF1 >8 weeks before enrolment, 
which is optimally treated with pharmacotherapy and/or device therapy (detailed in note 
below), as indicated, with at least intermittent need for diuretic treatment.
                                               

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Note: Patients for whom additional pharmacological or device therapy is contemplated, or 
should be considered, must not be enrolled until therapy has been optimised and is stable for 
≥4 weeks.
4
LVEF >40% and evidence of structural heart disease (ie, left ventricular hypertrophy or 
left atrial enlargement2) documented by the most recent echocardiogram, or cardiac 
magnetic resonance imaging within the last 12 months prior to enrolment (Visit 1).
Note: for all patients:
If there is more than 1 assessment of LVEF, the value from the most recent measurement 
should be used in assessing eligibility. The LVEF should be reported by the Investigator as a 
single value; if only a range of LVEF is available which includes 40%, a repeat 
echocardiogram should be performed as part of screening.
Patients with known HF but without a recent (≤12 months) assessment of left ventricular 
function will undergo a local echocardiogram at the time of enrolment (Visit 1).
For patients with prior acute cardiac events (eg, as defined in Exclusion Criterion 9), or 
procedures (eg, percutaneous coronary intervention, coronary artery bypass grafting, valve 
repair or replacement, implantation of cardiac resynchronisation therapy device or any other 
surgical, device or pharmacological intervention [eg, initiation of beta-blocker ]) that might 
change LVEF, or pharmaceutical therapies that may change LVEF, qualifying cardiac 
imaging assessment must be obtained at least 12 weeks following the 
procedure/event/therapy.
5
NT-proBNP ≥250 pg/mL (≥29.51 pmol/L) at Visit 1 for patients without ongoing atrial 
fibrillation/flutter. If atrial fibrillation/flutter is present at Visit 1, NT-proBNP must be 
≥500 pg/mL (≥59.08 pmol/L).
Note: For the purpose of this study, atrial fibrillation/flutter must be present on ECG 
performed on Visit 1 to be considered present.
6
Patients should receive background standard of care as described below:
All patients will be treated according to locally recognised guidelines on standard of care 
treatment for patients with HFpEF. Therapy should have been individually optimised and 
stable for ≥4 weeks (this does not apply to diuretics – see Note, below) and include (unless 
                                               

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contraindicated or not tolerated) treatment of co-morbidities (including high blood pressure, 
ischaemic heart disease, atrial fibrillation/flutter).
Note: Most patients with HF require treatment with a diuretic to control sodium and water 
retention leading to volume overload. It is recognised 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 (with respect to HF symptoms, renal function, blood pressure, and electrolyte 
status). Specifically, patient volume status should be individually optimised on a stable dose 
of diuretics for at least 2 weeks prior to screening.
Note: Optimised and stable treatment applies also past Visit 1 and until patient is randomised.
7
6MWD ≥100 metres and ≤425 metres at both the Enrolment and Randomisation A and
Randomisation B (Visits 1 and 2a and 2b).
Note: To further minimise testing variability due to patient performance, baseline 6MWD will 
be compared at the Enrolment (Visit 1) and Randomisation A (Visit 2a). If the 6MWD (at 
Visit 1 [Enrolment]) is within ±15% of the 6MWD observed at Randomisation A, the patient 
is randomised. If this 15% requirement is not met, the patient will undergo a third test at 
Randomisation B (Visit 2b), within 1 week after Randomisation A. The 6MWD obtained at 
Randomisation A should be within ±15% of the value obtained at Randomisation B. If this 
requirement is met, the patient is randomised at Randomisation B. If the 15% requirement is 
not met, the patient cannot be included in the study. The patient is not eligible for rescreening 
due to a failure to meet the variability criteria for 6MWD.
Let E be the 6MWD at Visit 1 (Enrolment), let Ra be the 6MWD at Visit 2a (Randomisation 
A) and let Rb be the 6MWD at Visit 2b (Randomisation B). The 15% variability criterion at 
Visit 2a (Randomisation A) is fulfilled if E ≥ Ra*0.85 and E ≤ Ra*1.15. The 15% variability 
criterion at Visit 2b (Randomisation B) is fulfilled if Ra ≥ Rb*0.85 and Ra ≤ Rb*1.15.
Example 1: 
If a subject has 6MWD at Visit 1 (Enrolment) equal to 170 metres and 6MWD at Visit 2a 
(Randomisation A) equal to 200 metres, then the variability is (170-200)/200 which is within 
±15% and the subject fulfils the variability requirement in inclusion criterion #7.
Example 2: 
If a subject has 6MWD at Visit 1 (Enrolment) equal to 200 metres and 6MWD at Visit 2a 
(Randomisation A) equal to 170 metres, then the variability is (200-170)/170 which is not 
within ±15% and the subject does not fulfil the variability requirement in inclusion criterion 
#7.
Example 3:
If a subject has 6MWD at Visit 2a (Randomisation A) equal to 340 metres and 6MWD at Visit 

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2b (Randomisation B) equal to 400 metres, then the variability is (340-400)/400 which is 
within ±15% and the subject fulfils the variability requirement in inclusion criterion #7.
If the 6MWD is outside of ≥100 metres and ≤425 metres at any visit until randomisation is 
completed, the patient is no longer eligible to continue in the study, is not eligible for 
rescreening, and should be withdrawn from the study.
5.2
Exclusion criteria 
1
Presence of any condition that precludes exercise testing such as:
(a) claudication that limits exertion
(b) uncontrolled bradyarrhythmia or tachyarrhythmia (according to Investigator 
judgement)
(c) clinically significant musculoskeletal disease or orthopaedic conditions that limit the 
ability to walk (eg, arthritis or injury in the foot, leg, knee or hip)
(d) pulmonary diagnoses (as described in note below)
(e) severe obesity (body mass index ≥50.0 kg/m2)
(f) amputation with artificial limb without stable prosthesis function for the past 
3 months
(g) any condition that, in the opinion of the Investigator, would contraindicate the 
assessment of 6MWT (eg, severe visual impairment)
(h) any condition other than HF that, in the opinion of the Investigator, is the primary 
limitation to exercise
Note: Although patients with stable pulmonary and musculoskeletal disease may be included 
in this study, these conditions must not be the primary cause for activity limitation. These 
patients must be optimally treated and their pulmonary or musculoskeletal condition 
considered stable to be able to participate in the study.
2
Participation in a structured exercise training programme in the 1 month prior to 
screening or planned to start during the trial.
Note: 1 month is interpreted as 4 weeks.
3
Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomisation or 
previous intolerance to an SGLT2 inhibitor.
4
Type 1 diabetes mellitus.
5
eGFR <25 mL/min/1.73 m2 (chronic kidney disease-epidemiology collaboration 
[CKD-EPI] formula) at Visit 1 (Enrolment), unstable or rapidly progressing renal disease 
at the time of randomisation.
6
Systolic blood pressure (BP) <95 mmHg on 2 consecutive measurements at 5-minute 
intervals, at Visit 1, or at Visit 2a or Visit 2b (Randomisation A or Randomisation B).

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7
Systolic BP ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications 
or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements at 5-minute 
intervals, at Visit 1 (Enrolment) or at Visit 2a or Visit 2b (Randomisation A or 
Randomisation B).
8
Current acute decompensated HF or hospitalisation due to decompensated HF <4 weeks 
prior to enrolment.
9
Myocardial infarction, unstable angina, coronary revascularization (percutaneous 
coronary intervention or coronary artery bypass grafting), ablation of atrial 
fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation 
therapy device within 12 weeks prior to enrolment. Before enrolment, these patients must 
have their qualifying LVEF assessment at least 12 weeks after the event.
10 Planned coronary revascularization, ablation of atrial fibrillation/flutter and/or valve 
repair/replacement.
11 Stroke or transient ischemic attack within 12 weeks prior to enrolment.
12 Probable alternative or concomitant diagnoses which in the opinion of the Investigator 
could account for the patient's HF symptoms and signs (eg, anaemia, hypothyroidism).
13 Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary 
disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic 
oral steroid therapy, or hospitalisation for exacerbation of COPD requiring ventilatory 
assist within 12 months prior to enrolment).
14 Previous cardiac transplantation, or complex congenital heart disease. Planned cardiac 
resynchronisation therapy. Prior implantation of a ventricular assistance device or similar 
device, or implantation expected after randomisation. 
15 HF due to any of the following: known infiltrative cardiomyopathy (eg, amyloid, sarcoid, 
lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac 
tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic 
cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, or 
uncorrected primary valvular disease.
16 A life expectancy of <2 years due to any non-cardiovascular condition, based on 
Investigator's clinical judgement.
17 Active malignancy requiring treatment (with the exception of basal cell or squamous cell 
carcinomas of the skin).
18 Acute or chronic liver disease with severe impairment of liver function (eg, ascites, 
oesophageal varices, coagulopathy).
19 Women of child-bearing potential (ie, those who are not chemically or surgically 
sterilised or post-menopausal):
(a) Who are not willing to use a medically accepted method of contraception considered 
reliable in the judgment of the Investigator, OR 

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(b) Who have a positive urine pregnancy test at Visit 1 (Enrolment) or at Visit 2a or 
Visit 2b (Randomisation A or Randomisation B), OR
(c) Who are breast-feeding.
20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
personnel and/or personnel at the study site).
21 Previous randomisation in the present study.
22 Participation in another clinical study with an IP or device during the last month prior to 
enrolment.
23 Inability of the patient, in the opinion of the Investigator, to understand and/or comply 
with study medications, procedures and/or follow-up (especially completing ePRO 
assessments) OR any conditions that, in the opinion of the Investigator, may render the 
patient unable to complete the study. Therefore, patients who are unable to read (eg, are 
blind or illiterate) should be excluded from participating in this trial.
5.3
Lifestyle restrictions (not applicable)
5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently randomised to a study treatment. Any patient who does not fulfil all
inclusion criteria or who meets 1 or more exclusion criterion should not be randomised under 
any circumstances. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious AE (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after 30 days. Note: the patient is not eligible for rescreening if he or she fails to 
meet the inclusion or variability criteria for the 6MWD. Patients must sign a new ICF before 
rescreening. Patients may only be rescreened once. Rescreened patients should be assigned the 
same patient number as for the initial screening. However, rescreening should be documented 
in the eCRF so that its effect on study results, if any, can be assessed.
6
STUDY TREATMENTS
Study treatment is defined as any IPs (including marketed product comparator and placebo) or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to dapagliflozin or matching placebo.

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6.1
Treatments administered
6.1.1
Investigational products
Table 3
Study treatments
Dapagliflozin
Placebo
Investigational product name:
Dapagliflozin 10 mg
Matching placebo
Dosage formulation:
Green, diamond shaped, film 
coated tablets 10 mg
Green, diamond shaped, film 
coated tablets placebo
Route of administration 
Oral
Oral
Dosing instructions:
Once daily
Once daily
Packaging and labelling
IP will be provided in bottles 
(155 tablets per bottle). Each 
bottle will be labelled in 
accordance with Good 
Manufacturing Practice 
Annex 13 and in accordance with 
each country’s regulatory 
requirements.
IP will be provided in bottles 
(155 tablets per bottle). Each 
bottle will be labelled in 
accordance with Good 
Manufacturing Practice Annex 13 
and in accordance with each 
country’s regulatory 
requirements.
Provider
AstraZeneca 
AstraZeneca 
IP investigational product
The tablets contain lactose, in quantities not likely to cause discomfort in lactose-intolerant 
individuals.
6.2
Preparation/handling/storage/accountability
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and resolved 
before use of the IP, if appropriate.
Only patients enrolled and randomised in the study may receive IP and only authorised site 
staff may supply or administer IP.
All IP should be kept in a secure place under appropriate storage conditions. The label on the 
IP bottle specifies the appropriate storage conditions.
The Investigator is responsible for IP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
The Investigator will retain the returned IP until it is collected for destruction, along with any 
IP not dispensed. The AstraZeneca representative or delegate is responsible for confirming the 
Investigator or delegate has recorded the quantities of returned and unused tablets at a patient 

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level before IP is destroyed. The AstraZeneca representative or delegate will advise on the 
appropriate method for destruction of unused IP.
The administration of all IP should be recorded in the appropriate sections of the eCRF.
6.3
Measures to minimise bias: randomisation and blinding
Withdrawn patients will not be replaced.
All patients will be randomly assigned to IP centrally using an interactive voice/web response 
system (IxRS). Randomisation to IP will be performed in balanced blocks to ensure 
approximate balance between the treatment groups (1:1). The randomisation codes will be 
computer-generated and loaded into the IxRS database. Before the study is initiated, the 
telephone number and call-in directions and/or the log-in information and directions for the 
IxRS will be provided to each site.
If a randomised patient withdraws from the study, then his/her enrolment/randomisation code 
cannot be reused. Withdrawn randomised patients will be included in the intent-to-treat 
analysis.
The IxRS will provide the Investigator with the kit identification number to be allocated to the 
patient when IP is dispensed. Site personnel will do a kit verification in IxRS before providing 
the IP bottle to the patient. Routines for this will be described in the IxRS user manual that 
will be provided to each site.
The blinding of treatment is ensured by using a double-blind technique. Individual treatment 
codes, indicating the randomised treatment for each patient, will be available to the 
Investigator(s) or pharmacists from the IxRS. Instructions for code breaking/unblinding will 
be described in the IxRS user manual that will be provided to each site.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomisation. 
The study site should discuss any potential unblinding (excluding emergency situations) with 
the AstraZeneca study Physician and prior to initiating the unblinding process. The date and 
reason that the blind was broken must be recorded in the source documentation and eCRF as 
applicable. The Investigator is to document and report the action to AstraZeneca, without 
revealing the treatment given to the patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.

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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.
6.3.1
Stratification and capping
The recruitment will be monitored continually in order to achieve adequate proportions of 
patient subpopulations. The IxRS will be programmed to automatically send alerts at 
predefined levels for both stratification and capping, whilst also allowing manual closure (or 
re-opening) as necessary.
6.3.1.1
Stratification
Randomisation will be stratified in IxRS based on patients with and without T2DM at the time 
of randomisation to ensure approximate balance between treatment groups in the proportions 
of patients with T2DM. Stratification by T2DM status at the time of randomisation is based 
on:

Established diagnosis of T2DM (medical history)
OR

HbA1c ≥6.5% (48 mmol/mol) shown at the central laboratory test at enrolment (Visit 1).
6.3.1.2
Capping
The intention is to enrol a typical cross-section of patients with HFpEF to the study.
The numbers of patients randomised to IP will be monitored to ensure the following
characteristics are appropriately represented in the study, and caps may be applied in IxRS:

T2DM status: the number of randomised patients with and without T2DM will be 
monitored in order to ensure a minimum of 30% in each subpopulation. Randomisation 
may be capped (ie, no more patients can be randomised in a specific subpopulation) if the 
pre-determined limit is reached.

LVEF value: the proportion of patients with LVEF above 40% and below 50% will be 
monitored to ensure a representative proportion in the study.

Atrial fibrillation/flutter status: the proportion of patients with atrial fibrillation/flutter 
will be monitored to ensure a representative proportion in the study.
6.4
Treatment compliance
Dispensing of IP to the patient should be recorded in the appropriate sections of the eCRF. 
Any change from the dosing schedule, dose interruptions and dose discontinuations should be 
recorded in the eCRF.

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Patients will be asked to bring their bottle of tablets of IP to the clinic at all of their visits. At 
each visit, any patient found to be non-compliant will be counselled on the importance of 
taking his or her IP as prescribed. The Investigator or delegate will enter the number of 
returned tablets in the eCRF.
If the patient forgets to bring his or her bottle of IP to Visit 5 (Final visit), or a Visit for early 
withdrawal from the study, where dosing occurs in the clinic for PK purposes, a new bottle 
will be dispensed in accordance with the IxRS. 
Site personnel are responsible for managing the IP from receipt by the study site until the 
destruction or return of all unused IP. The Investigator(s) is responsible for ensuring that the 
patient has returned all unused IP.
Information regarding overdose of IP is given in Section 8.4.3.
6.5
Concomitant therapy
All patients should be treated according to local standard of care of HFpEF and existing 
co-morbidities (including treatment for hypertension, ischemic heart disease, atrial 
fibrillation/flutter, diabetes, hyperlipidaemia). Background medications should be part of 
clinical practice and will not be provided by the Sponsor.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrolment or receives 
during the study must be recorded in the eCRF at the time points listed in the Schedule of 
Activities (Table 1), along with:

Reason for use

Dates of administration, including start and end dates

Dosage information, including dose, route, and frequency
6.5.1
Prohibited medications
Concomitant treatment (ie, treatment in combination with IP) with open-label 
SGLT2-inhibitors (eg, dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin, 
luseogliflozin, and fixed-dose combinations containing these drugs) during the study is 
prohibited for all patients. Also, in situations where the patient is not on IP, treatment with 
open-label SGLT2 inhibitors could interfere with the interpretation of the study. If treatment 
with a SGLT2-inhibitor alone or in combination is deemed essential, IP must be discontinued 
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6.5.2
Background medication
6.5.2.1
Heart failure background standard of care
Dapagliflozin or matching placebo will be added on to the patient’s background standard of 
care therapy for HFpEF.
Patients’ background standard of care therapies for HFpEF should be given according to local 
guidelines, including diuretics when needed to control symptoms and volume overload, and 
adequate treatment of co-morbidities such as hypertension and ischaemic heart disease. Each 
patient is to be treated with a diuretic regimen aimed at achieving optimal fluid/volume status 
for that individual (with respect to HF symptoms, renal function, blood pressure, and 
electrolyte status).
Background standard of care therapies will be recorded in the eCRF as concomitant 
medication.
6.5.2.2
Anti-diabetes background treatment for patients with T2DM
More than 40% of patients with established HF are estimated to have T2DM (Kristensen et al 
2016). Therefore, it is expected that a large proportion of patients will have an established 
T2DM diagnosis when enrolled in this study and that some patients will develop T2DM 
during the study. Treatment of diabetes should follow established guidelines, such as the 
glycaemic goals recommended by the American Diabetes Association and the European 
Association for the Study of Diabetes in their joint Position Statement (Inzucchi et al 2012, 
Inzucchi et al 2015).
Diabetes medications at baseline and during the study will be recorded in the eCRF. Patients 
with T2DM at randomisation will continue their T2DM treatment. SGLT2-inhibitors are 
prohibited (Section 6.5.1). Patients treated with insulin or insulin secretagogues have a higher 
risk of experiencing hypoglycaemic events compared with those treated with other 
anti-diabetic agents. If needed, T2DM treatments may be adjusted at the discretion of the 
Investigator or diabetes health care provider.
6.5.3
Other concomitant treatment
Other medication (with the exception of those 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.
6.6
Dose modification (not applicable)
6.7
Treatment after the end of the study
Patients will receive their last dose of IP at Visit 5 (Final visit) for PK assessment. Remaining 
IP will be collected at that time. Post-study treatment will not be provided by the Sponsor. 

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Patients should receive standard of care therapy after Visit 5 (Final visit), at the discretion of 
the Investigator. 
7
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1
Discontinuation of investigational product
Discontinuation from IP is not the same as a withdrawal from the study. If the patient 
temporarily or permanently discontinues IP, the patient should remain in the study 
(ie, continue to participate in scheduled study visits and evaluations) and it is important that 
the scheduled study visits and data collection continue according to the study protocol until 
study closure.
Patients may be discontinued from IP in the following situations:

Contraindication to further dosing with IP, in the opinion of the Investigator, such as AE 
or other safety reasons

Severe non-compliance with the study protocol

Diabetic ketoacidosis (DKA): Consider temporarily interrupting IP if DKA is suspected. 
If DKA is confirmed, IP should be discontinued permanently (Section 8.3.1.2)

Positive pregnancy test (discontinue IP and notify Sponsor representative) (Section 8.4.2)

Patient decision: The patient is at any time free to discontinue treatment, without 
prejudice to further treatment
Table 1 outlines data to be collected at the time of treatment discontinuation, and any further 
evaluations that need to be completed.
7.1.1
Temporary discontinuation 
Every attempt should be made to maintain patients on IP during the course of the study. If IP 
has been interrupted, it should be re-introduced as soon as, in the opinion of the Investigator, 
the patient’s condition is stable.
7.1.1.1
Unexpected acute declines in eGFR
If an unexpected, acute decline in kidney function is observed (see the Note below), the 
patient should be evaluated and temporary interruption of IP should be considered. Volume 
depletion, hypotension, inter-current medical problems and concomitant medications may 
cause increases in blood creatinine. Urinary tract infection and urinary obstruction should be 
considered (the latter especially in men). Several drugs may cause a decline in kidney 
function, especially non-steroidal anti-inflammatory drugs and certain antibiotics such as 
trimethoprim. If any drug is suspected of causing or contributing to worsening kidney 
function, their use should be re-considered.

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Note: Whether an acute decline in eGFR has occurred is based on the Investigator's 
judgement. However, the following may be considered: eGFR value has declined ≥50% 
compared with baseline or a doubling of serum creatinine compared to the most recent 
measurement.
7.1.1.2
Volume depletion/hypotension
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should, in addition to considering temporary interruption of IP, have their regular 
medication reviewed, and consideration should be given to reducing the dose of, or stopping 
concomitant medications, as assessed on an individual basis, including diuretics and drugs that 
lower blood pressure. The need for conventional diuretics (or the dose of diuretic used) should 
be re-evaluated in light of the patient’s symptoms and signs.
7.1.1.3
Patients at risk of volume depletion
Temporary interruption of IP may be considered in patients thought to be at risk of volume 
depletion/hypotension, such as patients with an acute medical illness potentially causing 
volume depletion because of inadequate fluid intake or fluid/blood loss (eg, gastroenteritis, 
gastrointestinal haemorrhage), or those undergoing major surgery.
7.1.2
Rechallenge
Patients who have temporarily discontinued IP can resume treatment as soon as, in the opinion 
of the Investigator, the patient’s condition is stable and the patient wishes to resume. No 
minimum time period is necessary before treatment can resume.
7.1.3
Procedures for discontinuation of investigational product
The Investigator should instruct the patient to contact the site before or at the time if IP is 
stopped. A patient that decides to discontinue IP will always be asked about the reason(s) and 
the presence of any AEs. The date of last intake IP should be documented in the eCRF. All IP 
should be returned by the patient at his/her next on-site study visit or unscheduled visit.
Patients permanently discontinuing IP should be given locally available standard of care 
therapy, at the discretion of the Investigator.
Discontinuation of IP, for any reason, does not affect the patient´s participation in the study. 
The patient should continue attending subsequent study visits and data collection should 
continue according to the study protocol. If the patient does not agree to continue study visits 
in-person, a modified follow-up must be arranged to ensure the collection of endpoints and 
safety information. This could be a telephone contact with the patient, a contact with a relative 
or treating physician, or information from medical records. The approach taken should be 
recorded in the medical records.

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7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site. To optimise the chance of 
getting in contact with the patient during the study, Investigators should record as much 
contact information as possible at the start of the study including home phone, mobile/cell 
phone, holiday home phone, family member phone numbers, email address, and social media 
contact details.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed potentially lost to follow up, the Investigator or designee must 
make every effort to regain contact with the patient, or the patient’s immediate family, by 
eg, repeat telephone calls, certified letter to the patient´s last known mailing address or 
local equivalent methods. These contact attempts should be documented in the patient’s 
medical record. 

Efforts to reach the patient should continue until the end of the study. Should the patient 
be unreachable at the end of the study the patient should be considered to be lost to follow 
up with unknown vital status at end of study and censored at latest follow-up contact.
7.3
Withdrawal from the study
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. Withdrawal of 
consent should only occur if the patient has received appropriate information about, and does 
not agree to, any kind of further assessments or contact, including modified follow-up options. 
Discontinuation of IP in itself is not considered withdrawal of consent.
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he or she may request destruction of any samples taken, 
and the Investigator must document this in the site study 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 patients as medically indicated.

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If a patient withdraws from participation in the study, then his or her enrolment and 
randomisation codes cannot be reused. Withdrawn patients will not be replaced.
If applicable, the patient will return any wearable activity monitors (accelerometers) that were 
provided for use at home.
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at study closure from publicly available 
sources, in accordance with local regulations. Knowledge of the vital status at study closure in 
all patients is crucial for the integrity of the study. 
Data to be collected at the time of withdrawal from the study and any further evaluations that 
need to be completed are listed in Table 1. All IP should be returned by the patient.
7.4
Discontinuation of the study
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant,

Are assessed as causally related to IP, and

Are not considered to be consistent with continuation of the study
Regardless of the reasons for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests and wellbeing.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 

Inadequate recruitment of participants by the investigator 

Discontinuation of further study intervention development

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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timings are summarised in the Schedule of Activities (Table 1).
The web-based data capture system will be used for data collection and query handling. The 
Investigator will ensure that data are recorded in the eCRFs as specified in the study protocol 
and in accordance with the eCRF instructions provided.
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and ensures the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRF. A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine whether the patient should continue or discontinue IP.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Table 1), is essential and required for study conduct.
The maximum amount of blood scheduled to be collected from each patient over the duration 
of the study, excluding any extra assessments that may be required, will not exceed 28 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Enrolment period
Visit 1, Enrolment (Week -2; Day -14 ± 7)
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened, and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the patient’s routine clinical management and obtained before 
signing of the ICF may be used for screening or baseline purposes, provided the procedures 
meet the protocol-specified criteria and were performed within the time frame defined in the 
Schedule of Activities (Table 1).

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At Visit 1 (Enrolment), the following procedures and assessments will be completed:

The patient will sign the ICF.

Patients who agree to blood sampling for genetic research must sign the genetic 
component of the form.

The Investigator will review the inclusion and exclusion criteria and assign the enrolment 
number using IxRS.

Demography, surgical and medical history (including prior cardiac imaging assessments, 
including echocardiogram and magnetic resonance imaging if required) and concomitant 
medications will be recorded.

The following PROs will be administered and must be completed before any further 
assessments are administered after signing the ICF:

KCCQ

PGIS in HF symptoms

Dyspnoea and fatigue

European Quality of Life 5-dimensional, 5-level health status questionnaire 
(EQ-5D-5L)

A physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

12-lead electrocardiogram (ECG) will be recorded.

Systolic and diastolic blood pressure and pulse rate will be measured and recorded.

Body weight, height and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and the Borg CR10 Scale® for dyspnoea 
and fatigue immediately before doing the 6MWT and again immediately after completing 
the 6MWT. At selected sites a subset of patients will wear an accelerometer (for use in 
the clinic only: wearable activity monitor A) while they perform the 6MWT. If the 
6MWD is outside the range of ≥100 metres and ≤425 metres the patient is NOT eligible
for inclusion OR rescreening in the study, and will, thus, be considered a screen failure.

Blood samples will be collected for the following efficacy and safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor for this initial 
screening sample, after which, at subsequent study visits, the values for NT-proBNP and 
HbA1c will be blinded.

Urine pregnancy test (beta-human chorionic gonadotropin [β-hCG]) will be conducted 
(for female patients of child-bearing potential only). The pregnancy test will be performed 
locally, using a dipstick provided by the central laboratory.

If applicable, the patient will be given the first wearable activity monitor to take home 
and he or she will be instructed on how to use it.

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
SAEs will be recorded.
Treatment period
Visit 2, Randomisation (Day 1)
Randomisation may occur at Visit 2a (Randomisation A) or Visit 2b (Randomisation B) 
depending on the outcome of the 6MWT at Visit 2a. If certain criteria are met, patients may be 
retested for the 6MWT at Visit 2b (Randomisation B) if the 6MWD recorded at Visit 2a 
(Randomisation A) does not result in exclusion from the study, but also does not permit their 
inclusion at Visit 2a (Randomisation A).
Before Visit 2a (Randomisation A), the Investigator will assess eligibility based on the central 
laboratory assessments from Visit 1 (Enrolment). Patients not eligible will be considered 
screen failures and should not continue to complete Visit 2a (Randomisation A), and they 
should also return the wearable device (the accelerometer: wearable activity device B #1).
At Visit 2a (Randomisation A), the following assessments and procedures will be completed:

The Investigator will review all of the inclusion and exclusion criteria to confirm the 
patient continues to be eligible to participate in the study.

The following PROs will be administered and must be completed before any further 
assessments are administered:

KCCQ

PGIS in HF symptoms

Dyspnoea and fatigue

EQ-5D-5L

Changes in surgical and medical history (including cardiac imaging assessments 
including echocardiogram and magnetic resonance imaging if required) and concomitant 
medications will be reviewed and recorded.

A physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

Systolic and diastolic blood pressure and pulse rate will be measured and recorded.

Body weight and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and the Borg CR10 Scale® for dyspnoea 
and fatigue immediately before doing the 6MWT and again immediately after completing 
the 6MWT. At selected sites a subset of patients will wear an accelerometer (for use in 
the clinic only: wearable activity monitor A) while they perform the 6MWT.

If the 6MWD is outside the range of ≥100 metres and ≤425 metres, the patient is 
NOT eligible for inclusion OR rescreening in the study, and will, thus, be considered 
a screen failure.

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
If the 6MWD at Visit 2a (Randomisation A) is within the range of ≥100 metres and 
≤425 metres, and the 6MWD recorded at Visit 1 (Enrolment) is within ±15% of the 
6MWD recorded at Visit 2a (Randomisation A), the patient can be randomised with 
the rest of the assessments at Visit 2a being completed. 

If the 6MWD recorded at Visit 1 (Enrolment) is not within ±15% of the 6MWD 
recorded at Visit 2a (Randomisation A) the patient must stop Visit 2a 
(Randomisation A) immediately, but may be rescheduled for a third 6MWT within 
1 week at Visit 2b (Randomisation B).
Note: Visit 2b (Randomisation B) is completed in exactly the same manner as Visit 2a 
(Randomisation A) starting with the PRO assessments, followed by recording any 
changes in surgical and medical history, and concomitant medications; conducting a 
physical examination; evaluating and recording NYHA Functional Classification; 
measuring and recording blood pressure and pulse rate; and assessing and recording body 
weight and waist circumference, then:

If the 6MWD is outside the range of ≥100 metres and ≤425 metres, the patient is 
NOT eligible for inclusion OR rescreening in the study, and will, thus, be considered 
a screen failure.

If the 6MWD at Visit 2b (Randomisation B) is within the range of ≥100 metres and 
≤425 metres, and the 6MWD recorded at Visit 2a (Randomisation A) is within ±15% 
of the 6MWD recorded at Visit 2b (Randomisation B), the patient can be randomised 
with the rest of the assessments at Visit 2b (Randomisation B) being completed. 

If the 6MWD recorded at Visit 2a (Randomisation A) is not within ±15% of the 
6MWD recorded at Visit 2b (Randomisation B), the patient must stop Visit 2b 
(Randomisation B) immediately, is not included or eligible for rescreening and is 
considered a screen failure.

Blood samples will be collected for the following efficacy or safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor with the exception 
of NT-proBNP and HbA1c, which will be blinded after the initial screening sample.

Urine pregnancy test (beta-human chorionic gonadotropin [β-hCG]) will be conducted 
(for female patients of child-bearing potential only). The pregnancy test will be performed 
locally, using a dipstick provided by the central laboratory.

The patient will be randomised to a treatment group (10 mg dapagliflozin or matching 
placebo in a 1:1 ratio) using the IxRS.

The patient will be dispensed IP, instructed to take the IP in accordance with the protocol 
without interruptions, and to bring the dispensed bottle to all study visits.

If the patient has consented to sampling for genetic research, a blood sample will be 
collected.

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
The patient will take his or her IP in the clinic for PK assessment. The time of dosing will 
be recorded in the eCRF.

A blood sample will be collected for a single, post-dose PK assessment (taken between 
30 minutes and 4 hours after dosing in the clinic). The time of blood sample collection 
will be recorded in the eCRF.

If applicable, the first wearable activity monitor that was administered for use at home 
will be collected.

AEs will be recorded.
Visit 3 (Week 8; Day 56 [± 7])
At Visit 3, the following assessments and procedures will be completed:

The following PROs will be administered:

KCCQ

PGIS in HF symptoms

PGIC in HF symptoms 

PGIC in walking ability

Dyspnoea and fatigue

OTB

Changes in concomitant medications will be reviewed and recorded.

Physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

Systolic and diastolic blood pressure and pulse rate will be measured and recorded.

Body weight and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and the Borg CR10 Scale® for both 
dyspnoea and fatigue immediately before doing the 6MWT and again immediately after 
completing the 6MWT. At selected sites a subset of patients will wear an accelerometer 
(for use in the clinic only: wearable activity monitor A) while they perform the 6MWT.

Blood samples will be collected for the following efficacy or safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor with the exception 
of NT-proBNP and HbA1c, which will be blinded after the initial screening sample.

If applicable, the second wearable activity monitor (wearable activity monitor B #2) will 
be dispensed for immediate use at home, and the third wearable activity monitor 
(wearable activity monitor B #3) will be dispensed for delayed use at home, starting at 
Week 14.

The numbers of used and unused tablets will be recorded and IP compliance will be 
checked and the same bottle will be given back to the patient.

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
AEs will be recorded.
Visit 4 (Week 14; Day 98 [± 7])
A telephone visit will be conducted at Week 14 for the following tasks:

For those patients using wearable activity monitors at home, the patient will be reminded 
to wear the third activity monitor at home starting at Week 14, and to return the second 
and third monitors at Visit 5 (Final visit). 

The patient will be reminded to attend the next study visit having not taken his or her IP 
at home on that day, as IP will be taken in the clinic instead, and that the patient needs to 
bring the IP bottle with them.

Changes in concomitant medications will be recorded.

AEs will be recorded.
In exceptional cases, for the patient’s convenience, it is allowed to conduct this visit on-site.
Visit 5 (Final visit) (Week 16; Day 116 [± 7])
At Visit 5, the following assessments and procedures will be completed:

The following PROs will be administered:

KCCQ

PGIS in HF symptoms

PGIC in HF symptoms

PGIC in walking ability

Dyspnoea and fatigue

EQ-5D-5L

OTB

Changes in concomitant medications will be reviewed and recorded.

A physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

Systolic and diastolic blood pressure and pulse rate will be measured and recorded.

Body weight and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and the Borg CR10 Scale® for both 
dyspnoea and fatigue immediately before doing the 6MWT and again immediately after 
completing the 6MWT. At selected sites a subset of patients will wear an accelerometer 
(for use in the clinic only: wearable activity monitor A) while they perform the 6MWT.

Blood samples will be collected for the following efficacy or safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 

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haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor with the exception 
of NT-proBNP and HbA1c, which will be blinded after the initial screening sample.

The patient will take his or her IP in the clinic for PK assessment. The time of dosing will 
be recorded in the eCRF.

A blood sample will be collected for a single, post-dose PK assessment (taken between 
30 minutes and 4 hours after dosing in the clinic). The time of blood sample collection 
will be recorded in the eCRF.

If applicable, the second and third wearable (wearable activity monitors B #2 and #3) 
activity monitors that were administered for use at home will be collected.

The numbers of used and unused tablets will be recorded and IP compliance will be 
checked.

AEs will be recorded.
Visit for early withdrawal from the study
As far as possible, all assessments planned for the Study Closure Visit (Visit 5) should be 
performed at an Early Withdrawal Visit. At a minimum, safety assessments, PROs, and the 
6MWT (if the patient is able) should be performed. It should be noted that this visit is ONLY 
for patients who choose to leave the study early and, by extension, discontinue study 
medication.
The following assessments and procedures will be completed, where possible:

The following PROs will be administered:

KCCQ

PGIS in HF symptoms

PGIC in HF symptoms

PGIC in walking ability

Dyspnoea and fatigue

EQ-5D-5L

OTB

Changes in concomitant medications will be reviewed and recorded.

A physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

Systolic and diastolic blood pressure and pulse rate will be measured and recorded.

Body weight and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and the Borg CR10 Scale® for both 
dyspnoea and fatigue immediately before doing the 6MWT and again immediately after 

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completing the 6MWT. A subset of patients will wear an accelerometer (for use in the 
clinic only) while they perform the 6MWT.

Blood samples will be collected for the following efficacy or safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor with the exception 
of NT-proBNP and HbA1c, which will be blinded after the initial screening sample.

The patient will take his or her IP in the clinic for PK assessment. The time of dosing 
will be recorded in the eCRF.

A blood sample will be collected for a single, post-dose PK assessment (taken between 
30 minutes and 4 hours after dosing in the clinic). The time of blood sample collection 
will be recorded in the eCRF.

If applicable, any wearable activity monitors that were administered for use at home will 
be collected.

The numbers of used and unused tablets will be recorded and IP compliance will be 
checked.

AEs will be recorded.
Visit for early treatment discontinuation
As far as possible, all assessments planned for Visit 5 (Final visit) should be performed at an 
Early Treatment Discontinuation Visit. At a minimum, safety assessments, PROs, and the 
6MWT (if the patient is able) should be performed. It should be noted that this visit is ONLY 
for patients who choose to discontinue treatment early, but who remain in the study 
(ie, continue attending study visits and completing study assessments).
The following assessments and procedures will be completed, where possible:

The following PROs will be administered:

KCCQ

PGIS in HF symptoms

PGIC in HF symptoms

PGIC in walking ability

Dyspnoea and fatigue

EQ-5D-5L

OTB

Changes in concomitant medications will be reviewed and recorded.

A physical examination will be conducted.

NYHA Functional Classification will be evaluated and recorded.

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
Body weight and waist circumference will be assessed and recorded.

The patient will do the 6MWT. This includes administering a suite of assessments: seated 
pulse rate, blood pressure, oxygen saturation and Borg CR10 Scale® for both dyspnoea 
and fatigue immediately before doing the 6MWT and again immediately after completing 
the 6MWT. A subset of patients will wear an accelerometer (for use in the clinic only) 
while they perform the 6MWT.

Blood samples will be collected for the following efficacy or safety 
assessments: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 
laboratory values will be available to the study sites and to the Sponsor with the exception 
of NT-proBNP and HbA1c, which will be blinded after the initial screening sample.

If applicable, any wearable activity monitors that were administered for use at home will 
be collected.

The numbers of used and unused tablets will be recorded and IP compliance will be 
checked.

AEs will be recorded.
Unscheduled visit
An unscheduled visit may be performed at any time after randomisation, if required in the 
opinion of the Investigator where the following assessment will be completed:

AEs will be recorded.
8.1
Efficacy assessments
8.1.1
Clinical outcome assessment
A clinical outcome assessment is any assessment that may be influenced by human choices, 
judgement, or motivation and may support either direct or indirect evidence of treatment 
benefit. The following clinical outcome assessments will be used in this study:

Performance outcome (PerfO) (Section 8.1.1.1)

PRO (Section 8.1.1.2)
A PerfO is based on a task performed by a patient according to instructions administered by a 
health care professional. The PerfO in this study will be the 6MWD. A PRO is any report of 
the status of a patient’s health condition that comes directly from the patient, without 
interpretation from anyone else. PROs have become an essential endpoint when evaluating 
benefit/risk of treatments in clinical studies. The following PROs will be used in this study:

KCCQ

PGIS in HF symptoms

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
PGIC in HF symptoms

PGIC in walking ability

Dyspnoea and fatigue

EQ-5D-5L

OTB

Borg CR10 Scale®
8.1.1.1
6MWD
One of the primary efficacy variables used in this study is the 6MWD (used to measure 
change in exercise capacity). The 6MWD will be measured at the 6MWT, conducted at the 
time points specified in Table 1.
The 6MWD will be measured based on the American Thoracic Society (ATS) guidelines 
(American Thoracic Society 2002). 
First, patient pulse rate, blood pressure, and oxygen saturation are recorded. Then, 
immediately before starting the 6MWT, the patient will stand and, using the Borg CR10 
Scale® (Section 8.1.1.2 and Appendix P), assess his or her perceived level of dyspnoea and 
fatigue before exertion.
At selected sites, a subset of at least 100 patients will wear an activity monitor (Monitor A) 
during the 6MWT. The wearable activity monitor will be distinct from the activity monitors 
some patients will be given to wear at home. The activity monitors worn during the 6MWT 
will be for use in the clinic only. Data collected by the wearable activity monitors will be 
uploaded to the vendor’s server and then provided to the sponsor. Data collected by the 
wearable activity monitors will not be shown to the patient or investigator. The instructions 
for using the wearable activity monitors will be provided in a separate document.
After completing the Borg CR10 Scale®, the patient will walk as far as he or she can in 
6 minutes. The 6MWD will be assessed under standard test conditions, in accordance with the 
ATS guidelines. Whenever possible, the same person will conduct the 6MWT at each visit. 
The distance walked (metres) will be measured manually and recorded on paper before being 
transferred to the eCRF. 
Immediately after completing the 6MWT, the patient will use the Borg CR10 Scale® again to 
reassess his or her perceived level of dyspnoea and fatigue following exertion. Finally, patient 
pulse rate, blood pressure, and oxygen saturation will again be recorded.
A number of measures have been introduced to minimise variability in patient performance of 
the 6MWT. Prior to initiating testing, every effort should be made by the Investigator to 
establish that the patient is in their “usual” state of health: meaning that the patient has no 

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concurrent medical issues (eg, upper respiratory infection, COPD/chronic HF exacerbation, 
exacerbation of musculoskeletal difficulties, etc) that might adversely affect his or her 
performance of the 6MWT. In the event that such conditions are present, the test should be 
aborted and rescheduled within a 14 day window, to allow time for the resolution of the acute 
medical issue and the patient to return to his or her “usual” state of health. 
For both 6MWD and other variables measured as part of the 6MWT, the value recorded at 
Visit 2a (Randomisation A) will be the baseline value, except for patients who were 
successfully retested for the 6MWT, where it will be the Visit 2b (Randomisation B) value.
8.1.1.2
Patient-reported outcomes
PROs are described individually in the following sections.
The PGIC in walking ability and the Borg CR10 Scale® are administered and recorded on 
paper separately from the other PROs (the KCCQ, PGIS in HF symptoms, PGIC in HF 
symptoms, Dyspnoea and Fatigue, EQ-5D-5L, and OTB; the results of these are recorded on a 
site-based electronic tablet by the patient and are termed ePROs). The PGIC in walking ability 
will be recorded by the patient on paper. The Borg CR10 Scale® forms part of the suite of 
assessments that are performed before and after the 6MWT (Section 8.1.1.1). 
The ePROs are administered and recorded as follows: Patients will perform the ePRO 
assessments using a site-based electronic tablet during clinic visits at the time points given in 
Table 1 before the 6MWT. The ePRO assessments must be completed by the patient as soon 
as he/she arrives at the study site and will take approximately 10 minutes to complete.
Each site must allocate the responsibility for the administration of the ePROs to a specific 
individual and, if possible, assign a backup person to cover if that individual is absent. A key 
aspect of study success is to have high PRO compliance. Therefore, it is essential that site 
staff follow the Schedule of Activities (Table 1) and make sure the device is set up properly 
(including using the appropriate time zone), charged, and fully functional at all times in order 
to minimise missing data.
It is important that the site staff explain the value and relevance of PRO data: to hear directly 
from patients how they feel. The following best practice guidelines should be followed:

Patients must not receive help from relatives, friends, or site personnel to answer or 
clarify the PRO questionnaires, in order to avoid bias.

The PRO questionnaires must be completed before any other study procedures are 
conducted at a given visit.

The PRO questionnaires must be completed before being seen by the Investigator.

The PRO questionnaires must be completed by the patient in private.

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
The appointed site personnel should also stress that the information is confidential. 
Therefore, if the patient has any medical problems, he or she should discuss them with the 
doctor or research nurse separately from the ePRO assessment.

The appointed site personnel must show patients how to use the ePRO device, in 
accordance with the instructions provided.

The appointed site personnel should remind patients that there are no right or wrong 
answers, and the patient should be given sufficient time to complete the PRO 
questionnaires at his or her own speed.
Kansas City Cardiomyopathy Questionnaire
Two of the primary efficacy variables are based on the KCCQ (provided in Appendix H), used 
to assess HF symptoms and physical limitation. 
The values recorded at Visit 2a (Randomisation A) will be the baseline values, except for 
patients who were successfully retested for the 6MWT, where values recorded at Visit 2b 
(Randomisation B) will be the baseline values.
The KCCQ is a 23-item, self-administered disease-specific instrument and has shown to be a 
valid, reliable and responsive measure for patients with HF (Greene et al 2018, Spertus et al 
2005). The KCCQ was developed to measure the patient’s perception of their health status 
independently, which includes HF-related symptoms (frequency, severity and recent change), 
impact on physical and social function, self-efficacy and knowledge, and how the patients’ HF 
affects their quality of life. Summary scores and domain scores are transformed to a range of 0 
to 100. Higher scores represent a better outcome.
Patient global impression of severity in heart failure symptoms
The PGIS (provided in Appendix I) item assesses how a patient perceives his or her overall 
current severity of HF symptoms. Patients will choose from 6 response options ranging from 
‘no symptoms’ to ‘very severe.’
The values recorded at Visit 2a (Randomisation A) will be the baseline values, except for 
patients who were successfully retested for the 6MWT, where values recorded at Visit 2b 
(Randomisation B) will be the baseline values.
Patient global impression of change in heart failure symptoms
The PGIC (provided in Appendix J) item assesses how a patient perceives his or her overall 
change in HF symptoms since the start of the study. Patients will choose from 7 response 
options ranging from ‘much better’ to ‘much worse.’

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Patient global impression of change in walking ability
The PGIC (provided in Appendix K) item assesses how a patient perceives his or her overall 
change in walking ability since the start of the study. Patients will choose from 7 response 
options ranging from ‘much better’ to ‘much worse.’
Dyspnoea and fatigue
The dyspnoea and fatigue (provided in Appendix L and Appendix M, respectively) items are 
single questions, each asking the patient to rate his or her shortness of breath and fatigue, 
respectively, on a scale from 0 to 10.
The values recorded at Visit 2a (Randomisation A) will be the baseline values, except for 
patients who were successfully retested for the 6MWT, where values recorded at Visit 2b 
(Randomisation B) will be the baseline values.
EQ-5D-5L
The EQ-5D-5L (provided in Appendix N) is a self-reported questionnaire that is used to 
derive a standardised 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.
The values recorded at Visit 2a (Randomisation A) will be the baseline values, except for 
patients who were successfully retested for the 6MWT, where values recorded at Visit 2b 
(Randomisation B) will be the baseline values.
Overall treatment benefit
This item (provided in Appendix O) consists of 2 questions measuring the patient’s rating of 
treatment benefit. The first question assesses the patient’s impression of the benefits relative 
to the negative effects. The second question assesses whether the patient would elect to 
continue the treatment after the end of the study if it were an option.
Borg CR10 Scale®
The Borg CR10 Scale® (provided in Appendix P) is a non-linear scale, ranging from 0 
(‘nothing at all’) to an un-numbered maximum (‘absolute maximum; highest possible’), that is 
used to measure a patient’s self-assessment of his or her dyspnoea and fatigue immediately 
before and immediately after each 6MWT. The results will be recorded by site staff first onto 
paper before transfer into the CRF (Borg 2007).
8.1.2
Oxygen saturation
Oxygen saturation forms part of the suite of assessments administered during the 6MWT 
(Section 8.1.1.1) and will be recorded at the time points given in Table 1. Oxygen saturation 

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will be assessed using a standard pulse oximetry device in a sitting position before and after 
the 6MWT.
The Visit 2a (Randomisation A) results will be the baseline values, except for patients who 
were successfully retested for the 6MWT, where values recorded at the Visit 2b 
(Randomisation B) will be the baseline values.
8.1.3
Physical activity measured at home (accelerometer, Monitor B)
A subset of at least 100 patients (in predefined countries; the countries will be informed if 
they will participate or not) will receive wearable activity monitors (Monitor B) to wear at 
home for 3 periods of 7 days as shown in Table 1. Patients will be instructed to wear their 
activity monitor for as long as possible (ideally 24 hours per day for 7 days). The purpose of 
wearing the monitors is to assess the total time spent in light to vigorous physical activity 
(secondary efficacy endpoint), and the changes in the amount, duration and intensity of 
physical activity parameters (exploratory endpoints) from Visit 1 (Enrolment) at Visit 5 (Final 
visit; Week 16). Patients will return all of their activity monitors to the site staff.
Data collected by the wearable activity monitors will be uploaded to the vendor’s server and 
will be provided to the Sponsor. Data collected by the wearable activity monitors will not be 
shown to the patients or the investigators. The specific activity monitor endpoints and their 
analysis are described in the SAP.
Summary data recorded during 7 days from Visit 1 (Enrolment) to Visit 2a (Randomisation A) 
will form the baseline values for endpoints derived from the wearable activity monitor worn at 
home (Monitor B).
8.1.4
Serum NT-proBNP
Blood samples for serum NT-proBNP assessment will be collected at the time points given in 
Table 1. Serum NT-proBNP will be assessed by the central laboratory and post-screening 
results will be blinded to all staff associated with conducting the study. There are no plans or 
processes available to share the blinded data at a later stage (eg, after database lock) and, in 
effect, the data will remain permanently blinded for the study sites, while they will be 
available unblinded to the Sponsor after database lock.
The Visit 2a (Randomisation A) result will be the baseline value, except for patients who were 
successfully retested for the 6MWT, where values recorded at Visit 2b (Randomisation B) 
will be the baseline value.
8.1.5
New York Heart Association Functional Classification
NYHA Functional Classification (provided in Appendix Q) will be assessed by the 
Investigators at the time points given in Table 1 and results will be recorded in the eCRF.

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The value recorded at Visit 2a (Randomisation A) will be the baseline value, except for 
patients who were successfully retested for the 6MWT, where values recorded at Visit 2b 
(Randomisation B) will be the baseline value.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Table 1).
8.2.1
Physical examination
A physical examination will be performed at the time points specified in Table 1 and include 
an assessment of general appearance, respiratory and cardiovascular systems (including 
oedema) and abdomen. Investigators should pay special attention to clinical signs related to 
previous serious illnesses. New or worsening abnormalities may qualify as AEs 
(Section 8.3.7).
Physical examination findings will be recorded in the eCRF.
8.2.2
Electrocardiograms
A 12-lead ECG will be performed at Visit 1 (Enrolment); the rhythm will be recorded in the 
eCRF.
8.2.3
Vital signs
Systolic and diastolic blood pressure and pulse rate will be performed at the time points 
specified in Table 1 and all results will be recorded in the eCRF.
The measurements should be done before any blood sampling or the 6MWT. The 
measurements will be assessed in a sitting position with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
The measurements should be preceded by at least 5 minutes of rest for the patient in a quiet 
setting without distractions (eg, television, mobile/cell phones).
It should be noted that both blood pressure and pulse rate form part of the suite of assessments 
that are administered as part of the 6MWT (Section 8.1.1.1). Ideally, both measurements 
should be taken 3 times at a site visit: once for vital signs, then again before and after the 
6MWT. However, as all of these measurements are taken in a sitting position, at the 
Investigator’s discretion, the blood pressure and pulse rate values taken for vital signs can be 
used for the values before the 6MWT.

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8.2.4
Body weight, height and waist circumference
Body weight, height and waist circumference will be assessed at the time points specified in 
Table 1 and results will be recorded in the eCRF. The patient’s body weight, height and waist 
circumference will be measured with light clothing and no shoes. If the patient has a 
prosthetic limb, this should be worn consistently during all weight measurements. 
8.2.5
Clinical safety laboratory assessments
The following clinical safety laboratory assessments (non-fasting) will be performed at the 
time points specified in Table 1:

Sodium

Potassium

Creatinine (for calculation of eGFR using the CKD-EPI equation [Levey at al 2009]):

GFR=141x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black]
Where:

Scr is serum creatinine in mg/dL,

κ is 0.7 for females and 0.9 for males,

α is -0.329 for females and -0.411 for males,

min indicates the minimum of Scr/κ or 1, and

max indicates the maximum of Scr/κ or 1 
The equation does not require weight because the results are reported normalised to 1.73 m² 
body surface area, which is an accepted average adult surface area.

Haematocrit

HbA1c
Clinical laboratory samples will be analysed at a central laboratory and post-screening results 
will be available to the study sites and to the Sponsor with the exception of HbA1c, which will 
be blinded while the trial is being conducted. There are no plans or processes available to 
share the blinded data at a later stage (eg, after database lock) and, in effect, the data will 
remain permanently blinded for the study sites, while they will be available unblinded to the 
Sponsor.

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The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
study site as source data for laboratory variables. 
Information on how AEs based on laboratory test results should be recorded and reported is 
given in Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
8.2.6
Other safety assessments
Patients at risk of volume depletion due to co-existing conditions or concomitant medications, 
such as loop diuretics, should have careful monitoring of their volume status, as judged by the 
investigator.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE, SAE, AE leading to discontinuation of IP (DAE), AE 
leading to amputation or an event potentially placing the patient at risk for a lower limb 
amputation (preceding events). Information on how to follow up AEs is given in
Section 8.3.3. 
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs, SAEs, or DAEs. Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
Safety information on AEs, SAEs and DAEs, amputations, AEs leading to amputation and 
potential risk factor AEs for amputations affecting lower limbs will be collected and entered 
into eCRFs by site personnel according to the study visit schedule.
If the potential efficacy event fulfils SAE criteria (Appendix B 2) the site is to record and 
report these events to the Sponsor or designee within timelines described in Section 8.3.2.

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8.3.1.1
AEs leading to amputation, and potential risk-factor AEs for amputations 
affecting lower limbs (‘preceding events’)
AEs leading to amputation and potential risk-factor AEs for amputations affecting lower limbs 
(‘preceding events’) will be included as AEs of special interest in this study. To ensure that 
data on amputations are collected systematically, amputations and underlying conditions 
relevant to amputation will be recorded on a specific eCRF page. The AE leading to 
amputation should be recorded in the eCRF as an AE or SAE.
Events potentially placing the patient at risk for a lower limb amputation (“preceding events”) 
should also be recorded in the eCRF as an AE or SAE whether or not an amputation has taken 
place. These will be collected on a dedicated eCRF page.
8.3.1.2
DKA events
For events of Diabetic Ketoacidosis (DKA - see definition below) reported in this study, 
additional information will be recorded on a specific eCRF page in addition to the AE/SAE 
form.
DKA events will not be adjudicated in this study.
DKA definition:
A diagnosis of DKA should only be made in a clinical setting consistent with DKA (based on 
patient history, symptoms, and physical examination) and in the absence of more likely 
alternative diagnoses and causes of acidosis (such as lactic acidosis). The following 
biochemical data should support diagnosis:

Ketonaemia ≥3.0 mmol/L and/or significant ketonuria (more than 2+ on standard 
urinesticks).
AND

At least 1 of the following criteria suggesting high anion gap metabolic acidosis:

Arterial or venous pH ≤7.3

Serum bicarbonate ≤18 mEq/L

Anion gap [Na – (Cl + HCO3)] >10
8.3.1.3
Capture of additional laboratory values
Any additional safety laboratory assessments during the study period, including creatinine, 
will be obtained according to the Investigator’s medical judgment in the course of standard 
care using local laboratories. Laboratory values would be recorded only on SAE eCRFs as 
part of narrative information, in accordance with the Investigator’s judgment.

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8.3.2
Time period and frequency for collecting AE and SAE information 
Non-serious AEs will be collected from the time of randomisation until the end of Visit 5 
(Final visit). SAEs will be collected from the time of signing the ICF until the end of the 
Visit 5 (Final visit).
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of them being available.
Investigators are not obligated to seek AE or SAE actively in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he or she considers the event to be reasonably related to the IP or study participation, the 
Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE or SAE report, the Investigator is required to follow each patient 
proactively at subsequent visits/contacts. All SAEs and events of amputation and potential 
preceding events, will be followed until resolution, stabilisation, the event is otherwise 
explained, or the patient is lost to follow-up. 
Any AEs that are unresolved at the patient’s last visit 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) or SAE(s) at the 
end of the study, if judged necessary.
8.3.4
AE data collection
AE data will be collected in accordance with the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0.
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity grade: (mild, moderate or severe)

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

Outcome.

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In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

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)

Causality assessment to other medication
8.3.5
Causality collection
The Investigator will assess causal relationship between 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 IP?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
AEs based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
AEs based on examinations and tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the clinical study report. Deterioration from baseline in protocol-mandated laboratory values 
or vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria, or 
are the reason for discontinuation of treatment with the IP.

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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 or vital 
sign will be considered as additional information. Wherever possible, the reporting 
Investigator uses the clinical, rather than the laboratory term (eg, anaemia versus low 
haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding on physical examination 
compared with the baseline assessment will be reported as an AE unless unequivocally related 
to the disease under study. 
8.3.8
Hy’s Law
Information relating to Hy’s Law is given in Appendix E. Dapagliflozin has an established 
safety profile; therefore, no liver function tests are planned in this study. The Investigator 
should be vigilant for cases of Potential Hy’s Law cases from ad hoc laboratory tests or AEs. 
Additional safety samples, for example, liver function tests to determine Potential Hy’s Law 
cases, may be collected if clinically indicated at the discretion of the Investigator. The date, 
time of collection and results (values, units and reference ranges) will be recorded on the 
appropriate page of the CRF.
8.3.9
Disease-under study (not applicable)
8.3.10
Disease progression (not applicable)
8.4
Safety reporting and medical management
8.4.1
Reporting of SAEs
All SAEs must 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 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs 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 1 calendar 
day ie, immediately but no later than 24 hours of when he or she becomes aware of it.

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Once the Investigators or other site personnel indicate an AE is serious in the 
electronic/web-based data capture system, an automated email alert is sent to the designated 
AstraZeneca representative.
If the electronic/web based data capture system is not available, then the Investigator or other 
study site staff reports a SAE to the appropriate AstraZeneca representative by telephone. The 
AstraZeneca representative will advise the Investigator/study site staff how to proceed.
Further guidance on the definition of an SAE is given in Appendix B.
8.4.2
Pregnancy and maternal exposure
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study patient has received any IP. If a pregnancy is 
reported, the Investigator should inform the Sponsor within 24 hours of learning of the 
pregnancy. Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs.
Women of child-bearing potential who are not using contraception as defined in Section 5.2, 
Exclusion Criterion 19 are not allowed to be included in this study. Should a pregnancy still 
occur, the IP should be discontinued immediately and the pregnancy reported to AstraZeneca.
Dapagliflozin must not be used in the second and third trimesters of pregnancy. In the time 
period corresponding to second and third trimester of pregnancy with respect to human renal 
maturation, maternal exposure to dapagliflozin in rat studies was associated with increased 
incidence and/or severity of renal pelvic and tubular dilatations in progeny.
There are no adequate and well-controlled studies of dapagliflozin in pregnant women. When 
pregnancy is detected, IP should be discontinued.
8.4.3
Overdose
Dapagliflozin has been well tolerated at doses of up to 500 mg/day in single-dose testing in 
healthy volunteers and up to 100 mg/day in repeat-dose testing for 14 days in healthy 
volunteers and patients with T2DM. 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.

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For further information regarding overdose, refer to the Investigator’s Brochure.

An overdose without associated symptoms is only recorded on the Overdose eCRF 
module.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
If an overdose with an AstraZeneca IP occurs in the course of the study, then the Investigator 
or other site personnel inform appropriate AstraZeneca representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply (Section 8.3.2). 
For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs during the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day ie, 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 (for Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication error can be found in Appendix B.
8.5
Pharmacokinetics
At Visit 2a (Randomisation A) (Day 1), or Visit 2b (Randomisation B) (Day 1) as applicable, 
and Visit 5 (Week 16/Day 116 [± 7]) (or Study Withdrawal Visit, if possible), patients will 
take their dose of IP in the clinic so that PK can be evaluated. One blood sample (2 mL) will 
be collected from each patient no earlier than 30 minutes after dosing and no later than 4 hours 
after dosing.
The purpose of the PK assessment is to explore the exposure-response relationship for 
efficacy and safety endpoints. Results will be reported separately from the clinical study 
report.

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Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
Sponsor and site study files, but will not constitute a protocol amendment. The institutional 
review board (IRB)/independent ethics committee (IEC) will be informed of any safety issues 
that require alteration of the safety monitoring scheme or amendment of the ICF.
8.5.1
Determination of drug concentration
Samples for determination of dapagliflozin concentration in plasma will be analysed by 
Covance Bioanalytical laboratory on behalf of AstraZeneca, using an appropriate bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report.
8.5.2
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report is finalised or 6 months after the 
draft Bioanalytical Report (whichever is earlier) is issued, unless requested for future 
analyses.
PK samples may be disposed of or anonymised by pooling. Additional analyses may be 
conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the 
clinical study report.
8.6
Pharmacodynamics (not applicable)
8.7
Genetics 
Genetic testing is not evaluated in this study. However, a blood sample will be collected for 
future exploratory genetic evaluation from patients who have provided separate informed 
consent specifically for genetic evaluation. Results will be reported separately from the results 
of this study.
8.7.1
Collection of mandatory genetic samples (not applicable)
8.7.2
Optional exploratory genetic sample
Approximately 6 mL blood will be collected for DNA isolation from patients who have 
consented to participate in future exploratory genetic evaluations. Participation is optional. 
Patients who do not wish to participate in the genetic research may still participate in the 
study.

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Information regarding genetic research, including details on processes for collection and 
shipment and destruction of these samples, can be found in Appendix D.
8.7.3
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or in accordance with local regulations from the date of the patient’s last visit, after 
which they will be destroyed. DNA is a finite resource that may be used up during analyses. 
The results of any further analyses will be reported separately in a scientific report or 
publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organisations working with the DNA.
8.8
Biomarkers (not applicable)
8.9
Health economics (not applicable)
9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives using the 
statistical analytical software, SAS. 
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 SAP will preferably be prepared and approved before the first patient is 
randomised, and any subsequent amendments will be documented, with final amendments 
completed prior to database lock and study unblinding.
9.1
Statistical hypotheses
The primary objectives of this study are to demonstrate superiority of dapagliflozin (Active
treatment) over placebo (Control) in terms of KCCQ-TSS, KCCQ-PLS, and 6MWD.
Consequently, the statistical hypotheses used for the family of primary endpoints are the 
following:

H0: µ(A) = µ(C)

Versus

H1: µ(A) ≠ µ(C)

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Where H0: and H1: are the null and alternative hypotheses, respectively and µ(A) and µ(C) 
represent the mean responses among patients receiving Active and Control treatment, 
respectively. 
9.2
Sample size determination 
Enrolment in this study is intended to yield approximately 500 patients randomised to 
treatment. This sample size estimate is based on the primary endpoints, KCCQ-TSS, KCCQ-
PLS, and 6MWD, as well as the assumption that mortality over the entire 16-week treatment 
period is about 5% in each treatment arm. 
 
 
 
 
 
 
 
 
 
9.3
Populations for analyses
9.3.1
Enrolled
All patients who sign the ICF will be included in the Enrolled Population.
9.3.2
Full analysis set
All patients representing the study inclusion/exclusion criteria and who have been randomised 
to IP will be included in the Full Analysis Set (FAS), irrespective of their protocol adherence, 
addition or modification of background rescue medications, switches to alternative 
medications, and continued participation in the study. Patients will be analysed according to 
their randomised IP assignment, irrespective of the treatment they actually received. The FAS 
will be considered the primary analysis set for the primary and secondary variables and for the 
exploratory efficacy variables.
9.3.3
Safety analysis set
All randomised patients who received at least 1 dose of randomised treatment will be included 
in the Safety Analysis Set. Patients will be analysed according to the treatment actually 
received. For any patients given incorrect treatment, ie, randomised to one of the treatment 

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groups, but actually given the other treatment, the treatment group will be allocated as 
follows: Patients who received both incorrect and correct treatment will be analysed according 
to their randomised treatment. Patients who received only the incorrect treatment will be 
analysed according to that treatment.
The Safety analysis set will be considered the primary analysis set for all safety variables.
9.4
Statistical analyses
9.4.1
Efficacy analyses
The primary and secondary efficacy endpoints will be evaluated under a combined treatment 
policy (intent-to-treat) and composite variable strategy estimand, including differences in the 
outcome variable at the end of the 16-week treatment period. The intent-to-treat approach is 
employed to reflect the effect of the initially assigned randomised study drug, irrespective of 
exposure to study drug, concomitant treatment as well as subsequent treatment after 
discontinuation of study drug. A composite variable strategy approach is employed to account 
for deaths occurring during the follow-up period.
9.4.1.1
Analysis of the primary efficacy variables
The primary efficacy endpoints are change from baseline in each of KCCQ-TSS, KCCQ-PLS, 
and 6MWD at Week 16. Each of these will be analysed based on a rank ANCOVA model 
with rank-based change from baseline at Week 16 as the outcome. The rank-based baseline 
value will be included as a covariate along with the stratification factor used in the 
randomisation; further details are available in the SAP. Ties will be assigned the mean of the 
corresponding ranks.
In this analysis, data that are missing due to death will be ranked “worse” than observed data 
and data missing for reasons other than death, and the ranking amongst the deceased patients 
will be based on last value while alive. Missing data due to reasons other than death (eg, 
missing visits, early withdrawal from the study, including lost to follow-up) will be replaced 
by multiple imputation with predictive mean matching. Rank ANCOVA will then be applied 
to each imputation dataset and results will be pooled. Sensitivity analyses will be performed to 
assess the robustness of the treatment effect from the handling of missing data and are 
described in detail in the SAP.
The mean difference in change from baseline 6MWD will also be presented, both as an 
absolute change and as a percentage of baseline.

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The magnitude of treatment effect in KCCQ-TSS and KCCQ-PLS will also be presented as 
the number and percentage of patients by treatment group across the following categories of 
change from baseline:

Death

Deterioration from baseline (change from baseline ≤-5)

Stable (-5< change from baseline <5)

Improvement (change from baseline ≥5)
The magnitude of treatment effect in 6MWD will also be presented as the number and 
percentage of patients by treatment group in the following categories of change from baseline:

Death

No improvement from baseline (change from baseline ≤0 metres)

Minimal improvement (0< change from baseline <30 metres)

Improvement (change from baseline ≥30 metres)
Clinical meaningfulness has not been demonstrated for the pre-specified categories. 
Therefore, thresholds for clinically meaningful within-patient change for KCCQ-TSS, KCCQ-
PLS, and 6MWD will be assessed using pre-specified methods described in the SAP and the 
derived thresholds will be the main categories used to assess the magnitude of treatment 
effect. 
To provide a visual display of the relative benefit of dapagliflozin over placebo across 
different ranges of response at Week 16, empirical cumulative distribution functions for each 
treatment group will be presented.
9.4.1.2
Analysis of the secondary efficacy variable
Analysis of endpoints using data retrieved from wearable activity monitors will be performed 
in the same way as for the primary endpoint family. Sensitivity analysis for the secondary 
endpoint is described in detail in the SAP.
Change in total time spent in light to vigorous physical activity from baseline to end of study, 
will be based on wearable activity monitor data collected at baseline and at the end of the 16-
week treatment period. Baseline will be measured for all subjects included in the FAS, at sites 
with wearable devices, over one week, between enrolment (Visit 1) and the first 
randomisation attempt (Visit 2a). Change from baseline will be measured over one week 
leading up to Week 16. At each time point, up to seven days of wearable activity monitor data 
will be analysed. Empirical cumulative distribution functions will be presented to show the 
individual-level effects across a range of definitions of responders at Week 16. The threshold 

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for clinically meaningful within-patient change will be evaluated using a completely pre-
specified algorithm with anchor-based methods, the details of which are described in the SAP.
9.4.2
Safety analyses
All safety analyses will be performed on the Safety Analysis Set. Safety data will be 
summarised descriptively and will not be formally tested. Patients who received IP which is 
not consistent with the treatment he or she was randomised to receive will also be listed.
The numbers and percentages of patients with AEs, SAEs, DAEs, AEs leading to amputations, 
and potential preceding events for lower limb amputations will be summarised by treatment 
group, and by system organ class and preferred term.
For safety analyses, summaries will be provided using both on-treatment observations and for 
pre-specified safety variables using all observations, regardless of whether patients are on or 
off IP.
Details of the analysis and presentation of data for other safety variables (physical 
examination findings, systolic and diastolic blood pressure, pulse rate, body weight, and 
clinical safety laboratory assessments) will be provided in the SAP.
9.4.3
Other analyses 
Exploratory analyses, including subgroup analyses, will not be controlled for multiplicity. 
Details of the analyses planned for the exploratory endpoints (Table 2) and a list of subgroup 
variables and categories, are described in the SAP.
PK analyses and results will be presented separately from the main clinical study report.
9.4.4
Methods for multiplicity control
The type I error rate will be controlled to support superiority claims for dapagliflozin 
compared with placebo. The overall type I error (alpha) will initially be split between the 
KCCQ-TSS, KCCQ-PLS, and 6MWD. Testing will proceed to the secondary endpoint if 
statistical significance is demonstrated for at least 1 endpoint in the primary endpoint family. 
The multiplicity testing procedure will be described in detail in the SAP.
9.5
Interim analyses
Given the short duration of the study, an interim analysis will not be performed.
9.5.1
Data monitoring committee
A data monitoring committee will not be used for this study because of the short study 
duration and the accumulated safety profile of dapagliflozin.

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Diabetes Complications 2017;31(7):1215-21.
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;9:e002560.
Lam et al 2011
Lam CSP, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart 
failure with preserved ejection fraction. European Journal of Heart Failure 2011;13:18–28.
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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.
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Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al, for the 
CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in 
type 2 diabetes. 2017; 377:644-57.
O’Keeffe et al 1998
O’Keeffe ST, Lye M, Donnnellan C, Carmichael DN. Reproducibility and responsiveness of 
quality of life assessment and six-minute walk test in elderly heart failure patients. Heart 
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Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection 
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Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC 
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Rådholm et al 2018
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Change in the Six-minute Walk Test in Individuals with Chronic Heart Failure: A Systematic 
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Shoemaker MJ, Curtis AB, Vangsnes E, Dickinson MG. Clinically Meaningful Change 
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Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. 
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed consent process

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The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. 
Subjects or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF. Subjects must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative. 
If a subject declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the subject and he/she will not be 
excluded from other aspects of the study.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorised designee will 
explain to each subject the objectives of the exploratory research. Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The subject will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Subjects who decline to participate 
in this optional research will indicate this in the ICF. If a subject withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analysed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
A 4
Data protection
Each subject will be assigned a unique identifier by the Sponsor. Any subject records or data 
sets transferred to the Sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 

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The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
There will not be a data monitoring committee in this study because of the short duration of 
the study and the accumulated safety profile of dapagliflozin.
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded in the eCRF unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 

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Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of AEs
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of SAE
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent 1of the outcomes listed above
B 3
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.

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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the subject or may require 
medical treatment to prevent 1 or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
B 6
Intensity rating scale
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to interpreting the causality question
When making an assessment of causality, consider the following factors when deciding 
whether there is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course:  Exposure to suspect drug. Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

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
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 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 recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or participant.

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Medication error includes situations where an error:  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IxRS errors)

Wrong drug administered to participant (excluding IxRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IxRS - including those which lead to 1 of the above 
listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of human biological samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.

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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, 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 eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient

temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)

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.

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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may affect a subject’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
affect drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting subjects.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically-guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, ie, the 
entire genome. 
The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on HF with preserved ejection fraction continues 
but no longer than 15 years or other period in accordance with local requirements.
D 2
Genetic research plan and procedures
SELECTION OF GENETIC RESEARCH POPULATION
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.

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Inclusion criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and provide informed consent for the genetic 
sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Withdrawal of consent for genetic research  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2a or 
Visit 2b (Randomisation A or Randomisation B), as applicable. Although DNA is stable, early 
sample collection is preferred to avoid introducing bias through excluding subjects who may 
withdraw due to an AE; such subjects would be important to include in any genetic analysis. If 
for any reason the sample is not drawn at Visit 2, it may be taken at any visit until the last 
study visit. Only 1 sample should be collected per subject for genetics during the study. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).

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The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study. A copy of the signed and dated 
consent form must be given to the patient and the original filed at the study centre. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease. The researchers can 

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only use this information for health-related research purposes. Researchers may see summary 
results, but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A SAP may be 
prepared where appropriate.

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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL). It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug induced liver injury caused by the IP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2×ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP). 
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 ×ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases

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In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
The Investigator will remain vigilant for any local laboratory reports where the identification 
criteria are met; where this is the case the Investigator will:

Notify the AstraZeneca representative,

Request a repeat of the test (new blood draw),

Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result.
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.
E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.

Complete the 3 Liver CRF Modules as information becomes available

If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s Law cases

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The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP. 
The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AstraZeneca standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.

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Appendix F
Medical device incidents: definition and procedures for 
recording, evaluating, follow-up, and reporting (not 
applicable)

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Appendix G
Abbreviations 
Abbreviation or special 
term
Explanation
AE
adverse event
ANCOVA
Analysis of covariance
ATS
American Thoracic Society
CKD-EPI
chronic kidney disease epidemiology collaboration (formula)
COPD
chronic obstructive pulmonary disease
(e)CRF
(electronic) case report form
CTCAE
Common Terminology Criteria for Adverse Event
DAE
adverse event leading to discontinuation of investigational product
DKA
diabetic ketoacidosis
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
EQ-5D-5L
European Quality of Life 5-dimension, 5-level health status questionnaire
FAS
Full Analysis Set
GCP
Good Clinical Practice
HbA1c
glycated haemoglobin
HF
heart failure
HFpEF
heart failure with preserved left ventricular ejection fraction
HFrEF
heart failure with reduced left ventricular ejection fraction
ICF
informed consent form
ICH
International Conference for Harmonisation
IEC
Independent ethics committee
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. 
IRB
Institutional review board
IxRS
interactive voice/web response system
KSSQ
Kansas City Cardiomyopathy Questionnaire
LVEF
left ventricular ejection fraction
MET
metabolic equivalent of task
MRI
magnetic resonance imaging
6MWD
6-minute walk distance
6MWT
6-minute walk test
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association

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Abbreviation or special 
term
Explanation
OTB
overall treatment benefit
PerfO
Performance outcome
PGIC
patient global impression of change
PGIS
patient global impression of severity
PK
pharmacokinetic
PLS
physical limitation score
(e)PRO
(electronic) patient-reported outcome
QoL
Quality of Life 
SAE
serious adverse event 
SAP
statistical analysis plan
SGLT2
Sodium-glucose co-transporter-2 
T2DM
Type 2 diabetes mellitus
TSS
total symptom score

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Appendix H
The Kansas City Cardiomyopathy Questionnaire

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Appendix I
Patient Global Impression of Severity in 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

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Appendix J
Patient Global Impression of Change in 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

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Appendix K
Patient Global Impression of Change in Walking Ability
Overall, how would you rate the change in your walking ability since starting this study?
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse

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Appendix L
Patient Rating of Dyspnoea
Overall, how would you rate your shortness of breath in the past 7 days?
0
1
2
3
4
5
6
7
8
9
10
No 
shortness 
of breath
As bad as 
you can 
imagine

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Appendix M Patient Rating of Fatigue
Overall, how would you rate your fatigue in the past 7 days?
0
1
2
3
4
5
6
7
8
9
10
No 
fatigue
As bad as 
you can 
imagine

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Appendix N
European Quality of Life EQ-5D-5L Questionnaire

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Appendix O
Patient Overall Treatment Benefit
Thinking about both the positive and negative aspects of the study medication, the benefits of 
the study medication were:

much greater than the negative effects

somewhat greater than the negative effects

equal to the negative effects

somewhat less than the negative effects

much less than the negative effects
If you had the option, would you continue taking the study medication after the study ends?

Yes

Unsure

No

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Appendix P
The Borg CR10 Scale®

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At the beginning of the 6MWT the investigator shows the Borg CR10 Scale® to the patient 
(on paper) and asks the patient: “Please grade your perceived level of shortness of breath 
using this scale”. Then the investigator asks: “Please grade your perceived level of fatigue 
using this scale”. At the end of the 6MWT, the investigator reminds the patient of the 
breathing number that they chose before the exercise and asks the patient to grade their 
breathing level again. Then the investigator asks the patient to grade their level of fatigue, 
after reminding them of their grade before the exercise.

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Appendix Q
New York Heart Association Functional Classification

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Title:
D169EC00001 Clinical Study Protocol version 3
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
06-Mar-2020 23:23 UTC
Content Approval
05-Mar-2020 22:35 UTC
Content Approval
06-Mar-2020 12:03 UTC
Content Approval
06-Mar-2020 09:40 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.