Clinical trial NCT03877237
Conditions: Heart Failure With Reduced Ejection Fraction (HFrEF)
Sponsor: AstraZeneca
Start date: 2019-04-09; Completion date: 2020-03-07
Enrollment: 313 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 Reduced Ejection Fraction (HFrEF)

Detailed description:

Arms: arm 1: Green, diamond shaped, film coated tablets 10 mg administered orally, once daily arm 2: Green, diamond shaped, film coated tablets placebo administered orally, once daily
Interventions: intervention 1: Dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks. intervention 2: Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol - 2.0
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Clinical Study Protocol 
Drug Substance
Dapagliflozin
Study Code
D169EC00002
Version
2.0
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 Reduced Ejection Fraction 
(HFrEF)
Short Title: DETERMINE-reduced – Dapagliflozin EffecT on ExeRcise 
capacity using a 6-MINutE walk test in patients with heart failure with 
reduced ejection fraction
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): EudraCT 2018-003442-16


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VERSION HISTORY
Version 1.0
15 January 2019
Initial creation
Version 2.0
4 March 2020
The main purpose of this amendment was to add 2 primary objectives 
to the study (ie, reduction in HF symptoms and reduction in 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. Some secondary 
objectives became exploratory objectives and other exploratory 
endpoints were revised. 
Clarifications were also made to text unrelated to the endpoints.
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): Two additional 
primary efficacy objectives/endpoints were added (ie, KCCQ-TSS 
and KCCQ-PLS) to create a primary endpoint family. Some 
secondary objectives became exploratory and certain exploratory 
objectives/endpoints were reordered and rephrased.
Section 4 (STUDY DESIGN): Updated to reflect changes in the 
objectives/endpoints as detailed in Section 3. 
Explanation/clarification was added for the choice of primary 
endpoints.
Section 6.3.1.2 (Capping): Updated to allow it on a level lower 
than the whole study.


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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 8.1 (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
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 4
LIST OF TABLES................................................................................................................ 7
LIST OF FIGURES .............................................................................................................. 7
LIST OF APPENDICES....................................................................................................... 7
1
PROTOCOL SUMMARY.................................................................................. 8
1.1
Schedule of Activities......................................................................................... 8
1.2
Synopsis ........................................................................................................... 14
1.3
Schema............................................................................................................. 20
2
INTRODUCTION............................................................................................ 21
2.1
Study rationale.................................................................................................. 21
2.2
Background ...................................................................................................... 22
2.3
Benefit/risk assessment..................................................................................... 23
2.3.1
Potential risks to patients .................................................................................. 23
2.3.1.1
Protection against risks ..................................................................................... 24
2.3.2
Potential benefits to patients ............................................................................. 24
2.3.3
Conclusion........................................................................................................ 24
3
OBJECTIVES AND ENDPOINTS................................................................... 25
4
STUDY DESIGN ............................................................................................. 27
4.1
Overall design................................................................................................... 27
4.2
Scientific rationale for study design .................................................................. 27
4.3
Justification for dose......................................................................................... 29
4.4
End of study definition...................................................................................... 30
5
STUDY POPULATION ................................................................................... 30
5.1
Inclusion criteria............................................................................................... 31
5.2
Exclusion criteria.............................................................................................. 33
5.3
Lifestyle restrictions (not applicable) ................................................................ 35
5.4
Screen failures .................................................................................................. 35
6
STUDY TREATMENTS.................................................................................. 36
6.1
Treatments administered................................................................................... 36
6.1.1
Investigational products.................................................................................... 36
6.2
Preparation/handling/storage/accountability...................................................... 36
6.3
Measures to minimise bias: randomisation and blinding.................................... 37
6.3.1
Stratification and capping ................................................................................. 38
6.3.1.1
Stratification..................................................................................................... 38


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6.3.1.2
Capping ............................................................................................................ 38
6.4
Treatment compliance....................................................................................... 39
6.5
Concomitant therapy......................................................................................... 39
6.5.1
Prohibited medications...................................................................................... 39
6.5.2
Background medication .................................................................................... 40
6.5.2.1
Heart failure background standard of care......................................................... 40
6.5.2.2
Anti-diabetes background treatment for patients with T2DM ............................ 40
6.5.3
Other concomitant treatment............................................................................. 40
6.6
Dose modification (not applicable) ................................................................... 41
6.7
Treatment after the end of the study.................................................................. 41
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 41
7.1
Discontinuation of investigational product........................................................ 41
7.1.1
Temporary discontinuation ............................................................................... 41
7.1.1.1
Unexpected acute declines in eGFR.................................................................. 41
7.1.1.2
Volume depletion/hypotension.......................................................................... 42
7.1.1.3
Patients at risk of volume depletion................................................................... 42
7.1.2
Rechallenge ...................................................................................................... 42
7.1.3
Procedures for discontinuation of investigational product ................................. 42
7.2
Lost to follow-up .............................................................................................. 43
7.3
Withdrawal from the study................................................................................ 43
7.4
Discontinuation of the study ............................................................................. 44
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 45
8.1
Efficacy assessments......................................................................................... 53
8.1.1
Clinical outcome assessment............................................................................. 53
8.1.1.1
6MWD ............................................................................................................. 54
8.1.1.2
Patient-reported outcomes................................................................................. 55
8.1.2
Oxygen saturation............................................................................................. 57
8.1.3
Physical activity measured at home (accelerometer, Monitor B)........................ 58
8.1.4
Serum NT-proBNP........................................................................................... 58
8.1.5
New York Heart Association Functional Classification..................................... 58
8.2
Safety assessments............................................................................................ 59
8.2.1
Physical examination ........................................................................................ 59
8.2.2
Electrocardiograms........................................................................................... 59
8.2.3
Vital signs......................................................................................................... 59
8.2.4
Body weight, height and waist circumference ................................................... 60
8.2.5
Clinical safety laboratory assessments............................................................... 60
8.2.6
Other safety assessments................................................................................... 61
8.3
Collection of adverse events ............................................................................. 61
8.3.1
Method of detecting AEs and SAEs .................................................................. 61
8.3.1.1
AEs leading to amputation, and potential risk-factor AEs for amputations 
affecting lower limbs (‘preceding events’) ........................................................ 62
8.3.1.2
DKA events...................................................................................................... 62
8.3.1.3
Capture of additional laboratory values............................................................. 62


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8.3.2
Time period and frequency for collecting AE and SAE information.................. 63
8.3.3
Follow-up of AEs and SAEs ............................................................................. 63
8.3.4
AE data collection............................................................................................. 63
8.3.5
Causality collection........................................................................................... 64
8.3.6
AEs based on signs and symptoms.................................................................... 64
8.3.7
AEs based on examinations and tests ................................................................ 64
8.3.8
Hy’s Law.......................................................................................................... 65
8.3.9
Disease-under study (not applicable)................................................................. 65
8.3.10
Disease progression (not applicable) ................................................................. 65
8.4
Safety reporting and medical management........................................................ 65
8.4.1
Reporting of SAEs............................................................................................ 65
8.4.2
Pregnancy and maternal exposure ..................................................................... 66
8.4.3
Overdose .......................................................................................................... 66
8.4.4
Medication error ............................................................................................... 67
8.5
Pharmacokinetics.............................................................................................. 67
8.5.1
Determination of drug concentration................................................................. 68
8.5.2
Storage and destruction of pharmacokinetic samples......................................... 68
8.6
Pharmacodynamics (not applicable).................................................................. 68
8.7
Genetics............................................................................................................ 68
8.7.1
Collection of mandatory genetic samples (not applicable)................................. 68
8.7.2
Optional exploratory genetic sample ................................................................. 68
8.7.3
Storage and destruction of genetic samples ....................................................... 69
8.8
Biomarkers (not applicable).............................................................................. 69
8.9
Health economics (not applicable) .................................................................... 69
9
STATISTICAL CONSIDERATIONS............................................................... 69
9.1
Statistical hypotheses........................................................................................ 69
9.2
Sample size determination ................................................................................ 70
9.3
Populations for analyses.................................................................................... 70
9.3.1
Enrolled............................................................................................................ 70
9.3.2
Full analysis set ................................................................................................ 70
9.3.3
Safety analysis set............................................................................................. 70
9.4
Statistical analyses............................................................................................ 71
9.4.1
Efficacy analyses .............................................................................................. 71
9.4.1.1
Analysis of the primary efficacy variables......................................................... 71
9.4.1.2
Analysis of the secondary efficacy variable....................................................... 72
9.4.2
Safety analyses ................................................................................................. 73
9.4.3
Other analyses .................................................................................................. 73
9.4.4
Methods for multiplicity control ....................................................................... 73
9.5
Interim analyses................................................................................................ 73
9.5.1
Data Mmonitoring committee ........................................................................... 73
10
REFERENCES................................................................................................. 74
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 78


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LIST OF TABLES
Table 1
Schedule of activities................................................................................. 9
Table 2
Study objectives....................................................................................... 25
Table 3
Study treatments ...................................................................................... 36
LIST OF FIGURES
Figure 1
Study design............................................................................................ 20
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 79
Appendix B
Adverse event definitions and additional safety information .................... 83
Appendix C
Handling of human biological samples .................................................... 87
Appendix D
Genetics................................................................................................... 89
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 93
Appendix F
Medical device incidents: definition and procedures for recording, 
evaluating, follow-up, and reporting (not applicable) ............................... 96
Appendix G
Abbreviations .......................................................................................... 97
Appendix H
The Kansas City Cardiomyopathy Questionnaire ..................................... 99
Appendix I
Patient Global Impression of Severity in Heart Failure Symptoms ......... 104
Appendix J
Patient Global Impression of Change in Heart Failure Symptoms .......... 105
Appendix K
Patient Global Impression of Change in Walking Ability....................... 106
Appendix L
Patient Rating of Dyspnoea.................................................................... 107
Appendix M
Patient Rating of Fatigue........................................................................ 108
Appendix N
European Quality of Life EQ-5D-5L Questionnaire ............................... 109
Appendix O
Patient Overall Treatment Benefit.......................................................... 112
Appendix P
The Borg CR10 Scale® ......................................................................... 113
Appendix Q
New York Heart Association Functional Classification.......................... 116


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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 call reminding 
patient to wear activity monitor 
B #3 and return it at Visit 5 
(Final Visit); and hold IP dose 
until at Visit 5 (Final Visit)
X
Check IP compliance
X
X
X
Collect unused IP
X
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)
AEs n
X
X
X
X
X
X
X
Sections 8.3 & 
8.4
a
Only patients with a difference in 6MWD >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.
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.
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.
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.


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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 ≤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).
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 ≤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. 
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.
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
United Kingdom
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 Reduced Ejection Fraction (HFrEF)
Short Title:
DETERMINE-reduced - Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE walk 
test in patients with heart failure with reduced 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 reduced 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 reduced ejection fraction 
(LVEF≤40%) [HFrEF] 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 
HFrEF
•
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; HFrEF  
heart failure with reduced 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 left ventricular reduced 
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 ≥18 years with chronic heart failure with reduced left ventricular ejection 
fraction (≤40% determined by echocardiogram, radionuclide ventriculogram, contrast 


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ventriculography, or cardiac magnetic resonance imaging) and NYHA Functional 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 600 patients 
will need to be enrolled to reach the target of approximately 300 randomised patients.
Study period
Estimated date of first patient enrolled Q1 2019.
Estimated date of last patient completed Q1 2020.
Number of patients
Approximately 600 patients will be enrolled to reach a target of approximately 
300 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 300 patients (approximately 150 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 300 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
Despite advances in the management and treatment of Chronic heart failure (HF) with reduced 
ejection fraction (HFrEF), 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 
former. For the purposes of this study, HFrEF is defined as LVEF ≤40%.
Risk of death for HFrEF patients is high (Shah et al 2017). 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 
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 


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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 HFrEF.
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 HFrEF 
patients (as a surrogate measure of daily activity) irrespective of diabetes status. Dapagliflozin 
lowers glycated haemoglobin (HbA1c) with a low risk of inducing hypoglycaemia. Possible 
mechanisms of SGLT2 inhibitor benefit in patients with HF could include osmotic diuresis 
and reduction in arterial stiffness, weight, systolic blood pressure, serum uric acid and 
albuminuria, conditions which are associated with increased cardiovascular and renal risk 
(Shigiyama et al 2017). Other potential mediators include a shift in fat oxidation and increased 
circulating concentrations of ketone bodies which may serve as a more sufficient fuel source 
for the failing heart (Ferrannini et al 2016). The alterations in haemodynamics and renal 
physiology are attributed to glucose-independent mechanisms and can therefore be expected 
to be similar even in the absence of diabetes (Rajasekeran et al 2016); dapagliflozin is 
believed to be nephroprotective through non-glycaemic mechanisms (Wanner et al 2016) 
which may reduce HF risk.
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 HFrEF 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.


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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 HFrEF 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 HFrEF, 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) 
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 


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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.
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 HFrEF. This clinical study will test the hypothesis that 


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dapagliflozin is superior to placebo in reducing patient-reported HF symptoms, reducing 
physical limitation, or improving exercise capacity in patients with HFrEF, with or without 
T2DM, in a rigorous fashion. The results could offer substantial benefit to patients with 
HFrEF, 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 reduced ejection fraction 
(LVEF≤40%) [HFrEF] 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 
HFrEF
•
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.


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Table 2
Study objectives
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.
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; HFrEF  
heart failure with reduced 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 


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4
STUDY DESIGN
4.1
Overall design
This is an international, multi-centre, parallel-group, randomised, double-blind, 
placebo-controlled, phase III study in HFrEF 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 HFrEF (defined in this study as LVEF ≤40% as diagnosed by 
echocardiogram, radionuclide ventriculogram, contrast ventriculography, or cardiac magnetic 
resonance imaging [MRI]) and New York Heart Association (NYHA) Functional Class II-IV, 
aged ≥18 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 
600 patients will need to be enrolled to reach the target of approximately 300 randomised 
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 atrial fibrillation status 
will be monitored to ensure they are representative.
The control group will receive matching placebo. All patients will be treated according to 
local guidelines on standard of care treatment for patients with HFrEF (either an 
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sacubitril/valsartan in combination with beta-blocker, as well as mineralocorticoid receptor 
antagonist where appropriate unless contraindicated or not tolerated), as well as,  treatment of 
HF symptoms (eg, diuretics) and co-morbidities (including treatment for high blood pressure, 
ischaemic heart disease, and atrial fibrillation). 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 
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 


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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 HFrEF. Slightly higher systemic exposure to 
dapagliflozin is expected in HFrEF patients when symptomatic, based on the dual renal and 
hepatic metabolism of dapagliflozin and the lower perfusion of these organs in this patient 
group. However, the increase in systemic exposure of 10 mg dapagliflozin is not anticipated to 
warrant dose adjustment in HF patients. Moreover, the anticipated slightly higher systemic 
exposure to dapagliflozin is likely to be beneficial in HF patients, by compensating for the 
reduced renal perfusion and consequently lower renal glucose and sodium filtered loads in 
these patients. Doses lower than 10 mg are therefore unlikely to provide as much benefit to 
patients with HF as the 10-mg dose. Lastly, no changes in dose of concomitant medications in 
the HFrEF 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 HFrEF, 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).
The recently completed (September 2018) pivotal study DECLARE-TIMI 58 (D1693C00001) 
assessed cardiovascular outcomes in 17160 patients with T2D and used a dose of 10 mg 


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dapagliflozin, the topline results from which suggest a reduction in the composite endpoint of 
CV death and hospitalisation for HF in favour of dapagliflozin versus placebo.
Current research therefore suggests that selecting a 10-mg dose of dapagliflozin is reasonable 
from the perspective of tolerability and 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 
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.


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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 ≥18 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.
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% (echocardiogram, radionuclide ventriculogram, contrast ventriculography, or 
cardiac MRI) 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 LV 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 
                                               
1 Typical symptoms associated with heart failure: breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, 
reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling;
Signs associated with HF: 
More specific: elevated jugular venous pressure, hepatojugular reflex, third heart sound (gallop rhythm), laterally 
displaced apical impulse.
Less specific: weight gain (>2 kg/week), weight loss (in advanced HF), tissue wasting (cachexia), cardiac 
murmur, peripheral oedema (ankle, sacral, scrotal), pulmonary crepitations, reduced air entry and dullness to 
percussion at lung bases (pleural effusion), tachycardia, irregular pulse, tachypnoea, cheyne stokes respiration, 
hepatomegaly, ascites, cold extremities, oliguria, narrow pulse pressure.


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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 ≥400 pg/mL (≥47.24 pmol/L) (or if hospitalised for HF within the previous 
12 months: NT-proBNP ≥300 pg/mL [35.43 pmol/L]) at Visit 1 (Enrolment). If 
concomitant atrial fibrillation at Visit 1, NT-pro-BNP must be ≥800 pg/mL 
(≥94.54 pmol/L) (irrespective of history of heart failure hospitalisation).
6
Patients should receive background standard of care as described below:
All HFrEF patients should be treated according to locally recognised guidelines on standard of 
care treatment with both drugs and devices, as appropriate.  Guideline-recommended 
medications should be used at recommended doses unless contraindicated or not tolerated.  
Therapy should have been individually optimised and stable for ≥4 weeks (this does not apply 
to diuretics - see Note below) before visit 1 and include (unless contraindicated or not 
tolerated):

an ACE inhibitor, or ARB or sacubitril/valsartan
and

a beta-blocker
and

if considered appropriate by the patient's treating physician; a mineral corticoid receptor 
antagonist
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.
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 


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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.
If the 6MWD is outside of ≥100 metres and ≤425 metres at any visit, 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.
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.


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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 (Enrolment), or at Visit 2a or Visit 2b (Randomisation A or 
Randomisation B).
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 
flutter/fibrillation, 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 flutter/fibrillation 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).


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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 
(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.


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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.
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 applicable.
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.


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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 
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 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.


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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.
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 HFrEF 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.

Atrial fibrillation status: the proportion of patients with atrial fibrillation will be 
monitored to ensure a representative proportion in the study.


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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.
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 HFrEF and existing 
co-morbidities (including treatment for hypertension, ischemic heart disease, atrial fibrillation, 
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 


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with a SGLT2-inhibitor alone or in combination is deemed essential, IP must be discontinued 
before that treatment is started. 
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 HFrEF.
Patients’ background standard of care therapies for HFrEF 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 (full 
details are found in inclusion criterion #6). 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.


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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. 
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, the patient should be evaluated 
and temporary interruption of IP should be considered. Volume depletion, hypotension, 
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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.
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 MRI, 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 MRI, 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 
assessment: 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 
assessment: 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.
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 
assessment: NT-proBNP, sodium, potassium, creatinine (for calculation of eGFR), 
haematocrit and HbA1c, which will all be carried out at a central laboratory. All 


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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 Study 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 
assessment: 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.

Systolic and diastolic blood pressure and pulse rate will be measured 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 
assessment: 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

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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 the 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 600 patients of which 
approximately 300 patients will be randomised 1:1 to each 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 


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received. For any patients given incorrect treatment, ie, randomised to one of the treatment 
groups, but actually given the other treatment, the treatment group will be allocated as 
follows: Patients who 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 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.
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 Mmonitoring 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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10
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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.


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A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. 
Subjects or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF. Subjects must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative. 
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. 


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The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
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 


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being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the 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 refrigerator 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 reduced 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 Statistical 
Analysis Plan 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.


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E 3
Identification of potential Hy’s Law cases
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.


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E 5
Review and assessment of potential Hy’s Law cases
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
CSP
clinical study protocol
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


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Abbreviation or special 
term
Explanation
NYHA
New York Heart Association
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:
D169EC00002 Clinical Study Protocol version 2
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
06-Mar-2020 23:25 UTC
Content Approval
05-Mar-2020 22:32 UTC
Content Approval
06-Mar-2020 12:07 UTC
Content Approval
06-Mar-2020 09:41 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
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Statistical Analysis Plan
Study Code
D169EC00002
Edition Number
3.0
Date
12 August 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 Reduced Ejection Fraction (HFrEF)


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
LIST OF ABBREVIATIONS ............................................................................................... 5
AMENDMENT HISTORY................................................................................................... 7
1
STUDY DETAILS ........................................................................................... 10
1.1
Study objectives................................................................................................ 10
1.1.1
Primary objective.............................................................................................. 10
1.1.2
Secondary objective.......................................................................................... 10
1.1.3
Safety objective ................................................................................................ 11
1.1.4
Exploratory objectives ...................................................................................... 11
1.2
Study design ..................................................................................................... 13
1.2.1
Randomisation.................................................................................................. 14
1.2.2
Number of subjects........................................................................................... 15
2
ANALYSIS SETS ............................................................................................ 16
2.1
Definition of analysis sets................................................................................. 16
2.1.1
Full analysis set ................................................................................................ 16
2.1.2
Safety analysis set............................................................................................. 16
2.2
Violations and deviations.................................................................................. 16
2.2.1
Deviations related to COVID-19....................................................................... 17
3
PRIMARY AND SECONDARY VARIABLES ............................................... 17
3.1
General definitions............................................................................................ 17
3.1.1
Definition of baseline........................................................................................ 17
3.1.2
Change from baseline ....................................................................................... 18
3.1.3
Visit windows................................................................................................... 19
3.1.4
Baseline and concomitant medication ............................................................... 20
3.2
Efficacy variable............................................................................................... 20
3.2.1
Primary efficacy variable .................................................................................. 20
3.2.2
Secondary efficacy variable .............................................................................. 22
3.2.3
Exploratory variables........................................................................................ 23
3.2.3.1
Change from baseline at week 16 in NT-proBNP.............................................. 23
3.2.3.2
Proportion of patients with worsened NYHA Functional Classification from 
baseline at week 16........................................................................................... 23
3.2.3.3
Change or relative change from baseline at end of study or week 16 in 
exploratory endpoints assessed using the wearable activity monitors................. 23
3.2.3.4
Change from baseline at week 16 in EQ-5D-5L ................................................ 24
3.2.3.5
Change from baseline at week 16 in dyspnoea and fatigue ................................ 25
3.2.3.6
Distribution of OTB at week 16........................................................................ 25
3.2.3.7
Change from baseline at week 16 in KCCQ domains ........................................ 25
3.2.3.8
Change from baseline at week 16 in oxygen saturation ..................................... 26
3.2.3.9
Change from baseline at week 16 in systolic BP ............................................... 26


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3.2.3.10
Change from baseline at week 16 in body weight.............................................. 26
3.2.3.11
Change from baseline at week 16 in eGFR........................................................ 27
3.3
Safety variables ................................................................................................ 27
3.3.1
Adverse events.................................................................................................. 27
3.3.2
Laboratory values ............................................................................................. 28
3.3.3
Vital signs......................................................................................................... 28
3.3.4
Physical examination ........................................................................................ 29
4
ANALYSIS METHODS................................................................................... 29
4.1
General principles............................................................................................. 29
4.1.1
Estimand for primary and secondary variables .................................................. 29
4.1.2
Hypotheses ....................................................................................................... 30
4.1.3
Confirmatory testing procedure......................................................................... 30
4.1.4
Incomplete dates............................................................................................... 34
4.1.5
Study drug compliance ..................................................................................... 36
4.2
Analysis methods.............................................................................................. 36
4.2.1
Subject disposition............................................................................................ 36
4.2.2
Demographic and baseline characteristics ......................................................... 36
4.2.3
Baseline and concomitant medication ............................................................... 36
4.2.4
Analysis of the primary efficacy variables......................................................... 36
4.2.4.1
Sensitivity analysis of the primary efficacy endpoints ....................................... 41
4.2.4.2
Supplementary analysis of primary efficacy endpoints...................................... 41
4.2.4.3
Subgroup analysis of the primary efficacy endpoints......................................... 42
4.2.5
Analysis of secondary efficacy variable ............................................................ 43
4.2.6
Analysis of safety variables............................................................................... 44
4.2.6.1
Adverse events.................................................................................................. 45
4.2.6.2
Serious adverse events (SAE) ........................................................................... 45
4.2.6.3
Adverse events leading to discontinuation (DAE) ............................................. 45
4.2.6.4
Amputations and preceding events.................................................................... 45
4.2.6.5
Laboratory evaluation....................................................................................... 45
4.2.6.6
Marked laboratory abnormalities....................................................................... 46
4.2.6.7
Vital signs......................................................................................................... 46
4.2.7
Analysis of exploratory efficacy endpoints........................................................ 47
5
INTERIM ANALYSES (NOT APPLICABLE) ................................................ 48
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 48
7
REFERENCES................................................................................................. 48
8
APPENDIX ...................................................................................................... 53
8.1
Accounting for missing data ............................................................................. 53
8.2
Wearable activity monitors ............................................................................... 55
8.3
Anchor-based analyses...................................................................................... 62
8.4
KCCQ scoring algorithm .................................................................................. 68


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LIST OF TABLES
Table 1 Visit windows ........................................................................................................ 19
Table 2 Marked abnormality criteria for safety laboratory variables .................................... 46
Table 3 Vital signs reference ranges.................................................................................... 47
Table 4 Endpoints based on data from wearable activity monitors....................................... 56
Table 5 Definition of transformed and raw numeric change from baseline values for PGIS 
in HF symptoms ...................................................................................... 64
Table 6 Definition of transformed and raw numeric change from baseline values for EQ-
5D-5L question: "Usual activities"........................................................... 66
LIST OF FIGURES
Figure 1 Study flow chart.................................................................................................... 14
Figure 2 Multiple testing strategy for three primary efficacy endpoints and secondary 
efficacy endpoint ..................................................................................... 33


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
6MWD
6-minute walk distance
6MWT
6-minute walk test
AE
Adverse event
AF
Atrial fibrillation/flutter 
ANCOVA
Analysis of covariance
ATC
Anatomical therapeutic chemical
BP
Blood pressure
CKD-EPI
Chronic kidney disease epidemiology collaboration equation
CMH
Cochran-Mantel-Haenszel test
CMWPC
Clinically meaningful within-patient change
COVID-19
Corona virus disease 2019
CSP
Clinical study protocol
CSR
Clinical study report
CV
Cardiovascular
DAE
Adverse event leading to discontinuation of investigational product
DKA
Diabetic ketoacidosis
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EQ-5D-5L
EuroQol five-dimensional five-level questionnaire
ePRO
Electronic patient-reported outcome
FAS
Full analysis set
FWER
Family wise error rate
HF
Heart failure
HFrEF
Heart failure with reduced ejection fraction
HL
Hodges-Lehmann
IP
Investigational product (dapagliflozin or matching placebo)
ITT
Intention to treat
IxRS
Interactive voice/web response system
KCCQ
Kansas city cardiomyopathy questionnaire
LVEF
Left ventricular ejection fraction
LVPA
Light to vigorous physical activity
MedDRA
Medical dictionary for regulatory activities


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Abbreviation or special 
term
Explanation
METs
Metabolic Equivalent of Task units
MI
Multiple imputation
MRI
Magnetic resonance imaging
MVPA
Moderate to vigorous physical activity
NC
Not calculable
NT-proBNP 
N-terminal pro b-type natriuretic peptide
NYHA
New York heart association
OTB
Overall treatment benefit
PGIS
Patient global impression of severity
PGIC
Patient global impression of change
PLS
Physical limitation score
PK
Pharmacokinetic
PRO
Patient-reported outcome
PT
MedDRA preferred term
PTDV
Premature treatment discontinuation visit
Q1
First quartile
Q3
Third quartile
QoL
Quality of life
SAE
Serious adverse event
SAP
Statistical analysis plan
SI
The international system of units
SOC
MedDRA system organ class
T2DM
Type 2 diabetes mellitus
TPA
Tipping point analysis
TSS
Total symptom score
VAS
Visual analogue scale
VMUs
Vector magnitude units
WHO
World health organisation


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AMENDMENT HISTORY
Date
Brief description of change
13 May 2020 / 
Version 2.0
Updated according to CSP amendment.
Amended to reflect the following (editorial updates are not listed):

The formal primary (6MWD), key secondary (KCCQ-TSS) and 
exploratory (KCCQ-PLS) objectives were modified into three 
primary objectives.

The hypothesis testing strategy was changed from a fixed sequence 
approach to a weighted Bonferroni approach, allocating alpha 
between the primary and secondary efficacy endpoint families.

Changed secondary efficacy endpoints, including vector magnitude 
units per minute, serum NT-proBNP, movement intensity during 
walking, and NYHA functional classification, to be exploratory 
endpoints.

Atrial fibrillation was changed to atrial fibrillation/flutter.

Exploratory endpoints, PGIS in HF symptoms, PGIC in HF 
symptoms, PGIC in walking ability, and BORG CR10 Scale@ for 
perceived dyspnoea and fatigue during 6MWT, were removed. 
PGIS and PGIC are intentionally simple instruments designed for 
use in anchor-based analyses and not for comparing treatment 
groups.

Missing data at baseline will be imputed assuming it is missing at 
random and clarification was added regarding which efficacy 
variables undergo multiple imputation.

Derivation of visit-specific summaries for MoveMonitor 
measurements was clarified.

Added the probability distribution function curves to anchor-based 
analyses.


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12 August 2020 / 
Version 3.0
Amended to reflect the following (editorial updates are not listed):

Statistical power was re-estimated for a comparison of group-level 
averages of within-patient change, instead of responder analysis (as 
in the CSP) due to a change of main estimation method for effect 
size from logistic regression to HL estimate of median difference.

Details were added regarding how alpha is distributed and 
propagated among the endpoints under type I error control.

In analyses of primary efficacy endpoints and secondary efficacy 
endpoint, ranking among the deceased patient in the primary 
analysis was changed to based on last value while alive, and ranking 
among the deceased patients in the sensitivity analysis was changed 
to based on time to death.

Added median estimate within each treatment group and HL 
estimate with the corresponding confidence interval for the median 
difference between treatment groups as treatment effect in the 
analyses of primary efficacy endpoints and secondary efficacy 
endpoint.

Added EQ-5D-5L question: "Usual activities" in the anchor-based 
analysis of KCCQ-PLS. Added the derivation of categories for this 
anchor variable based on EQ-5D-5L question: "Usual activities" at 
baseline and week 16 in Appendix 8.3.

Clarified mean change value in the endpoint (KCCQ-TSS, KCCQ-
PLS, or 6MWD) corresponding to the category ‘moderate or large 
improvement’ for each anchor variable will be used when 
determining the threshold for CMWPC that will be used to define 
responder.

Removed the anchor-based analysis and responder analysis for 
secondary efficacy endpoint, total time spent in LVPA.

Clarified the study was not impacted by COVID-19 and the 
analyses of the study will remain unchanged.

Clarified analyses of all MoveMonitor and MoveTest endpoints, 
including secondary efficacy endpoint, total time spent in LVPA, 
and exploratory efficacy endpoints, will use complete data, ie no 
patients with missing data due to reasons other than death. Only 
KCCQ endpoints (KCCQ-TSS, KCCQ-PLS, six domain scores and 
one summary score included in the exploratory efficacy endpoints) 
and 6MWD will use imputed datasets.


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Date
Brief description of change

Clarified subgroup analyses when subgroup category of a factor 
contains less than ten percent of the patients.

Added Appendix 8.4 to describe the scoring algorithm of KCCQ 
endpoints.


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1
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary Objective
Outcome Measures:
To determine whether dapagliflozin is 
superior to placebo in patients with chronic 
HF NYHA Functional Class II-IV and 
reduced ejection fraction (LVEF≤40%) 
[HFrEF] 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.
1.1.2
Secondary objective
Secondary Objective
Outcome Measure:
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 (MoveMonitor).
Baseline for wearable activity monitor MoveMonitor outcomes consists of a 7-day period 
measured on the week starting at enrolment visit. End of study for wearable activity monitor 
MoveMonitor outcomes consists of a 7-day period measured on the week starting at visit 4 
(week 14).


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1.1.3
Safety objective
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of
dapagliflozin compared to placebo in patients 
with HFrEF

AEs

SAEs

DAEs

AEs leading to amputation

Potential risk factor AEs for 
amputations affecting lower limbs

Laboratory tests

Vital signs
1.1.4
Exploratory objectives
Exploratory Objectives:
Outcome Measures:
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 (MoveMonitor).
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 
(MoveMonitor).
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 (MoveMonitor and
MoveTest), 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. 


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Exploratory Objectives:
Outcome Measures:
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 
during 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.
Baseline for wearable activity monitor MoveMonitor outcomes consists of a 7-day period 
measured on the week starting at enrolment visit. End of study for wearable activity monitor 
MoveMonitor outcomes consists of a 7-day period measured on the week starting at visit 4 
(week 14).


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1.2
Study design
This is an international, multicentre, parallel-group, randomised, double-blind, placebo-
controlled, phase III study in subjects with heart failure with reduced ejection fraction 
(HFrEF), evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in
addition to background regional standard of care therapy, including treatments to control co-
morbidities, on change in heart failure (HF) symptoms as measured by Kansas City 
Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), physical limitation as 
measured by Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ-
PLS), and exercise capacity as measured by 6-minute walk distance (6MWD). The scoring 
algorithm is described in Appendix 8.4.
HFrEF is defined in this study as left ventricular ejection fraction (LVEF) ≤40% as diagnosed 
by echocardiogram, radionuclide ventriculogram, contrast ventriculography or cardiac 
magnetic resonance imaging (MRI). Adult subjects with HFrEF, aged ≥18 years with New 
York Heart Association (NYHA) Functional Class II-IV and who meet all of the inclusion 
criteria and none of the exclusion criteria will be randomised in a 1:1 ratio to receive either 
dapagliflozin 10 mg or placebo once daily.
It is estimated that approximately 600 subjects at approximately 115 to 120 sites in 12 
countries will be enrolled to reach the target of approximately 300 randomised subjects, 
assuming a screen failure rate of 50%. The investigational product (IP) will be added to the 
prescribed background therapy for HF, and background therapy for Type 2 diabetes mellitus 
(T2DM) when applicable, as considered appropriate by the investigator and in accordance 
with regional standard of care.
The anticipated total study duration is approximately 12 months. The duration of the study 
may be changed if the randomisation rate is different than anticipated.


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Figure 1 Study flow chart
               
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
1.2.1
Randomisation
Subjects will be randomised 1:1 to either dapagliflozin 10 mg or placebo once daily. 
Randomisation will be stratified by T2DM status at randomisation (2 levels: with T2DM; 
without T2DM). For the purpose of stratification, T2DM is defined as established diagnosis of 
T2DM or HbA1c ≥6.5% (48 mmol/mol) shown at the central laboratory test at enrolment 
(visit 1; single measure).
Randomisation will be performed in balanced blocks of fixed size. The randomisation codes 
will be computer generated and loaded into the IxRS (Interactive Voice/Web Response 
System) database.
Subjects can be randomised at visit 2a [Randomisation A] or visit 2b [Randomisation B] 
depending on whether they fulfilled the 15% variability criterion for 6MWD. Subjects who 
fulfilled all other inclusion criteria and none of the exclusion criteria, with a 6MWD value at 
visit 1 [Enrolment] which was not within [85%, 115%] of the value at visit 2a [Randomisation 
A] (ie, there was >15% variability) will have a second randomisation attempt at visit 2b 
[Randomisation B], within 7 days of visit 2a [Randomisation A]. Such subjects can be 
randomised if they fulfil all inclusion criteria and none of the exclusion criteria and the 
6MWD value at visit 2a [Randomisation A] is within [85%, 115%] of the value at visit 2b 
[Randomisation B].


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The numbers of subjects randomised to IP will be monitored, on a study level, to ensure the 
following characteristics are appropriately represented in the study, and caps may be applied 
in IxRS:

T2DM status: the number of randomised subjects 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 subjects can be randomised in a specific subpopulation) if the 
pre-determined limit is reached.

Atrial fibrillation/flutter (AF) status: the proportion of subjects with AF will be monitored 
to ensure a representative proportion in the study.
1.2.2
Number of subjects
The study will enrol approximately 600 subjects of which approximately 300 subjects will be 
randomised 1:1 to each treatment. This sample size estimate is based on supporting the 
original primary efficacy endpoint, change from baseline at week 16 in 6MWD. No 
adjustment to sample size was made to support the addition of primary endpoints based on 
change from baseline at week 16 in KCCQ-TSS and KCCQ-PLS. Mortality over the entire 
study period is assumed to be 5% in each treatment group.
The sample size selection was based on the following assumptions:
 
 
 
 
 
 
 
 


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2
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Full analysis set
All patients who have been randomised to study treatment 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. By the intent-to-treat (ITT) principle, the FAS population 
will be considered the main analysis set for the primary and secondary efficacy variables and 
for the exploratory efficacy variables, unless otherwise specified.
2.1.2
Safety analysis set
All randomised patients who received at least 1 dose of IP 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 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 main analysis set for all safety 
variables.
2.2
Violations and deviations
Only important protocol deviations (IPDs) will be listed and tabulated in the CSR, and only 
for randomised patients (ie, not screen failures). These are defined as protocol deviations 
which may significantly affect the completeness, accuracy and/or reliability of the study data, 
or which may significantly affect a patient’s rights, safety or well-being. They will include 
(but are not limited to): 


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
Patients who were randomised but did not meet inclusion and exclusion criteria

Patients who received the wrong study treatment at any time during the study.

Patients who received prohibited concomitant medication, ie, open label SGLT2-
inhibitors taken alone or in combination with IP.
All IPDs except for dosing error will be identified and documented by the study team prior to 
unblinding of the trial. As far as possible, the occurrence of IPDs will be monitored (blinded) 
during the trial, with the emphasis on their future prevention.
IPDs will not be used to exclude any patient from any analysis set, nor to exclude any data 
from patients included in an analysis set. Patients having IPDs or any corona virus disease 
2019 (COVID-19) related protocol deviations will be summarised for FAS population by 
randomised treatment group and overall. Patients with IPDs or any COVID-19 related 
protocol deviations will be listed.
2.2.1
Deviations related to COVID-19
All protocol deviations related to COVID-19 will be summarised by randomised treatment 
group and overall.
3
PRIMARY AND SECONDARY VARIABLES
3.1
General definitions
3.1.1
Definition of baseline
For efficacy variables, the last non-missing measurement on or prior to the date of 
randomisation will serve as the baseline measurement. If no such non-missing value is 
available, the baseline value will be imputed as described in Appendix 8.1.
The following specific rules for capturing the various efficacy data are planned:
The last value on or prior to the randomisation visit will be used as baseline for all efficacy 
endpoints that are intended for on-site collection, except for overall treatment benefit (OTB),  
which is only measured post-baseline, and also the measurements taken right before and after 
the 6-minute walk test (6MWT), oxygen saturation (Section 3.2.3.8) and systolic BP (Section 
3.2.3.9), where the difference between the pre-6MWT value and post-6MWT value, at the 
randomisation visit, is used as the baseline value. Efficacy endpoints collected off-site, 
assessed by a wearable activity monitor (DynaPort MoveMonitor), are also handled 
differently.
Two types of accelerometers are used; the DynaPort MoveTest which is used by the patient in 
the clinic, at each visit, and the DynaPort MoveMonitor which is used by the patient at home 


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(see Appendix 8.2 for a detailed description of each wearable activity monitor). At a subset of 
study sites, labelled "sites with wearable devices", patients will wear a wearable activity 
monitor during the 6MWT; this one is for use in the clinic only (DynaPort MoveTest), and it is 
different to the wearable activity monitor that will be dispensed for use at home  At the same 
subset of study sites, patients will be dispensed a wearable activity monitor (DynaPort 
MoveMonitor) to wear at home. The data from these two types of wearable activity monitors 
(DynaPort MoveTest and DynaPort MoveMonitor) will never be merged together in the 
analyses of the efficacy endpoints since the parameters are completely different.
The last value on or prior to the randomisation visit will be used as baseline for the 
exploratory endpoints assessed by the wearable activity monitor MoveTest. Change from 
baseline at week 16 in distance walked during 6MWT and change from baseline at week 16 in 
number of stops during 6MWT are the only two exploratory endpoints based on the data 
collected by the wearable activity monitor MoveTest. The two endpoints based on MoveTest
data and the corresponding parameters in MoveTest data are listed in Appendix 8.2, Table 4.
For efficacy endpoints assessed using the wearable activity monitor MoveMonitor, the 
summarised values (per “visit”) using data collected between enrolment visit and 
randomisation visit, ie starting from visit 1 and collected in 7 consecutive days, will be used as 
baseline. For MoveMonitor data the measurement corresponding to a “visit” spans several 
days (theoretically, up to 14, as this is limited by the MoveMonitor device memory and 
settings). Therefore, in the dataset with daily summaries there is more than one record (day) 
associated with e.g. Visit 2 (Baseline), for each combination of subject/parameter/visit. Only 7 
days will be used to derive summarised values for each visit. For each pre-specified parameter
of interest (efficacy endpoint) in the MoveMonitor data, an algorithm is applied to derive visit 
summaries from daily data. Rules for which days to include in the visit summary, are defined 
in Section 3.1.3, Section 3.2.3.3, and Appendix 8.2 for MoveMonitor. The nine endpoints 
based on MoveMonitor data and the corresponding parameters in MoveMonitor data are listed 
in Appendix 8.2, Table 4.
For safety variables, the last non-missing measurement prior to first dose of study treatment 
will serve as the baseline measurement. If there is no value prior to first dose of study 
treatment, then the baseline value will not be imputed, and will be set to missing. This applies 
for safety variables including laboratory variables and vital signs.
3.1.2
Change from baseline 
Change from baseline is defined as (post-baseline value – baseline value).
Relative change from baseline is defined relative to the baseline value as (post-baseline value 
– baseline value)/baseline value and is only defined when the baseline value is not zero.


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3.1.3
Visit windows
All summaries and analyses for efficacy and safety endpoints, except for adverse events, will 
be presented by time points and a visit window approach will be used to classify the data 
record.  
It should be noted that the same approach as above will also be used to present data captured 
using the MoveTest. 
MoveMonitor data, however, will be aggregated for analysis at each relevant time point by 
summing or averaging over up to 7 days. Details about MoveTest and MoveMonitor data are 
described in Section 3.2.3.3 and Appendix 8.2.
A visit window will be derived using the study day. The study day is derived from the 
assessment date relative to the reference start date. For safety variables, the reference start 
date for these measurements is the date of first dose of IP, and study day is therefore defined 
as (Date of assessment – Date of first dose of IP) + 1 for post-baseline, and defined as (Date 
of assessment – Date of first dose of IP) for pre-baseline. For efficacy variables, the reference 
start date for these measurements is the date of randomisation, and study day is therefore 
defined as (Date of assessment – Date of randomisation) + 1 for post-baseline, and defined as 
(Date of assessment – Date of randomisation) for pre-baseline.
The derivation of visit window (using study day) is described in Table 1. The window for the 
scheduled visits following baseline will be constructed in such a way that the upper limit of 
the interval falls half way between the two visits. Intervals in the table are inclusive.
Table 1 Visit windows
Assessment
Visit
Target 
day
Target day
Visit window for safety 
variables
Visit window for efficacy 
variables
Screening/Baseline
1 & 2
See Section 3.1.1 for baseline definitions
Week 8
3
56
56
2 to 84
28 to 84
Week 16
5
112
112
≥85
≥85
Unless otherwise specified, if a patient has more than one measurement included within a 
window, the assessment closest to the target day will be used. In case of ties between 
observations located on different sides of the target day, the earlier assessment will be used. In 
case of ties located on the same side of the target day (ie, more than one value for the same 
day but different time), the value with the earlier entry date/time will be used. If the decision 
falls between two non-missing values recorded on the same day and there is no assessment 


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time associated with at least one of them, or the same assessment time is associated with both 
non-missing values, the average of the two values will be selected for analysis at that visit.
3.1.4
Baseline and concomitant medication
Medications taken by any patient at any time during the study will be coded using the 
Anatomical Therapeutic Chemical (ATC) classification system within the World Health 
Organisation (WHO) Drug Dictionary.
Baseline medication is defined as medication with at least one dose taken before date of 
randomisation and treatment is ongoing or stop date is on or after date of randomisation.
Concomitant medication is defined as medications taken on or after date of randomisation, 
except for study drug.
If the start or end date for the medication is completely or partially missing, the incomplete 
date will be handled using the method described in Section 4.1.4.
3.2
Efficacy variable
3.2.1
Primary efficacy variable
The primary efficacy variables are change from baseline in the KCCQ-TSS at week 16, 
change from baseline in the KCCQ-PLS at week 16 and change from baseline in 6MWD at 
week 16. The change from baseline is selected instead of the value at week 16, to facilitate 
clinical interpretation of estimated differences between treatment groups.
The KCCQ is a 23-item, self-administered disease-specific instrument, which has been shown 
to be a valid, reliable and responsive measure for patients with HF (Green et al 2000, FDA 
2020, Spertus et al 2005). The scoring algorithm is described in Appendix 8.4. 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 patient’s 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. The clinical summary score together with its 
components, KCCQ-TSS and KCCQ-PLS, are qualified as a drug development tool for 
clinical outcome assessment by the FDA (FDA 2020).
The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) 
domains into a single summary score. The KCCQ-PLS is calculated from the average of 
numerical values assigned to responses to 6 items and captures how the patient’s physical 
function is limited due to their HF.  The KCCQ-TSS and KCCQ-PLS are calculated for 


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assessments at enrolment and randomisation visits, visit 3 (week 8), visit 5 (week 16), and 
premature treatment discontinuation visit (PTDV) or early withdrawal visit. 
The 6MWD is the distance in meters that a patient can walk in a 6-minute period, measured 
by the site staff during 6MWT. The 6MWT will be conducted in accordance with the 
American Thoracic Society (ATS) guidelines (American Thoracic Society 2002). The 6MWD 
is measured at enrolment and randomisation visits, visit 3 (week 8), visit 5 (week 16), and 
PTDV or early withdrawal visit.
None of patients in FAS was affected by COVID-19 and the impact of COVID-19 to three 
primary efficacy variables is negligible as described in Section 4.2.4. 
In order to account for patients who die prior to the 16-week assessment and to accommodate 
non-normal distribution of the primary efficacy variables, hierarchical composite endpoints 
will be used. The values of change from baseline in KCCQ-TSS, KCCQ-PLS and 6MWD at 
week 16 in patients who survive to week 16 will be converted to ranks (across both treatment 
groups combined) with lower ranks attributed to worse outcomes (ie, lower ranks 
corresponding to negative or smaller values of change from baseline). Patients who die prior 
to the 16-week assessment will be assigned worse ranks than any patients surviving to 16 
weeks. The ranking amongst the deceased patients will be based on the last value while alive. 
Details are described in Section 4.2.4.
A 6MWD responder will be defined as a patient who had a clinically meaningful 
improvement in 6MWD. As a starting point, a responder is defined as a patient with a ≥30 
meters change from baseline at week 16 in 6MWD. Deaths are defined as non-responders. 
The 30-meter threshold is a pre-specified limit meant to approximate a threshold for clinically 
meaningful within-patient change (CMWPC), based on previous studies (Shoemaker et al 
2013, O’Keeffe et al 1998, Holland et al 2014, Ferreira et al 2016). However, since most of 
these studies looked at group-level estimates (difference between means) and not individual-
level estimates (e.g. comparison of proportions of responders) a threshold, or a range of 
thresholds, suited to the specific target population in this study (by being based on patients 
included in this study), will be estimated using the anchor-based methods described in 
Appendix 8.3 and will replace the 30-meter threshold. Estimation of such a threshold, or a 
range of thresholds, will be based on blinded data and will not be in any way contingent upon 
treatment assignment.
A KCCQ-TSS or KCCQ-PLS responder will be defined as a patient who had clinically 
meaningful improvement in that score.  As a starting point, in each of KCCQ-TSS and 
KCCQ-PLS, a responder is defined as a patient with a ≥5 point change from baseline at week 
16. Deaths are defined as non-responders. The 5-point threshold is a pre-specified limit meant 


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to approximate a threshold for CMWPC based on previous studies (Filippatos et al 2017). 
However, since most earlier studies have evaluated thresholds for other summary scores in the 
KCCQ (namely the overall summary score and clinical summary score) a threshold, or range 
of thresholds, specific to the KCCQ-TSS and KCCQ-PLS and suited to the specific target 
population in this study (by being based on patients included in this study) will be estimated 
using the same anchor-based methods as those used for 6MWD, c.f. Appendix 8.3, and these 
thresholds will replace the 5-point threshold. Estimation of such a threshold, or a range of 
thresholds, will be based on blinded data and will not be in any way contingent upon treatment 
assignment. 
3.2.2
Secondary efficacy variable
The secondary efficacy variable is change from baseline at the end of the study (ie, the week 
starting at week 14) in total time spent in light to vigorous physical activity (LVPA) measured 
in hours, as assessed by the wearable activity monitor MoveMonitor and defined as the wear 
time spent with an energy expenditure ≥1.5 Metabolic Equivalents of Task (METs). Relative 
change from baseline will serve as a supportive variable. Change and relative change from 
baseline at end of study for this variable are defined in Section 3.1.2.
MoveMonitor data will be collected at sites with wearable devices and in a period of 7 days at 
each time point. Data collected during the 7-day period starting on the day of visit 1 
(enrolment) will be retrieved at visit 2a and this data constitutes the baseline for each patient 
as defined in Section 3.1.1. Data collected during the 7-day period starting on the day of visit 
3 (week 8) and data collected during the 7-day period starting on the day of visit 4 (week 14), 
will be retrieved at visit 5 (week 16), these data comprise the follow-up for each patient. End 
of study refers to the 7-day period starting at visit 4 (week 14). 
For the secondary efficacy variable, a hierarchical composite endpoint will be derived using 
the same method as described in Section 3.2.1 and 4.2.4.
A threshold, or range of thresholds, for clinically meaningful within-patient change could 
theoretically  be estimated using the same methods as those used for the primary efficacy 
endpoints, c.f. Appendix 8.3, with appropriate anchors. However, only a subset of patients is 
expected to provide MoveMonitor data and for inclusion in anchor-based analyses patients are 
required to also provide data on the global anchor variables. Furthermore, the relevance global 
anchor variables for anchoring change from baseline at end of study in time spent in LVPA is 
not clear. Due to these factors, which severely reduce the reliability of any threshold derived 
in anchor-based analysis, an anchor-based analysis of the secondary endpoint will not be done 
for the CSR.


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3.2.3
Exploratory variables 
For each continuous exploratory endpoint, a hierarchical composite endpoint will be derived 
using the same method as described in Section 3.2.1 and Section 4.2.4, ie, NT-proBNP, 
dyspnoea and fatigue, KCCQ domains, oxygen saturation, systolic BP, body weight, eGFR or 
endpoints assessed using the wearable activity monitors.
3.2.3.1
Change from baseline at week 16 in NT-proBNP 
The exploratory efficacy variable is the change from baseline in serum NT-proBNP (pg/mL) 
at week 16. 
The serum NT-proBNP is collected at enrolment and randomisation visits, visit 3 (week 8), 
visit 5 (week 16), and PTDV or early withdrawal visit. 
3.2.3.2
Proportion of patients with worsened NYHA Functional Classification from 
baseline at week 16
The exploratory efficacy variable is the proportion of patients with worsened NYHA 
Functional Classification from baseline at week 16. 
The NYHA classification will be evaluated by the investigator and collected at enrolment and 
randomisation visits, visit 3 (week 8), visit 5 (week 16), and PTDV or early withdrawal visit.
For the main analysis the data will be dichotomised into patients with worsened NYHA class 
at week 16 (the NYHA class is higher than baseline) and patients with improved or unchanged 
NYHA class. Patients who died due to any cause prior to week 16 are classified as worsened. 
Patients with NYHA class IV at baseline can only "worsen" if they die prior to week 16.
3.2.3.3
Change or relative change from baseline at end of study or week 16 in 
exploratory endpoints assessed using the wearable activity monitors  
The exploratory efficacy variables based on data from the wearable activity monitor  
MoveMonitor and MoveTest are highlighted below, a detailed description of each endpoint is 
available in Appendix 8.2:

Change from baseline at end of study in vector magnitude units (VMUs) per minute, as 
assessed by the MoveMonitor

Change from baseline at end of study in movement intensity during walking measured 
in milli-g, as assessed by the MoveMonitor

Change from baseline at end of study in movement intensity when walking for 
durations of >20 seconds based on MoveMonitor data, defined as movement intensity 


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measured in milli-g, during periods when the physical activity was classified as 
‘walking’ and lasted for more than 20 seconds

Change from baseline at end of study in total number of steps based on MoveMonitor
data, defined as the total number of steps excluding steps from walking in stairs

Change from baseline at end of study in total time spent in moderate to vigorous 
physical activity (MVPA) based on MoveMonitor data, defined as the wear time spent 
with an energy expenditure ≥3 METs measured in hours

Change from baseline at week 16 in distance walked during 6MWT based on 
MoveTest data, defined as the total distance covered by the patient measured in meters

Change from baseline at week 16 in number of stops during 6MWT based on 
MoveTest data, defined as the total number of walking interruptions

Change from baseline at end of study in total number of sitting shifts during night rest 
based on MoveMonitor data, defined as a transition between a posture classified as 
‘sitting upright’ and any posture classified as ‘lying’ (ie, ‘prone’, ‘lying on the left’, 
‘lying on the right’ or ‘supine’)

Change from baseline at end of study in total number of activity counts during worn 
periods based on MoveMonitor data, activity counts are zero when the device is not 
worn

Total wear time at end of study based on MoveMonitor data, defined as the total time 
measured in hours when the number of activity counts was greater than zero
Baseline for MoveMonitor and MoveTest efficacy variables is defined in Section 3.1.1.  For 
MoveMonitor efficacy variables, end of study refers to the 7-day period starting at visit 4 
(week 14).
“Relative change from baseline” will serve as a supportive variable. 
For each exploratory efficacy endpoint assessed by the MoveMonitor or the MoveTest, a 
hierarchical composite endpoint will be derived using the same method as described in 
Section 3.2.1 and 4.2.4.
3.2.3.4
Change from baseline at week 16 in EQ-5D-5L
The EQ-5D-5L is a self-reported questionnaire that is used to derive a standardised measure of 
health status, also referred to as a utility score. 


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EQ-5D-5L is collected at enrolment and randomisation visits, visit 5 (week 16), and PTDV or 
early withdrawal visit.
The distribution of categorical responses to EQ-5D-5L, change from baseline at week 16, and 
the responses on the EQ-5D visual analogue scale (VAS) scores will be summarised. The 
VAS score has a range of 0-100, and higher scores represent a better outcome.
3.2.3.5
Change from baseline at week 16 in dyspnoea and fatigue
The dyspnoea and fatigue scales assess shortness of breath and fatigue, respectively, on a 
scale from 0 to 10, where 0 indicates no dyspnoea or fatigue, and 10 indicates the worst 
situation.  Dyspnoea and fatigue scales are collected at enrolment and randomisation visits, 
visit 3 (week 8), visit 5 (week 16), and PTDV or early withdrawal visit.
The exploratory endpoint will be the change from baseline at week 16 in dyspnoea and fatigue 
scales. Other time points will be summarised.
3.2.3.6
Distribution of OTB at week 16
The patient OTB uses a single question that assesses the patient’s impression of the benefits of 
the study medication relative to the negative effects. It has levels ranging from ‘much greater 
than the negative effects’, ‘somewhat greater than the negative effects’, ‘equal to the negative 
effects’, ‘somewhat less than the negative effects’, and ‘much less than the negative effects’. 
The levels will also be collapsed into four major groups – positive (‘much greater than the 
negative effects’), neutral (‘somewhat greater than the negative effects’ + ‘equal to the 
negative effects’ + ‘somewhat less than the negative effects’), negative (‘much less than the 
negative effects’), and death occurring prior to collection of the variable at the analysis time 
point. 
OTB is collected at visit 3 (week 8), visit 5 (week 16), and PTDV or early withdrawal visit.
The exploratory endpoint will be the distribution of OTB at week 16 (collapsed class variable 
described above).
The second question in the patient OTB is whether the patient would choose to continue 
taking study medication after the end of the study, if that was an option. The response options 
are "Yes", "Unsure" or "No". 
The distribution of responses at week 8 and week 16 will be reported.
3.2.3.7
Change from baseline at week 16 in KCCQ domains
The KCCQ domain and summary scores of interests include the TSS domains (symptom 
frequency and symptom burden), overall summary score, symptom stability domain, self-


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efficacy domain, social limitation domain and quality of life (QoL) domain. Domain and 
summary scores are transformed to a range of 0 to 100. Higher scores represent a better 
outcome. Scoring algorithm is defined in Appendix 8.4.
KCCQ is collected at enrolment and randomisation visits, visit 3 (week 8), visit 5 (week 16), 
and PTDV or early withdrawal visit.
The exploratory endpoints will be the change from baseline at week 16 in each KCCQ domain 
and summary score.
3.2.3.8
Change from baseline at week 16 in oxygen saturation
Oxygen saturation forms part of the suite of assessments administered during the 6MWT and 
will be assessed using a standard pulse oximetry device in a sitting position right before and 
after the 6MWT at enrolment and randomisation visits, visit 3 (week 8), visit 5 (week 16), and 
at PTDV or early withdrawal visit.
The oxygen saturation difference after 6MWT (referred to as "oxygen saturation delta") is 
defined as the value after 6MWT minus the value before 6MWT. 
The exploratory endpoint will be change from baseline at week 16 in oxygen saturation delta.
3.2.3.9
Change from baseline at week 16 in systolic BP
Systolic BP, diastolic BP and pulse rate are collected at enrolment and randomisation visits, 
visit 3 (week 8), visit 5 (week 16), and at PTDV or early withdrawal visit.
Systolic BP, diastolic BP and pulse rate are collected three times at each visit; once before 
conducting the 6MWT and twice as part of the suite of assessments administered during the 
test; right before and after the 6MWT.
The systolic BP data collected as part of the 6MWT before and after 6MWT will be used for 
analysis of exploratory efficacy endpoint. 
At each visit, the systolic BP difference after 6MWT (referred to as "systolic BP delta") is 
defined as the systolic BP value after 6MWT minus the value before 6MWT.
The exploratory endpoint will be change from baseline at week 16 in systolic BP delta.
3.2.3.10
Change from baseline at week 16 in body weight
Body weight is measured at enrolment and randomisation visits, visit 3 (week 8), visit 5 (week 
16), and at PTDV or early withdrawal visit.


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The exploratory endpoint will be change from baseline at week 16 in body weight. 
3.2.3.11
Change from baseline at week 16 in eGFR
The eGFR values will be calculated (in mL/min/1.73 m2) using the CKD-EPI formula (Levey 
et al 2009). eGFR = 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(Scr/κ, 1) indicates the minimum of Scr/κ or 1,

max(Scr/κ, 1)  indicates the maximum of Scr/κ or 1 
Age is rounded to years.
The eGFR values will be calculated at enrolment and randomisation visits, visit 3 (week 8), 
visit 5 (week 16), and at PTDV or early withdrawal visit.
The exploratory endpoint will be change from baseline at week 16 in eGFR. 
3.3
Safety variables 
3.3.1
Adverse events
The safety and tolerability of dapagliflozin in patients with HFrEF will be evaluated from 
adverse events (AEs), serious adverse events (SAEs), adverse events leading to 
discontinuation of IP (DAEs), AEs leading to amputation and relevant preceding AEs 
reflecting potential risk factors for lower limb amputations (“preceding events”). The AEs 
leading to amputation and preceding events are included as AEs of special interest in this 
study.
Amputation will be recorded in the eCRF as AE/SAE. The “preceding events”, defined as 
non-serious and serious events potentially placing the patient at risk for a lower limb 
amputation regardless of whether an amputation has taken place or not, will be recorded in the 
eCRF as AE/SAE as well. Safety analysis of "preceding events" will be based on the 
predefined list of preferred terms. Additional information about amputations with underlying 
conditions and preceding events will be collected on dedicated eCRF pages.
For any AEs reported by the Investigator as Diabetic Ketoacidosis (DKA), additional 
information will be recorded on specific eCRF pages in addition to the AE/SAE form. 


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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
DKA events will not be adjudicated in this study. DKA events may be presented if applicable. 
SAEs will be collected from time of informed consent until and including the patient’s last 
visit. Non-serious AEs will be collected from randomisation until and including the patient’s 
last visit. 
3.3.2
Laboratory values 
Blood samples will be taken at enrolment and randomisation visits, visit 3 (week 8), visit 5 
(week 16), and at PTDV or early withdrawal visit, for central laboratory assessment of the 
following laboratory variables:

Sodium

Potassium 

HbA1c 

Haematocrit

Creatinine

eGFR (calculated based on creatinine value, details in Section 3.2.3.11)
3.3.3
Vital signs
The following vital signs will be collected at enrolment and randomisation visits, visit 3 (week 
8), visit 5 (week 16), and at PTDV or early withdrawal visit:

Systolic BP

Diastolic BP 

Pulse rate


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
Waist circumference

Body weight 
Systolic BP, diastolic BP and pulse rate will be measured in a sitting position, and waist 
circumference and body weight will be measured in a standing position. The vital signs for 
safety analysis will use the data collected from VS form in eCRF (details in Section 3.2.3.9).
3.3.4
Physical examination
Physical examinations will be performed at enrolment and randomisation visits, visit 3 (week 
8), visit 5 (week 16), and at PTDV or early withdrawal visit.
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.
4
ANALYSIS METHODS
4.1
General principles
No multiplicity adjustment will be made to confidence intervals as they will be interpreted 
descriptively and used as a measure of precision. All p-values will be unadjusted. P-values for 
variables not included in the confirmatory testing scheme or above the pre-specified threshold 
for significance, in Section 4.1.3, will be regarded as nominal.
Stratification of analyses for T2DM status will be performed using the stratification values as 
entered in IxRS to determine the randomisation assignment.
Summary data, including the observed value and change from baseline value at week 16 or 
end of study in the endpoint at each analysis time point, will be presented in tabular format by 
treatment group. Categorical data will be summarised by the number and percentage of 
patients in each category by treatment group. Continuous data will be summarised by 
descriptive statistics as appropriate, including N, mean, SD, minimum, first quartile (Q1), 
median, third quartile (Q3) and maximum. 
4.1.1
Estimand for primary and secondary variables
The primary efficacy endpoints and secondary efficacy endpoint will be evaluated under a 
combined treatment policy (intent-to-treat) and composite variable strategy estimand, 
including differences in outcomes at the end of the 16-week treatment period, or at end of 
study (ie, the week starting at week 14, for variables captured with the MoveMonitor) 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 


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study drug. A composite variable strategy approach is employed to account for deaths 
occurring during the follow-up period. Deaths are regarded as intercurrent events and are 
incorporated into the hierarchical composite endpoint. The analysis will be performed for the 
FAS.
4.1.2
Hypotheses
For the primary efficacy endpoints KCCQ-TSS, KCCQ-PLS and 6MWD, and the secondary 
efficacy endpoint, total time spent in LVPA, the following hypotheses will be tested using the 
significance level specified in Section 4.1.3

H0: m(r(A)) = m(r(C))
versus

H1: m(r(A)) ≠ m(r(C))
Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and 
m(r(C)) represent the median of the ranked changes in each of the primary efficacy endpoints, 
KCCQ-TSS, KCCQ-PLS and 6MWD, from baseline at week 16, and the median of the ranked 
changes in secondary efficacy endpoint, total time spent in LVPA, from baseline at end of 
study among patients receiving dapagliflozin (Active) and placebo (Control) treatment, 
respectively. 
When applicable, for certain exploratory efficacy endpoints, the distribution of ranked values 
are replaced with the proportion of responders and the analogous null and alternative 
hypotheses then become

H0: OR[dapagliflozin:placebo] = 1
versus

H1: OR[dapagliflozin:placebo] ≠ 1
Where OR[dapagliflozin:placebo] represents the odds ratio for dapagliflozin versus placebo in 
a logistic regression model for the outcome of observing a response at week 16 compared to 
baseline in the endpoint of interest. 
4.1.3
Confirmatory testing procedure
To account for multiplicity when testing the primary efficacy endpoints (change in KCCQ-
TSS, KCCQ-PLS and 6MWD from baseline at week 16), and secondary efficacy endpoint 
(change in total time spent in LVPA from baseline at end of study), a pre-specified testing 
strategy will be followed to control the overall type I error rate. The testing will be performed 
according to a gatekeeping procedure (Dmitrienko et al 2011): the three tests of KCCQ-TSS, 


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KCCQ-PLS and 6MWD with a  family wise error rate (FWER) of 0.05 (2-sided) will be 
conducted first. The total alpha of 0.05 will be divided among the three primary efficacy 
endpoints using a weighted Bonferroni method, with 0.04990 (99.8% of the total alpha) 
assigned to KCCQ-TSS, 0.00005 (0.1% of the total alpha) assigned to each of KCCQ-PLS 
and 6MWD. The secondary efficacy endpoint, total time spent in LVPA, will not be tested 
unless the test of 6MWD is significant. As the testing procedure progresses, if a hypothesis 
test in the primary endpoint family is significant, its assigned alpha will be preserved and 
considered as unused and passed along fully or partially to the other tests in the primary 
endpoint family, as described below in Figure 2. The passed-along alpha will be added to the 
originally assigned alpha, before testing other endpoints in the primary family. The test of 
secondary endpoint will use only the unused alpha from the primary efficacy endpoints 
family. This testing strategy provides strong control of the overall type I error rate and as long 
as pre-specified alpha allocation is based on available evidence, should not inflate the type II 
error rate. The complete testing strategy is depicted in Figure 2.
The testing procedure will be as follows (numbering does not strictly imply a chronological 
order):
1
KCCQ-TSS, KCCQ-PLS and 6MWD will be tested first. The initial alpha allocated to 
them is 0.04990 for KCCQ-TSS, 0.00005 for KCCQ-PLS and 0.00005 for 6MWD.
2
KCCQ-TSS will be tested at the alpha level of 0.04990 (initial alpha) regardless of the 
outcome for the tests of KCCQ-PLS and 6MWD.
3
a. If the test of KCCQ-TSS is significant, KCCQ-PLS is tested at the alpha level of 
0.04990 = 0.00005 + 0.04985 (initial alpha allocated to KCCQ-PLS plus the amount 
passed from KCCQ-TSS).
b. If the test of KCCQ-TSS is not significant, KCCQ-PLS is tested at 0.00005 (initial 
alpha allocated to KCCQ-PLS).
4
a. If the test of KCCQ-TSS is significant, but test of KCCQ-PLS is not significant, 6MWD 
is tested at the alpha level of 0.00010 = 0.00005 + 0.00005 (initial alpha allocated to 
6MWD plus the amount passed directly from KCCQ-TSS). 
b. If the test of KCCQ-TSS is not significant, but the test of KCCQ-PLS is significant, 
6MWD is tested at 0.00010 = 0.00005 + 0.00005 (initial alpha allocated to 6MWD plus 
the amount passed directly from KCCQ-PLS).                                                                                                
c. If the test of KCCQ-TSS and the test of KCCQ-PLS are both significant, 6MWD is 
tested at 0.05000 = 0.00005 + 0.04985 + 0.00010 (initial alpha allocated to 6MWD plus 
the amount passed directly from KCCQ-TSS and amount passed through KCCQ-PLS).                               


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d. If the test of KCCQ-TSS and the test of KCCQ-PLS are both not significant, 6MWD is 
tested at 0.00005 (initial alpha allocated to 6MWD)                                                                                       
5
The secondary efficacy endpoint, total time spent in LVPA, will not be tested unless the 
test of 6MWD is significant. 
a. If the test of 6MWD is significant but neither of the test of KCCQ-TSS and the test of 
KCCQ-PLS is significant, the secondary efficacy endpoint of total time spent in LVPA is 
tested at the alpha level of 0.00005 (passed directly from 6MWD). 
b. If the test of 6MWD is significant but only one of the test of KCCQ-TSS and the test of 
KCCQ-PLS is significant, the secondary efficacy endpoint of total time spent in LVPA is 
tested at the alpha level of 0.00010 (passed from 6MWD, after passing alpha from KCCQ-
TSS or KCCQ-PLS to 6MWD).   
c. If the test of KCCQ-TSS, the test of KCCQ-PLS and the test of 6MWD are all 
significant, the secondary efficacy endpoint of total time spent in LVPA is tested at the 
alpha level of 0.05000 (full alpha).


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Figure 2 Multiple testing strategy for three primary efficacy endpoints and secondary efficacy endpoint
Arrows indicate the amount and direction of propagated alpha which is enabled if the test was significant at the specified limit. Arrows labelled “full” 
indicate that all available alpha is propagated in that direction.
KCCQ Kansas City Cardiomyopathy Questionnaire; TSS Total symptom score; PLS Physical limitation score; 6MWD 6-minute walk distance  


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4.1.4
Incomplete dates
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify on-study AEs and to classify baseline and concomitant 
medications. 
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented 
individually, imputed values will be flagged as such. 
Adverse Events Dates

The missing day of onset of an AE will be set to:

First day of the month that the event occurred, if the onset YYYY-MM is after 
the YYYY-MM of the first dose of study treatment

The day of the first dose of study treatment, if the onset YYYY-MM is the 
same as YYYY-MM of the first dose of study treatment

The date of informed consent, if the onset YYYY-MM is before the 
YYYY-MM of the first dose of study treatment.

The missing day of resolution of an AE will be set to:

The last day of the month of the occurrence. If the patient died in the same 
month, then set the imputed date as the death date.

If the onset date of an AE is missing both the day and month, the onset date will be
set to:

January 1 of the year of onset, if the onset year is after the year of the first dose 
of study treatment

The date of the first dose of study treatment, if the onset year is the same as the 
year of the first dose of study treatment

The date of informed consent, if the onset year is before the year of the first 
dose of study treatment

If the resolution date of an AE is missing both the day and month, the resolution
date will be set to:

The date of the last study visit, if the patient did not die in the same year.

The death date, if the patient died in the same year.
Baseline and Concomitant Medication Dates
Imputation of start and end dates allows medications for patients to be classified into the 
categories of baseline medication or concomitant medication (or both) for tables. An 


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assessment should be made as to the possibility that the patient’s medication could fall into 
each category given the information available for the dates. If it is possible given the date 
information that a patient’s medication could fall into a given category, then the patient’s 
medication should be included in tables for that category. If a particular category can be ruled 
out based on partial or full dates available, then the patient’s medication should be excluded 
from that category. 
Two variables, "Started >4 weeks prior to Visit 1" and “Treatment continues”, are collected in 
eCRF and will be used to classify baseline and concomitant medications.  In case these 
information variables are missing, the incomplete dates for medications will adhere to the 
following rules in order to classify baseline and concomitant medications. 

If both start date and end date are missing or incomplete, then start date should be
imputed first.

The missing day of start date of a medication will be set to the first day of the month
of the occurrence.

The missing day of end date of a medication will be set to the last day of the month
of the occurrence.

If the start date of a medication is missing both the day and month, the onset date will
be set to January 1 of the year of occurrence.

If the end date of a medication is missing both the day and month, the date will be set
to December 31 of the year of occurrence.

If the start date of a medication is null and the end date is not a complete date then
the start date will be set to the date of the first study visit.

If the start date of a medication is null and the end date is a complete date
if the end date is after the date of the first study visit then the start date
will be set to the date of the first study visit.
otherwise the start date will be set to the end date of the medication.

If the end date of a medication is null and the start date is not a complete date then
the end date will be set to the date of the last study visit if no permanent
premature discontinuation of IP occurred, otherwise discontinuation date.

If the end date of a medication is null and the start date is a complete date
if the start date is prior to the date of the last study visit then the end date
will be set to the date of the last study visit if no permanent premature
discontinuation of IP occurred, otherwise discontinuation date.
otherwise, the end date will be set to the start date of the medication.


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4.1.5
Study drug compliance
The percentage of study drug compliance for the overall treatment period will be derived for 
each patient based on pill counts as the number of pills taken (dispensed – returned), relative 
to the expected number of pills taken. The expected number of pills taken is defined as 
1*(date of last dose – date of first dose +1), excluding days of interruption. If the number of 
tablets dispensed or the number of tablets returned is missing for at least one observation, 
compliance is not calculated for that patient.
Study drug compliance will be presented descriptively, including mean, SD, median, Q1, Q3, 
minimum, maximum and 5% and 95% percentiles, for safety analysis set by treatment group 
as defined in Section 2.1.2.
4.2
Analysis methods
4.2.1
Subject disposition 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. The number of enrolled and not randomised subjects (and 
reason) will be summarised. The number and percentage of subjects will be presented by 
treatment and overall for the following categories: randomised, received IP, did not receive IP, 
completed treatment, discontinued treatment (and reason), subjects who discontinued IP but 
completed study assessments, subjects who completed study, and subjects who discontinued 
study (and reason). Death will be included among the reason for study discontinuation.  
4.2.2
Demographic and baseline characteristics
Demographic and baseline characteristics, including medical history, will be summarised, 
using frequency distributions and summary statistics by treatment and overall. No statistical 
test will be performed for comparison of any baseline measurement among treatment groups.
The demographic and baseline characteristics will also be summarised for FAS population by 
randomised treatment and overall for patients with and without T2DM at randomisation, and 
for patients with and without AF.
4.2.3
Baseline and concomitant medication
The frequency of baseline and concomitant medication will be presented for the FAS 
population per ATC classification, preferred name and treatment group. 
4.2.4
Analysis of the primary efficacy variables
The primary efficacy variables are the KCCQ-TSS, KCCQ-PLS and 6MWD and the endpoint 
for each is the change from baseline at week 16.


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Recognizing that the outbreak of COVID-19 was not simultaneous across the globe, each site 
in the study is elicited for a date after which their site was in some way affected by COVID-
19. The assumption here is that the onset date of COVID-19 provided by each site is a good 
proxy for the date when the outbreak of COVID-19, together with associated restrictions and 
social distancing, occurred in that region. This date should also be a good proxy (better than 
using a global date or a date per country) for when the patients, receiving care at that site, 
were potentially impacted in terms of lifestyle and behaviour. 
There are 49 patients in FAS with their end of study date later than February 01, 2020. Among 
those 49 patients, none of their end of study date was later than the onset date of COVID-19 at 
their study site. Based on the collected evidence, no patients in the FAS was affected by 
COVID-19 and the impact of COVID-19 to three primary efficacy variables is negligible.
Rank ANCOVA model
The hierarchical composite endpoint representing the patients’ vital status at week 16 and the 
change from baseline in primary efficacy endpoints at week 16 in surviving patients, as 
defined in Section 3.2.1, will be analysed using the rank ANCOVA method to test the null 
hypothesis of no differences in the distributions of ranked outcomes between the two 
treatment groups. 
First the change from baseline at week 16 in each of the primary efficacy endpoints and vital 
status at week 16, as well as values of the baseline covariate will be transformed to 
standardised ranks within each T2DM randomisation stratum, using fractional ranks (dividing 
by the denominator n+1) and the mean method for ties. Ranking for the hierarchical composite 
endpoint (3.2.1) will be performed so that patients who die prior to the week 16 assessment 
are assigned the worst ranks within each stratum. This will be implemented by assigning a 
temporary value which is lower than all observed negative change values to patients who died 
prior to week 16, before deriving fractional ranks. The ranking amongst the deceased patients 
will be based on the last value while alive, with the lower ranks assigned to smaller last value 
while alive.
Amongst the patients who survive to 16 weeks, the missing data on the outcome variable due 
to reasons other than death (eg, missing visits, early withdrawal from the study, including lost 
to follow-up) will be imputed prior to ranking. The missing value will be replaced by placebo-
based MI using predictive mean matching. The predictive mean matching method ensures that 
the imputed values remain in the permissible range of the outcome values. Details about the 
placebo-based MI are outlined in 8.1. The imputation model will include the stratification 
variable (T2DM at randomisation), and value of  the outcome variable at the previous visits.


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The patients who died will be added back to the imputed datasets, which contain the patients 
who survived to week 16, to construct the imputation FAS datasets. The hierarchical 
composite endpoint described above will be derived using the imputation FAS datasets.
Rank ANCOVA will be performed on each imputation FAS dataset. Separate ANCOVA 
models will be fitted to the ranked data for each randomisation stratum using a regression 
model with the ranked composite endpoint as the dependent variable, adjusting for the ranked 
baseline as a covariate. Residuals from this regression model will be captured for testing of 
differences between treatment groups. The Cochran-Mantel-Haenszel (CMH) test, stratified 
for the T2DM status at randomisation, using the values of the residuals as scores will be used 
to compare treatment groups. This analysis will be repeated for each imputed dataset, and the 
results will be combined using Rubin’s rule as implemented in the SAS Procedure 
MIANALYZE. The CMH tests statistic has a chi-square distribution. In order to apply 
Rubin’s combination rule, which assumes approximate normal distribution of the statistics 
being combined, a normalizing Wilson-Hilferty transformation will be applied to the CMH 
test statistics from each imputation FAS (Ratitch et al 2013). Only the p-value from the 
combined results will be presented for the confirmatory testing of the primary efficacy 
endpoints.
The effect size comparing treatment groups will be estimated using the Hodges-Lehmann 
(HL) estimate of the median difference between dapagliflozin and placebo, together with its 
95% confidence interval. The Hodges-Lehmann estimates of the median difference between 
groups are selected because they are not sensitive to outliers or skewed underlying 
distributions, and also because they can handle deaths by treating them as the worst possible 
outcome as done in the ranked approach. This handling of intercurrent events corresponds to 
interpreting the median as “the change from baseline value compared to which half of the 
patients had a better outcome”. The HL estimates is the median value of all paired differences 
between observations in dapagliflozin versus placebo groups, calculated using the imputed 
datasets created for the main analysis. The calculation will be repeated for each imputation 
dataset, and the results will be pooled using the central limit theorem to obtain the HL 
estimate and corresponding confidence interval.
Summaries based on non-missing data for KCCQ-TSS, KCCQ-PLS and 6MWD will be 
presented in tabular format by treatment group. In addition, the medians and 1st and 3rd
quartiles of change from baseline for each treatment group will be presented in a way which 
includes deaths, consistent with the primary efficacy estimand. These additional summary 
values will be calculated using complete data, ie, including patients who died prior to week 16 
but excluding patients with missing data due to reasons other than death. A temporary value 
which is lower than all observed negative change values will be assigned to the deceased 
patients, and the assigned value amongst the deceased patients will be based on the last value 


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while alive, with lower values assigned to smaller last values while alive. Therefore, the 
median represents the value compared to which half of the population had a “worse” change 
from baseline.
Responder analysis
For KCCQ-TSS, the number and percentage of patients by treatment group will be presented 
across the following categories of change from baseline:

Death

Deterioration from baseline (change from baseline at week 16 ≤-5)

Stable (-5 <change from baseline at week 16 <5)

Improvement (change from baseline at week 16 ≥5). 
where “5” will be replaced by the threshold for CMWPC estimated with anchor-based 
analysis using change from baseline at week 16 in PGIS in HF symptoms. 
For KCCQ-PLS, the number and percentage of patients by treatment group will be presented 
across the following categories of change from baseline:

Death

Deterioration from baseline (change from baseline at week 16 ≤-5)

Stable (-5 <change from baseline at week 16 <5)

Improvement (change from baseline at week 16 ≥5) 
where “5” will be replaced by the threshold for CMWPC estimated with anchor-based 
analysis using change from baseline at week 16 in EQ-5D-5L question: “Usual activities”. 
For KCCQ-TSS and KCCQ-PLS, the range of possible values is bounded (0-100). Therefore, 
unless ceiling values (near the upper end) are considered, the improvement definitions do not
allow all patients to qualify as having had an improvement. Therefore, one modification is
made to generalize the improvement definitions so that they also apply to such patients. A 
patient who has baseline score ≥95 is classified as having an improvement if their change 
from baseline at week 16 is positive (>0 points) and will be considered stable if their change 
from baseline is zero. In a similar situation, unless floor values (near the lower end) are
considered, the deterioration from baseline definitions do not allow all patients to qualify as 
having had a deterioration from baseline. Therefore, one modification is made to generalize 
the deterioration from baseline definitions so that they also apply to such patients. A patient 
who has baseline score ≤5 is classified as having a deterioration if their change from baseline 
at week 16 is negative (<0 points) and will be considered stable if their change from baseline 
is zero. This will be modified according to the estimated threshold for CMWPC in each of 
KCCQ-TSS and KCCQ-PLS.


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For 6MWD, number and percentage of patients in each treatment group will be summarised 
across the following categories:

Death

No improvement from baseline (change from baseline at week 16 in 6MWD ≤0 meters)

Minimal improvement (0<change from baseline at week 16 in 6MWD <30 meters)

Improvement (change from baseline at week 16 in 6MWD ≥30 meters)
where “30 meters” will be replaced by the threshold for CMWPC estimated with anchor-based 
analysis using PGIC in walking ability at week 16.
The threshold for CMWPC for each of the primary efficacy endpoint will be estimated with 
anchor-based analysis, the details of which are described in Appendix 8.3. Additionally, for 
KCCQ-TSS, if the derived threshold values for CMWPC do not exceed 10 points, then a 
logistic regression will be constructed with 10 points improvement from baseline at week 16 
to define responders, based on an exploratory analysis of the TOPCAT-HF and HF-ACTION 
datasets (data not published). The estimated responder threshold for CMWPC using anchor-
based analyses for improvement from baseline at week 16, in the KCCQ-TSS, KCCQ PLS 
and 6MWD, will be indicated in the empirical cumulative distribution function curves and 
probability density function curves (described in Appendix 8.3). The number and percentage 
of patients in each category will be summarised by treatment group.
The analysis of responders based on KCCQ-TSS, KCCQ-PLS and 6MWD, respectively, will 
use the imputation datasets created for the main analysis. A responder is defined as a patient 
who had an improvement from baseline in the outcome. Deaths are defined as non-responders, 
and responder status will be determined based on the change from baseline values derived 
from the imputed KCCQ-TSS, KCCQ-PLS and 6MWD values, respectively, for the patients 
who have missing data due to reasons other than death. The number and percentage of patients 
in the responder and non-responder categories will be presented by treatment group. The 
proportion of responder categories will be compared between treatment groups using a logistic 
regression model including treatment group, stratification variable (T2DM at randomisation), 
and baseline value of KCCQ-TSS, KCCQ-PLS and 6MWD, respectively. The observed 
proportion of responders, odds ratio between treatment groups and its 95% confidence interval 
and corresponding 2-sided p-value estimated from each imputed dataset will be combined 
using Rubin’s rule, and the combined results will be presented.
Empirical cumulative distribution function and probability density function curves will be 
presented by treatment group to display the relative benefit of dapagliflozin over placebo 
across different ranges of change from baseline at week 16 in each of the primary efficacy 
endpoints, where patients who die prior to week 16 assessment will be represented with a 


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value which is lower than all observed negative change values (eg, for KCCQ-TSS and 
KCCQ-PLS, this value will be -101). The patients who had missing outcome due to reason 
other than death will be excluded for the generation of the curves. 
4.2.4.1
Sensitivity analysis of the primary efficacy endpoints
The following sensitivity analyses will be performed to examine the robustness of main 
analysis results to missing data handling:
1. For FAS population, the missing due to reason other than death will be imputed in the 
same way as in the main analysis. Deaths prior to visit 5 (week 16) will be ranked worse 
than observed data. The ranking amongst the deceased patients will be based on time-to-
death, with lower ranks assigned to shorter time until death. The time-to-death equals the 
date of death minus date of randomisation + 1. This is done to address and evaluate the 
impact of potential treatment differences in mortality time, on the assessment of the 
primary efficacy endpoints. Rank ANCOVA model and HL estimate of median difference 
between treatment groups will be conducted in the same manner as in the main analysis.
2. For FAS population, tipping point analysis (TPA) where scenarios in terms of decreased 
improvement in patients in the active arm with missing data are explored to identify a 
‘tipping point’ where statistical significance would be lost. Details about the tipping point 
analysis are described in Appendix 8.1.
The sensitivity analyses are only meant to be used when assessing the robustness of the main 
results to assumptions made in the models and are not meant to be used for labelling claims 
and no control of Type I error is planned.
4.2.4.2
Supplementary analysis of primary efficacy endpoints
Number and percentage of deaths up to week 16 will be presented by treatment groups. To 
further explore the pattern of death during the study period and the difference on the pattern 
between the treatment groups, time to death will be presented by treatment group using a 
Kaplan-Meier curve (Kaplan and Meier 1958). The duration of follow-up is defined as time 
from the date of randomisation to date of death or date last known to be alive. If a subject die, 
the duration equals the date of death minus date of randomisation + 1. If a subject is last 
known to be alive, the duration equals the date subject last known to be alive minus date of 
randomisation + 1. Unless otherwise specified, the plot will be presented only when there are 
at least 5 events in one treatment group.
A supplementary analysis of KCCQ-TSS, KCCQ-PLS and 6MWD will be performed to 
examine the robustness of main analysis results to the influence of deaths, by using a different 
estimand. The supplementary analysis will use FAS population with deaths prior to visit 5 


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excluded (ie, only including the patients that survived to week 16), and all other missing data 
will be imputed in the same way as in the main analysis. ANCOVA model will be conducted 
with non-ranked value of change from baseline at week 16 in KCCQ-TSS, KCCQ-PLS and 
6MWD as the continuous outcome. The model will include a factor for treatment group, the 
stratification variable (T2DM status at randomisation), and baseline KCCQ-TSS, KCCQ-PLS 
and 6MWD value as covariates. The estimated mean for each treatment group, and the mean 
difference between treatment groups with 2-sided 95% confidence intervals and the nominal 
2-sided p-values estimated from each imputed dataset will be combined using Rubin’s rule, 
and the combined results will be presented.
No control of Type I error is planned for the supplementary analyses.
4.2.4.3
Subgroup analysis of the primary efficacy endpoints
The following baseline and demographic variables are defined for the purpose of efficacy 
subgroup analysis to assess consistency of effects:

T2DM status at randomisation (yes, no)

AF at baseline (yes, no)

Age (≤median, >median)

Sex (male, female)

Race (white, black/African American, Other)

Geographic region (Western Europe/North America vs rest of world)

NYHA class at baseline (II, III/IV)

NT-proBNP (≤median, >median)

eGFR (<60, ≥60)

“Site with wearable devices” (no, yes, ie, the site has wearable activity monitor devices), 
only for 6MWD
The geographic region of Western Europe/North American includes Denmark, Sweden, 
Canada, and United States. The number and percentages of patients in subgroups will be 
presented by treatment group in the baseline summary data. The summary of primary efficacy 
data will be presented by treatment group, stratified by each subgroup variable.
Since the data from MoveTest and MoveMonitor are collected in a subset of sites that have the 
capability of providing the wearable activity monitor to patients, a subgroup analysis of
6MWD will be performed to evaluate whether the estimated treatment effects on 6MWD are 
different between “site(s) with wearable devices” versus other sites.
For each of the primary efficacy endpoints, the subgroup analysis will be performed 
separately in each subgroup, using the same method, HL estimate of median difference 


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between treatment groups, rank ANCOVA model and placebo-based MI, as described in 
Section 4.2.4 for primary efficacy endpoints. The nominal 2-sided p-values and descriptive 
summary measures that are not sensitive to potential outliers (medians) will be presented for 
each subgroup. 
For KCCQ-TSS, KCCQ-PLS and 6MWD responders (as a binary outcome), respectively, the 
subgroup analysis will be performed to include each subgroup variable (if it’s not already in 
the model) and the interaction of the subgroup variable and treatment group in the logistic 
regression model that already had treatment group, stratification variable (T2DM status at 
randomisation), and baseline value as covariates. The imputed datasets used in the main 
responder analysis will be used for subgroup responder analysis.  The interaction p-value will 
be presented in addition to the observed proportion of responders for each treatment group, 
odds ratio between treatment groups with 95% confidence interval and p-value for each 
subgroup. Odds ratios with confidence intervals for all subgroup levels will be presented in a 
forest plot, including observed proportions and interaction p-value. The p-values for the 
subgroup analyses and interaction terms will not be adjusted for multiple comparisons as the 
tests are exploratory and will be interpreted descriptively.
If any subgroup category of a factor contains less than ten percent of the patients, that 
subgroup category will be excluded from the subgroup analysis using rank ANCOVA model 
or logistics regression model, and only descriptive data will be summarised for that subgroup 
category. 
4.2.5
Analysis of secondary efficacy variable
The secondary efficacy endpoint using data assessed by the wearable activity monitors 
MoveMonitor, ie, change and relative change from baseline at end of study in total time spent 
in LVPA, will be analysed using the same method, HL estimate of median difference and rank 
ANCOVA model to analyse the hierarchical composite endpoint, as described in Section 4.2.4
for the primary efficacy endpoints. The analyses use complete data, ie no patients with 
missing data due to reasons other than death, therefore, the HL estimate of median difference 
between treatment groups and its asymptotic 95% CI will be generated based on Wilcoxon’s 
rank sum test. All models (both for change from baseline and for relative change from 
baseline) are adjusted for the baseline value, by including this as a continuous variable in the 
model specification. The expected difference in the result, between models looking at change 
from baseline and models looking at relative change from baseline, is the scale of the outcome 
variable, ie the scale on which the difference between treatment groups is presented. One scale 
may be more intuitive for clinical interpretation than the other due to the sometimes 


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uncommon units provided in endpoints assessed by the wearable activity monitors (eg, milli-
g).
Summary data for total time spent in LVPA based on standard filters, 4 additional filter 
settings of interest and also without applying any filters at all (Appendix 8.2) will be presented 
by treatment group.
The sensitivity analysis ranking death based on time-to-death and the supplementary analyses 
using ANCOVA model will be performed in the same manner as described in Section 4.2.4.1
and Section 4.2.4.2 except for using complete data, ie no patients with missing data due to 
reasons other than death, to examine the robustness of main analysis results to the handling of 
death, respectively. No TPA will be conducted for the secondary efficacy endpoint.
Subgroup analyses will be performed in the same manner as described in Section 4.2.4.3 for 
the primary efficacy endpoints. The summary data, stratified by subgroups, will also be 
presented by treatment group.
4.2.6
Analysis of safety variables
Analysis set
For safety analyses, all summaries will be based on the safety analysis set (Section 2.1.2).
Exposure
The “Duration of exposure” to study drug will be defined as the length of period on study 
drug, calculated for each patient as (date of last dose – date of first dose +1). An alternative 
measure where days of interruption are removed will be calculated and termed “Duration of 
actual exposure”.
“Duration of exposure” and “Duration of actual exposure” will be presented descriptively. 
Patients who receive IP which is not consistent with the treatment he or she was randomised 
to receive will also be listed.
Treatment periods
The summaries for the “on-treatment” period will include data with onset date on or after first 
dose of randomised study drug and on or before 30 days after last dose of study drug, and no 
later than visit 5 (week 16). 
The summaries for the “on and off-treatment” period will include data with onset date on or 
after dose of randomised study drug.


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All summaries of safety endpoints described in 4.2.6.1 to 4.2.6.7 below will be presented for 
the on-treatment period, unless otherwise stated. 
4.2.6.1
Adverse events
Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs will use the version of MedDRA that is current at the time of database 
lock.
Summary tables of the number and percent of patients with AEs, SAEs, DAEs, AEs leading to
amputations and AEs leading to a risk for lower limb amputations (“preceding events”)  
(3.3.1) will be presented by treatment group. The number and percent of patients with AEs 
will also be presented by SOC, PT and treatment group.
4.2.6.2
Serious adverse events (SAE)
The number and percent of patients with SAEs will be presented by SOC, PT and treatment 
group. The most common SAEs will also be presented by PT only. The cut-off for most 
common SAEs will be data driven (based on blinded data) and if no appropriate cut-off is 
identified all SAEs will be presented by PT.
AEs with outcome death will be presented separately by SOC, PT and treatment group for the 
on and off treatment period.
4.2.6.3
Adverse events leading to discontinuation (DAE)
The number and percent of patients with DAEs will be presented by SOC, PT and treatment 
group.
4.2.6.4
Amputations and preceding events
The number and percent of patients with AEs leading to amputation and AEs reflecting 
potential risk factors for lower limb amputations (“preceding events”) (3.3.1) will be 
presented by SOC, PT and treatment group. Amputations are presented for the on and off 
treatment period.
4.2.6.5
Laboratory evaluation 
All summaries of clinical chemistry/haematology parameters will be based on samples 
analysed at the central laboratory, and presented in both SI units and conventional units.
Laboratory variables, including the absolute values at each scheduled visit and the 
corresponding change from baseline, will be summarised by treatment group. 


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4.2.6.6
Marked laboratory abnormalities
The number and percent of patients with a marked abnormality in clinical laboratory tests 
listed in Table 2 will be summarised over time by treatment group.
Laboratory abnormalities will be evaluated based on marked abnormality (MA) criteria for the 
laboratory variables listed in Table 2. When there is more than one limit for a variable, 
summaries will be provided for each limit.
An on-treatment value will be considered an MA if either 

the on-treatment value is beyond an MA limit AND the baseline value is not beyond the 
same limit,
OR

both the baseline and on-treatment value are beyond the same MA limit AND the on-
treatment values is more extreme (farther from the limit) than was the baseline.
If value at baseline is missing, MA is determined by the laboratory test results at each post 
baseline visit.
Table 2 Marked abnormality criteria for safety laboratory variables 
Marked Abnormality Criteria
Clinical laboratory variables
SI units
Low
High
Haematocrit
RATIO
< 0.20
>0.55
Haematocrit
RATIO
>0.60
Na (Sodium)
mmol/L
<130 mmol/L
>150 mmol/L
Na (Sodium)
mmol/L
<120 mmol/L
K (Potassium)
mmol/L
≤2.5 mmol/L
≥6.0 mmol/L
Creatinine
μmol/L
≥1.5X BL CREAT
BL is the baseline measurement
Laboratory MAs occurring during the on-treatment period will be summarised by treatment 
group. The directions of changes (high or low) in MAs will be indicated in the tables. 
Additionally, for each patient with a MA for a parameter, all the patient’s values of that 
parameter over the treatment period will be listed.
4.2.6.7
Vital signs
For vital signs, including body weight and waist circumference, the absolute values at each 
scheduled visit and the corresponding change from baseline, will be summarised by treatment 
group. 


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Absolute values and changes from baseline will also be listed and compared to the AZ-defined 
reference ranges (Table 3), and classified as low (below range), normal (within range or on the 
limits) or high (above range). All values falling outside the reference ranges will be flagged. 
Table 3 Vital signs reference ranges
Parameter
Standard Units
Lower 
Limit
Upper 
Limit
Change from Baseline 
Criteria
Diastolic Blood Pressure (sitting)
mmHg
60
100
±15
Systolic Blood Pressure (sitting)
mmHg
90
160
±30
Pulse Rate (sitting)
Beats/min
50
100
±20
4.2.7
Analysis of exploratory efficacy endpoints
The analysis of exploratory efficacy endpoints will use same approach as for the main analysis 
of primary and secondary efficacy endpoints, that is, use rank ANCOVA model to analyse the 
hierarchical composite endpoints for continuous outcome variables, and logistic regression 
model for binary outcome variables. For continuous outcomes, hierarchical composite 
endpoints will be derived, with a ranking scheme assigning deaths ranks which are lower than 
observed data ranks and ranking among deaths will be based on the last value while alive. For 
binary outcomes, deaths will be considered as not improved or as worsened, as appropriate. 
All exploratory endpoints, except for the KCCQ endpoints, will be analysed using complete 
data, ie, no multiple imputation (MI) of missing data is performed for patients with missing 
data due to reasons other than death. Summary data for each exploratory endpoint will be 
presented by treatment group. 
For KCCQ domains including TSS domains (symptom frequency and symptom burden), 
overall summary score, symptom stability domain, self-efficacy domain, social limitation 
domain and QoL domain. a placebo-based MI with predictive mean matching will be used to 
impute the missing scores due to reasons other than death (Appendix 8.1). HL estimation of 
the median difference between treatment groups and rank ANCOVA model will be performed 
in the same manner as in the main analysis. 
Analysis of change or relative change from baseline at week 16 in the exploratory endpoints 
assessed by MoveTest, and change or relative change from baseline at end of study in the 
exploratory endpoints assessed by MoveMonitor, including VMUs per minute and movement 
intensity during walking, will be performed using the same method; rank ANCOVA model to 
analyse the hierarchical composite rank-based endpoint, as described in Section 4.2.5 for the 
secondary efficacy endpoint assessed by MoveMonitor. These data will be analysed using 
complete data, ie no patients with missing data due to reasons other than death.


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Summary data for NYHA classification at baseline and each analysis time point, and across 
the categories for worsened NYHA classification from baseline at week 16 will be presented 
by treatment group. Analysis of the proportions of patients with worsened NYHA 
classification from baseline at week 16 will be performed using logistic regression, classifying 
all deaths prior to week 16 assessment as worsened NYHA classification. The logistic 
regression model will include treatment group, stratification variable (T2DM status at 
randomisation), and baseline NYHA class (a categorical variable) as covariates. The observed 
proportion, odds ratio between treatment groups and its 95% confidence interval and 
corresponding 2-sided p-value will be presented. 
Summary data for OTB at week 8 and week 16 will be presented by treatment group. Logistic 
regression will be performed to analyse the proportion of patients with positive OTB at week 
16 (versus all other collapsed categories and death). The logistic regression model will include 
treatment group and stratification variable (T2DM at randomisation) as covariates.
The responses to the individual questions of EQ-5D-5L and EQ-VAS score will be 
summarised at baseline and week 16. Change from baseline at week 16 will be summarised to 
the following categories: question completed at baseline and the time point, and 3 derived 
categories (No change from baseline, Deteriorated from baseline and Improved from baseline) 
for each individual question, and change from baseline in EQ-VAS score at week 16 will be 
summarised, with mean, SD, median, Q1 and Q3.
Analyses of change from baseline at week 16 in NT-proBNP, oxygen saturation difference 
after 6MWT, dyspnoea and fatigue, systolic BP difference after 6MWT, body weight, and 
eGFR will be performed using same method, rank ANCOVA model to analyse the 
hierarchical composite endpoint, as described in Section 4.2.4 for the primary efficacy 
endpoints. The comparison using rank ANCOVA model will adjust for baseline value as 
covariate and is stratified by the stratification variable (T2DM at randomisation).
5
INTERIM ANALYSES (NOT APPLICABLE)
6
CHANGES OF ANALYSIS FROM PROTOCOL
Statistical power was re-estimated for a comparison of group-level averages of within-patient 
change, instead of responder analysis (as in the clinical study protocol (CSP)) due to a change 
of main estimation method for effect size from logistic regression to the HL estimate of 
median difference. The sample size estimation remains unchanged.
7
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under sedentary conditions using a tri-axial seismic accelerometer. Obesity 2009 Jun; 
17(6):1287-1292.
Van Remoortel et al 2012
Van Remoortel H, Giabedoni S, Raste Y, Burtin C, Louvaris Z, Gimeno-Santos E, et al. 
Validity of activity monitors in health and chronic disease: a systematic review. Int J Behav 
Nutr Phys Act 2012 Jul 9; 9:84.
Van Roie et al 2019
Van Roie E, Van Driessche S, Hujiben B, Baggen R, van Lullem RC, Delecluse C. A body-
fixed-sensor-based analysis of stair ascent and sit-to-stand to detect age-related differences in 
leg-extensor power. PLoS One 2019 Jan 17; 14(1):e0210653.


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Zakeri et al 2015
Zakeri R, Levine JA, Koepp GA, Borlaug BA, Chirinos JA, LeWinter M, et al. Nitrate's effect 
on activity tolerance in heart failure with preserved ejection fraction trial: rationale and 
design. Circ Heart Fail 2015;8(1):221-8.


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8
APPENDIX
8.1
Accounting for missing data
Subject retention and follow-up are at the forefront of study planning and conduct, and the 
amount of incomplete follow-up is expected to be small. Because of the short study duration, 
the number of deaths observed during the study is expected to be low. Deaths will be included 
in each estimand as described in 4.1.1.
Note that MI of missing data is not performed for safety variables and is not performed for all 
efficacy variables. A placebo-based MI will be undertaken for the following efficacy
variables:

KCCQ (KCCQ-TSS, KCCQ-PLS, six domain scores and one summary score included 
in the exploratory efficacy endpoints, no explicit imputation of the 23 individual 
items/questions), TPA is only performed for KCCQ-TSS and KCCQ-PLS

6MWD
Furthermore, imputation is always done for the values at each visit. This means the change 
values (or relative change values) are never directly imputed. Only the components of the 
change (and relative change) are imputed for the efficacy variables listed above. The 
exploratory efficacy variables which are directly imputed for the values at each visit using MI 
are KCCQ domain and summary scores.
Placebo-based MI
In the main analysis, the underlying assumption is that the trajectory for subjects in the 
dapagliflozin group who dropped out for a treatment-related reason is similar to that of the 
placebo subjects, and that subjects who dropped out for other reason also have a similar 
trajectory as the completers in the placebo group and are imputed assuming missing not at 
random. This placebo-based MI will be done by constructing the imputation of missing 
observations in the treatment groups using the observed data in the placebo group only, that is, 
one imputation model of placebo outcomes will be used to impute missing values for all 
discontinued subjects in both treatment groups. For ITT analyses, this approach is considered 
more conservative than assuming data is missing completely at random (which would be the 
case if missing data was simply excluded) or assuming that data is missing at random (which 
would be the case if a mixed model with repeated measures was used directly) because the 
assumptions mean that as soon as subjects withdraw for a treatment related reason, they begin 
to worsen immediately.


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Predictive mean matching approach
The first step in placebo-based predictive mean matching consists of estimating regression 
coefficients from a linear regression model among subjects in the placebo arm without 
missing data. New regression coefficients are then drawn at random from the posterior 
predictive distribution of the linear model and the new coefficients are then used to generate 
predicted values for all subjects, including both those with missing data and those without. 
The set of closest subjects is then identified for each subject with missing data and a 
replacement for each missing value is drawn at random from the observed data among the 
closest subjects. This process, except for the first deterministic linear regression step, is 
repeated for each imputation dataset. The missing data on the outcome variable at baseline, 
visit 3 and 5 will be imputed in a sequential manner. Missing data at baseline will be imputed 
making the most liberal assumptions, because the likelihood of baseline data being missing 
should not be influenced by randomised treatment assignment. Then, the missing data at visit 
3 will be imputed (treated as monotone missing data) including the potentially imputed 
baseline value as a covariate in the imputation model, and finally the missing data at visit 5 
will be imputed in a similar way except that the (potentially imputed) value at baseline and at 
visit 3 will be used as a covariate in the imputation model for visit 5. 
Tipping point analysis
A TPA will be employed, to assess the sensitivity of the results of the main analysis to the 
handling of missing data. The TPA will only be performed for the primary efficacy endpoints 
and only when a main analysis result is statistically significant. In TPA, missing data is first 
replaced using the MI procedure described above. The imputed post-baseline values in the 
active arm are then subsequently shifted toward a null hypothesis, until the significance of 
model estimates is overturned. The plausibility of the magnitude in the shift parameter 
required to overturn the significance is then interpreted from a clinical perspective, to evaluate 
the robustness of the results to the approach used to handle missing data. The upper boundary 
for shift parameter for 6MWD is set to 100 meters, since if a shift parameter of 100 meters 
could not overturn the significance, it indicates that significance is not sensitive to the 
handling of missing data. For KCCQ-TSS and KCCQ-PLS, the upper limit of the shift 
parameter is set to 40 points. Values will not be shifted outside of the range of the outcome 
variable.


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8.2
Wearable activity monitors
Data from wearable activity monitors
Two types of wearable activity monitors (DynaPort MoveTest and DynaPort MoveMonitor;
McRoberts BV, The Hague, The Netherlands) are available for all patients who are 
randomised at a subset of sites where the devices are available. The two different wearable 
activity monitors are identical in dimensions and appearance but serve different purposes; the 
MoveTest is intended for supervised use at the site for a few minutes at a time and the 
MoveMonitor is intended for unsupervised use at home over several days. The DynaPort 
device (both types) contains a tri-axial accelerometer, a rechargeable battery, raw data storage 
on a Micro-SD card. The device is worn on a belt around the waist and the dimensions are 85 
mm x 58 mm x 11.5 mm, it weighs 55 grams, the sample frequency is 100 Hz and the battery 
lifetime can sustain at least 7 days of continuous measurement. Both wearable activity 
monitors only need to be placed around the waist (like a belt) and worn by the patient, as 
instructed. No additional manipulation is required by the patient (eg, turning the device on/off 
or starting/stopping the measurement). The setup of the wearable activity monitors is handled 
entirely by the site staff.
The first wearable activity monitor is the MoveTest, used at the site during the 6MWT (Van 
Roie et al 2019). The MoveTest assesses performance during the 6MWT and can potentially 
provide different, more granular data on physical ability than the manual 6MWT. In addition 
to an estimate of the distance walked during the 6MWT, for use in an exploratory analysis, the 
MoveTest also provides other parameters for use in exploratory endpoints to assess physical 
ability (Table 4). The analysis time points for variables collected using the MoveTest are the 
same as for the primary efficacy endpoints. As the MoveTest is used during in-clinic visits, 
more than one measurement can be available for a given visit, in the same way as for other 
variables measured in-clinic and such cases will be handled in the same way as specified in 
Section 3.1.3. The two endpoints measured using the MoveTest are designated as exploratory.
The second wearable activity monitor is the MoveMonitor, used by the patient at home, to 
assess physical ability during day-to-day activities. The MoveMonitor has a validated 
classification algorithm by which activities such as sitting, standing and walking can be 
identified, along with postures such as prone, lying, sitting and standing, and different 
measures of physical activity can be assessed using these classifications (Langer et al 2009, 
Dijkstra et al 2010, Storm et al 2015). As the MoveMonitor is used by the patient at home, 
more than one measurement cannot be available for a given time period unless the use of the 
wearable activity monitor was not according to the instructions. Any such violation of 
instructions will result in a missing per “visit” summary value for that time period, as the 
integrity of the collected data cannot be ascertained.


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Data from the two different types of wearable activity monitors (in-clinic versus at home) will 
never be aggregated.
Data collected from the MoveMonitor will span a period of 7 days at each time point for 
collection. Data collected during the 7-day period starting on the day of the enrolment visit 1 
will be retrieved at visit 2a and this data constitutes the baseline for each patient. Data 
collected during the 7-day period starting on the day of visit 3 (week 8) and data collected 
during the 7-day period starting on the day of visit 4 (week 14), will be retrieved at visit 5 
(week 16) and these data comprise the follow-up for each patient. 
Daily summaries for each of the MoveMonitor parameters that are specified as secondary or 
exploratory efficacy endpoints are aggregated, using pre-specified algorithms, into per-visit 
summaries at baseline, the week starting on the day of visit 3, and the week starting on the day 
of visit 4 (end of study). The change from baseline (or relative change from baseline) at end of 
study will constitute the endpoint for all variables based on the MoveMonitor data.
The secondary and exploratory endpoints using MoveMonitor and MoveTest data are 
summarised in Table 4.
Table 4 Endpoints based on data from wearable activity monitors
Endpoint
Secondary/
Exploratory
MoveMonitor/
MoveTest
Change from baseline at end of study in total time spent in LVPA
Secondary
MoveMonitor
Change from baseline at end of study in VMUs per minute 
Exploratory
MoveMonitor
Change from baseline at end of study in movement intensity during 
walking 
Exploratory
MoveMonitor
Change from baseline at end of study in movement intensity when 
walking for durations of >20 seconds
Exploratory
MoveMonitor
Change from baseline at end of study in number of steps, excluding steps 
from walking in stairs
Exploratory
MoveMonitor
Change from baseline at end of study in total time spent in MVPA 
Exploratory
MoveMonitor
Change from baseline at Week 16 in distance walked during 6MWT
Exploratory
MoveTest
Change from baseline at Week 16 in number of stops during 6MWT
Exploratory
MoveTest
Change from baseline at end of study in number of sitting shifts during 
night rest
Exploratory
MoveMonitor
Change from baseline at end of study in total number of activity counts 
during worn periods (activity counts are zero when the device is not worn)
Exploratory
MoveMonitor
Total wear time at end of study
Exploratory
MoveMonitor
Baseline for wearable activity monitor MoveMonitor outcomes consists of a 7-day period 
measured on the week starting at enrolment visit. End of study for wearable activity monitor 


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MoveMonitor outcomes consists of a 7-day period measured on the week starting at visit 4 
(week 14).
For the main analysis of endpoints based on the MoveMonitor, a set of predefined data 
reduction rules, referred to as ‘filters’, are employed to ensure that the MoveMonitor data 
collected corresponds to instructed use and is representative of the physical ability intended to 
be captured. This is common practice in studies using wearable activity monitors and has been 
shown to positively influence the reliability of the data (Colley et al 2010). Filters will define 
the data considered available for the analysis of each endpoint. The same set of predefined 
filters will be applied to all endpoints measured using the MoveMonitor. To assess the 
sensitivity of the results to the filter definitions, additional analyses will be performed with 
predefined variations of the filter definitions and also without applying any filters at all.
Filter definitions
Filters are comprised of data reduction rules, used to ensure that the MoveMonitor data 
contributing to the analysis of endpoints come from periods when the device was used 
according to instructions, that the data sufficiently reflects the activity during each day and 
that the period of use is long enough to be representative of physical ability during day-to-day 
activities.
The standard filter, applied at each analysis time point, has the following rules:

A minimum of 10 hours of wear time, between 6:00 AM and 10:00 PM, will be 
required for the data during a day to be considered ‘sufficient’.

A minimum of 3 days with ‘sufficient’ data, out of the total 7 days, will be required for 
a patient to be considered to have a non-missing value in the analysis.
The standard filter is used for all efficacy endpoints based on MoveMonitor data. To assess the 
sensitivity of the results to the filter definitions, the variations of the filter rules will be applied 
to the secondary efficacy endpoints, ie, total time spent in LVPA.
Variations of the filters rules consist of:

Setting the minimum no. of hours of wear time, between 6:00 AM and 10:00 PM, to 6 
hours and 14 hours, respectively, for data to be classified as ‘sufficient’.

Setting the minimum no. of days with ‘sufficient’ data to 1 day and 5 days, out of the 
total 7 days, for the patient to be classified as having a non-missing outcome in the 
analysis.


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The variations of the filter rules yield 4 additional filter settings of interest:

The first variation consists of requiring a minimum of 3 days with at least 6 hours of 
wear time, out of the total 7 days, between 6:00 AM and 10:00 PM.

The second variation consists of requiring a minimum of 3 days with at least 14 hours 
of wear time, out of the total 7 days, between 6:00 AM and 10:00 PM.

The third variation consists of requiring a minimum of 1 day, out of the total 7 days, 
with at least 6 hours of wear time, between 6:00 AM and 10:00 PM.

The fourth variation consists of requiring a minimum of 5 days, out of the total 7 days, 
with at least 14 hours of wear time, between 6:00 AM and 10:00 PM.
In addition of 4 additional filter settings of interest listed above, total time spent in LVPA will 
also be derived based on all available MoveMonitor data collected during the 7-day period at 
baseline and at end of study, regardless of the number of days or number of hours per day 
during which the device was worn (as long as it is possible to derive per-visit summaries). 
This analysis does not apply any filters at all.
Summary data for total time spent in LVPA based on standard filters, 4 additional filter 
settings of interest and also without applying any filters at all will be presented by treatment 
group. 
Sensitivity analyses and supplemental analyses defined for the primary efficacy endpoints 
(except for TPA) will also be performed for the secondary efficacy endpoint based on 
MoveMonitor data, ie, total time spent in LVPA. Additional analysis of total time spent in 
LVPA may be performed if deemed appropriated.
No sensitivity analyses and supplemental analyses will be performed for exploratory 
objectives.
Handling of missing data due to death
Deaths are included in the definition of the estimand and handled by the ranking scheme, 
analogously to the primary efficacy endpoints.
Handling of missing data not due to death
Missing data which is not due to death will be excluded from analysis of all MoveMonitor and 
MoveTest endpoints. 


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The secondary efficacy variable based on data from the MoveMonitor
The secondary efficacy variable based on data from the MoveMonitor is change from baseline 
at end of study in total time spent in LVPA, as assessed by the MoveMonitor.
Secondary endpoint: change from baseline at end of study in total time spent in LVPA
Total time spent in LVPA is defined as the total wear time spent with an energy expenditure 
≥1.5 METs. These calculations rely on the estimation of energy expenditure, which has been 
validated previously (Van Hees et al 2009, Van Remoortel et al 2012, Brandes et al 2012, 
Rabinovich et al 2013). Total time spent in LVPA is measured in hours. Time spent in LVPA 
per day is calculated as the sum of all time spent with an energy expenditure ≥1.5 METs 
during each day. After applying the filters for MoveMonitor data, the time spent in LVPA per 
day will be summed over the days that have “sufficient” wear time at baseline, week 8 and 
end of study, respectively. The estimand for change from baseline at end of study in total time 
spent in LVPA is defined analogously to the primary efficacy endpoints, with intercurrent 
events handled in the same way.
Change in total time spent in LVPA from baseline at end of study will then be calculated as
	
 −
where LVPABL represents the total time spent in LVPA at baseline and LVPAEOS represents the 
time spent in LVPA at end of study.
Analysis of the secondary efficacy variable
The main estimator for the secondary efficacy variable from the MoveMonitor is the rank that 
will be used for rank ANCOVA model, with deaths handled analogously to the primary 
efficacy endpoints. 
Exploratory endpoint: change from baseline at end of study in VMUs per minute
VMUs per minute is defined as the root mean square of the values along the y-signal (y-axis: 
caudal-cranial) and are calculated according to the norm. VMUs per minute represent a proxy 
for the intensity of effort (CHMP/EMA/SAWP 2018). The unit for VMUs is activity counts. 
The VMUs per minute, per day, is calculated as the sum of the VMUs per minute measured 
during all worn periods during each day, independent of activity (Shoemaker et al 2013). 
After applying the filters for MoveMonitor data, the VMUs per minute per day will be 
summed over the days that have “sufficient” wear time at baseline, week 8 and end of study, 
respectively. The estimand for change from baseline at end of study in VMUs per minute is 


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defined analogously to the primary efficacy endpoints, with intercurrent events handled in the 
same way.
Change in VMUs per minute from baseline at end of study will then be calculated as
	
 −
where VMUBL represents the mean VMUs per minute at baseline and VMUEOS represents the 
mean VMUs per minute at end of study.
Exploratory endpoint: change from baseline at end of study in movement intensity during 
walking
Movement intensity during walking will be assessed by MoveMonitor data as mean movement 
intensity during periods classified as ‘walking’ (at least 3 consecutive steps during a 
‘standing’ posture are required for the classification as 'walking'). Movement intensity is 
defined as the root mean square of the sum of the values along the x-, y-, and z-signals (x-
axis: posterior-anterior; y-axis: caudal-cranial; z-axis: medial-lateral). The unit for movement 
intensity is milli-g (1 milli-g = 9.81 × 10-3 ms-2). The daily mean movement intensity is 
calculated as the sum of mean movement intensity measured during each walking period 
divided by the sum of the lengths of the walking periods. After applying filters to the 
MoveMonitor data, the mean movement intensity per day will be summed over the days that 
have “sufficient” wear time at baseline, week 8 and end of study, respectively. The estimand 
for change from baseline at end of study in movement intensity during walking is defined 
analogously to the primary efficacy endpoints, with intercurrent events handled in the same 
way.
Change in movement intensity during walking from baseline at end of study will then be 
calculated as
	
 −
where MIBL represents the mean movement intensity during walking at baseline and MIEOS
represents the mean movement intensity during walking at end of study.
Other exploratory endpoints based on data from MoveMonitor and MoveTest:

Change from baseline at end of study in movement intensity when walking for 
durations of >20 seconds based on MoveMonitor data, defined as movement intensity 
measured in milli-g, during periods when the physical activity was classified as 
‘walking’ and lasted for more than 20 seconds


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
Change from baseline at end of study in total number of steps based on MoveMonitor
data, defined as the total number of steps excluding steps from walking in stairs

Change from baseline at end of study in total time spent in MVPA based on 
MoveMonitor data, defined as the wear time spent with an energy expenditure ≥3 
METs measured in hours

Change from baseline at week 16 in distance walked during 6MWT based on 
MoveTest data, defined as the total distance covered by the patient measured in meters

Change from baseline at week 16 in number of stops during 6MWT based on 
MoveTest data, defined as the total number of walking interruptions

Change from baseline at end of study in total number of sitting shifts during night rest 
based on MoveMonitor data, defined as a transition between a posture classified as 
‘sitting upright’ and any posture classified as ‘lying’ (ie, ‘prone’, ‘lying on the left’, 
‘lying on the right’ or ‘supine’), with night rest defined as the longest period >3 hours
without interruptions of more than 30 minutes (eg, walking) identified through a 
process where, between 12:00 PM on the day of interest and 12:00 PM the following 
day, all lying periods ≥10 minutes are stitched together with sitting and not wearing 
periods <15 minutes

Change from baseline at end of study in total number of activity counts during worn 
periods based on MoveMonitor data, activity counts are zero when the device is not 
worn

Total wear time at end of study based on MoveMonitor data, defined as the total time 
measured in hours when the number of activity counts was greater than zero
Analysis of the exploratory efficacy endpoints 
The estimand for each exploratory endpoint is defined analogously to the primary efficacy 
endpoints, with intercurrent events handled in the same way. The estimator and estimation of 
treatment effect for each exploratory endpoint, are analogous to those for the primary efficacy 
endpoints. Each exploratory endpoint based on MoveMonitor data will be analysed by both 
change from baseline and relative change from baseline relative to baseline.


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8.3
Anchor-based analyses
Clinically meaningful threshold
Thresholds for meaningful within-subject change will be estimated according to predefined 
algorithms using anchor-based approaches, supplemented with empirical cumulative 
distribution function curves and probability density function curves. Clinically meaningful 
thresholds will be estimated for the following efficacy variables:

Change from baseline in KCCQ-TSS at week 16

Change from baseline in KCCQ-PLS at week 16

Change from baseline in 6MWD at week 16
The analysis will be performed on the FAS population, across both treatment groups. Anchor-
based analysis will only include patients who survived to week 16 with complete data, ie, no 
patients with missing change value at week 16 due to any reason, for variables included in that 
analysis.
Anchor-based approaches
Anchor-based approaches estimate a threshold by ‘anchoring’ the results on a separate 
variable, often a patient-reported outcome (PRO) with a simpler scale, referred to as an anchor 
variable or a global anchor. The anchor-based analyses in this study will employ the following 
PROs as global anchors:

PGIS in HF symptoms (used for KCCQ-TSS)

PGIC in HF symptoms (used as a supportive global anchor for KCCQ-TSS)

PGIC in walking ability (used for 6MWD and as a supportive global anchor for 
KCCQ-PLS)

EQ-5D-5L question: "Usual activities" (used for KCCQ-PLS)
For each anchor, meaningful change will be evaluated using observed scores according to a 
predefined algorithm. The responses to the PGIS and PGIC scales, and the EQ-5D-5L 
question at visit 5 (week 16) will be used in the analysis. For PGIS and EQ-5D-5L, the 
baseline value (randomisation) will also be used in the analysis.
Categorisation of anchors


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The PGIS and PGIC scales, and the EQ-5D-5L question will be categorised to provide a 
clearer difference between patients who have and have not experienced different degrees of 
change according to the anchors. 
The PGIC in walking ability and PGIC in HF symptoms assess how a patient perceives his or 
her overall change in walking ability or HF symptoms since the start of the study. These scales 
have levels ranging from ‘much worse’ to ‘much better’. The values are supplied on an 
ordinal scale and should never be analysed as continuous variables. The ordinal responses to 
PGIC at visit 5 (week 16) will be assigned the following numeric values to allow 
categorisation:

-3 (‘much worse’)

-2 (‘moderately worse’)

-1 (‘a little worse’)

0 (‘about the same’)

+1 (‘a little better’)

+2 (‘moderately better’)

+3 (‘much better’)
The numeric values above are arbitrary. They may seem to imply equidistant categories, but 
this is merely an illusion (we could have assigned logarithmic values and the categorisation 
process would have worked equally well). There is nothing continuous about the ordinal 
verbal response options in a PGIC scale. The numeric values are simply a representation, to 
aid in explaining the collapsing of certain categories. Having noted that, the following 
categories will be defined, using the numeric values assigned above, for PGIC at visit 5 (week 
16):

‘moderate or large deterioration’ (-2 to -3)

‘large deterioration’ (-3)

‘moderate deterioration’ (-2)

‘small deterioration’ (-1)

‘stable’ (0)


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
‘small improvement’ (+1)

‘moderate improvement’ (+2)

‘large improvement’ (+3)

‘moderate or large improvement’ (+2 to +3)
The PGIS in HF symptoms instrument 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’, ‘very mild’, ‘mild’, ‘moderate’, to ‘severe’, and ‘very severe’. The values are 
supplied on an ordinal scale and should never be analysed as continuous variables. The ordinal 
responses to PGIS at baseline and visit 5 (week 16) will be assigned the following numeric 
values to allow categorisation:

1 (‘no symptoms’)

2 (‘very mild’)

3 (‘mild’)

4 (‘moderate’)

5 (‘severe’)

6 (‘very severe’)
Again, similar to what was done for the PGIC, the PGIS contains ordinal verbal response 
options. Numeric values are somewhat arbitrarily assigned to illustrate the "number of steps" a 
patient has moved in a shift table. Having noted that, the following numerical change values 
are defined, in Table 5, based on the numeric values assigned to each response option in PGIS.
Collapsed or “transformed” categories corresponding to ‘moderate or large deterioration’ (+3 
to +5) and ‘moderate or large improvement’ (-3 to -5) will also be defined in accordance with 
the categories for PGIC. 
Table 5 Definition of transformed and raw numeric change from baseline values for 
PGIS in HF symptoms
PGIS in HF symptoms at baseline
PGIS in HF 
symptoms at week 16
No symptoms
(1)
Very mild
(2)
Mild
(3)
Moderate 
(4)
Severe
(5)
Very severe
(6)
No symptoms (1)
Stable (0)
SIm (-1)
MIm (-2)
LIm (-3)
LIm (-4)
LIm (-5)


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Table 5 Definition of transformed and raw numeric change from baseline values for 
PGIS in HF symptoms
PGIS in HF symptoms at baseline
PGIS in HF 
symptoms at week 16
No symptoms
(1)
Very mild
(2)
Mild
(3)
Moderate 
(4)
Severe
(5)
Very severe
(6)
Very mild (2)
SDt (+1)
Stable (0)
SIm (-1)
MIm (-2)
LIm (-3)
LIm (-4)
Mild (3)
MDt (+2)
SDt (+1)
Stable (0)
SIm (-1)
MIm (-2)
LIm (-3)
Moderate (4)
LDt (+3)
MDt (+2)
SDt (+1)
Stable (0)
SIm (-1)
MIm (-2)
Severe (5)
LDt (+4)
LDt (+3)
MDt (+2)
SDt (+1)
Stable (0)
SIm (-1)
Very severe (6)
LDt (+5)
LDt (+4)
LDt (+3)
MDt (+2)
SDt (+1)
Stable (0)
Transformed change from baseline scores are given as LDt, MDt, etc. and raw change from 
baseline scores are given in parentheses as (+5), (+4), (+3), (+2), (+1), (0), (-1), (-2), (-3), (-4) 
or (-5). 
LDt Large deterioration. MDt Moderate deterioration. SDt Small deterioration. SIm Small 
improvement. MIm Moderate improvement. LIm Large improvement. HF Heart failure. PGIS 
Patient global impression of severity.
EQ-5D-5L question: "Usual activities" asks how the patient is limited in their usual activities 
(eg, work, study, housework, family or leisure activities). This is about as close of an anchor 
as we can muster up for the KCCQ-PLS. Patients will choose from 5 response options ranging 
from ‘I have no problems doing my usual activities’, ‘I have slight problems doing my usual 
activities’, ‘I have moderate problems doing my usual activities’, ‘I have severe problems 
doing my usual activities’, to ‘I am unable to do my usual activities’. The values are supplied 
on an ordinal scale and should never be analysed as continuous variables. The ordinal 
responses to EQ-5D-5L question: "Usual activities" at baseline and visit 5 (week 16) will be 
assigned the following numeric values to allow categorisation:

1 (‘I have no problems doing my usual activities’)

2 (‘I have slight problems doing my usual activities’)

3 (‘I have moderate problems doing my usual activities)

4 (‘I have severe problems doing my usual activities’)

5 (‘I am unable to do my usual activities’)
Based on the numeric values assigned to each response option in EQ-5D-5L question: "Usual 
activities", numerical change values are defined, as in Table 6. Collapsed or “transformed” 
categories corresponding to ‘moderate or large deterioration’ (+2 to +4) and ‘moderate or 
large improvement’ (-2 to -4) will also be defined in accordance with the categories for PGIS.


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Table 6 Definition of transformed and raw numeric change from baseline values for 
EQ-5D-5L question: "Usual activities"
EQ-5D-5L question: "Usual activities" at baseline
EQ-5D-5L 
question: "Usual 
activities" at 
week 16
I have no 
problems 
doing usual 
activities
(1)
I have slight 
problems 
doing usual 
activities
(2)
I have 
moderate
problems 
doing usual 
activities
(3)
I have severe
problems 
doing usual 
activities
(4)
I am unable 
to do usual 
activities
(5)
I have no 
problems doing 
usual activities 
(1)
Stable (0)
SIm (-1)
MIm (-2)
LIm (-3)
LIm (-4)
I have slight 
problems doing 
usual activities
(2)
SDt (+1)
Stable (0)
SIm (-1)
MIm (-2)
LIm (-3)
I have moderate 
problems doing 
usual activities
(3)
MDt (+2)
SDt (+1)
Stable (0)
SIm (-1)
MIm (-2)
I have severe 
problems doing 
usual activities
(4)
LDt (+3)
MDt (+2)
SDt (+1)
Stable (0)
SIm (-1)
I am unable to do 
usual activities
(5)
LDt (+4)
LDt (+3)
MDt (+2)
SDt (+1)
Stable (0)
Transformed change from baseline scores are given as LDt, MDt, etc. and raw change from 
baseline scores are given in parentheses as (+4), (+3), (+2), (+1), (0), (-1), (-2), (-3) or (-4). 
LDt Large deterioration. MDt Moderate deterioration. SDt Small deterioration. SIm Small 
improvement. MIm Moderate improvement. LIm Large improvement. EQ-5D-5L EuroQol 
five-dimensional five-level questionnaire.
Utilisation of anchors
The main anchor used to establish the threshold for CMWPC from baseline at week 16 in 
KCCQ-TSS is change from baseline PGIS in HF symptoms at week 16, using the category 
‘moderate or large improvement’(defined by combining the categories ‘moderate 
improvement’ and ‘large improvement’). The analyses of other categories for PGIS in HF 
symptoms and the analysis of PGIC in HF symptoms will be regarded as supportive.


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The main anchor used to establish the threshold for CMWPC from baseline at week 16 in 
KCCQ-PLS is change from baseline in EQ-5D-5L question: "Usual activities" at week 16, 
using the category ‘moderate or large improvement’ (defined by combining the categories 
‘moderate improvement’ and ‘large improvement’). The analyses of other categories for EQ-
5D-5L question: "Usual activities" and the analysis of PGIC in walking ability will be 
regarded as supportive.
The main anchor used to establish the threshold for CMWPC from baseline at week 16 in 
6MWD is PGIC in walking ability at week 16, using the category ‘moderate or large 
improvement’. The analyses of other categories of PGIC in walking ability will be regarded as 
supportive. 
Anchor-based analysis
The change from baseline at week 16 in the KCCQ-TSS, KCCQ-PLS and 6MWD will be 
used repeatedly in the anchor-based analyses. 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum and maximum) and empirical 
cumulative distribution function curves and probability density function curves will be 
presented for each combination of anchor, category and endpoint. The empirical cumulative 
distribution function curves display a continuous plot of the change from baseline on the 
horizontal axis, and the cumulative percent of patients experiencing changes from baseline up 
to that level on the vertical axis. The probability distribution function curves will display 
kernel density curves for all the categories of change from baseline overlaying the histogram 
with all categories combined. The percent of patients with change from baseline within each 
category in the histogram is displayed on the vertical axis.
Establishing the clinically meaningful threshold
To have a completely prespecified decision algorithm for defining the thresholds for 
CMWPC, threshold value will be defined by the mean change from baseline at week 16 value 
in the endpoint (KCCQ-TSS, KCCQ-PLS or 6MWD) corresponding to the category 
‘moderate or large improvement’, for change from baseline at week 16 in PGIS in HF 
symptoms (for KCCQ-TSS), for change from baseline at week 16 EQ-5D-5L question "Usual 
activities (for KCCQ-PLS), or in PGIC in walking ability at week 16 (for 6MWD). Rounding 
up to the nearest integer, will be done when determining threshold values. The reason why the 
collapsed category is selected is because small sample sizes are expected in the extreme 
category (‘large improvement’) and there will be a more balanced number of patients 
compared to the ‘stable’ category.


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8.4
KCCQ scoring algorithm
The KCCQ is a 23-item, self-administered disease specific instrument, which has been shown 
to be a valid, reliable and responsive measure for patients with HF (Green et al 2000, FDA 
2020, 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 patient’s HF affects their quality of life. 
The 23 items and corresponding 15 questions are listed in the Appendix H of the CSP. The 6
items in question 1 constitute the PLS. The question 2 is for the symptom stability domain. 
The questions 3, 5, 7 and 9 constitute the symptom frequency domain, and the questions 4, 6 
and 8 constitute the symptom burden domain. The total symptom score incorporates the 
symptom frequency (4 items) and symptom burden (3 items). The questions 10 and 11 
constitute the self-efficacy domain. The questions 12, 13 and 14 (3 items) constitute quality of 
life (QoL) domain. The question 15 is for the social limitation domain. Overall summary score 
is the average of the physical limitation score, total symptom score, quality of life score, and 
the social limitation score.
Each KCCQ item or question is scored by assigning each response an ordinal value, beginning 
with 1 for the response that implies the lowest level of functioning. If at least half of the 
components within the domain are not missing, then the domain score can be calculated by 
summing the responses of the questions actually answered within the domain. Scale scores are 
transformed to a 0 to 100 range by subtracting the lowest possible scale score, dividing by the 
range of the scale and multiplying by 100. If the domain has more than one component, the 
domain score will be the mean value of the transformed score over the components actually 
answered. Higher scores represent a better outcome. The scoring algorithm of each domain 
and summary score is described in detail below. 
Physical Limitation
Code responses to each of Questions 1a-f as follows:
Extremely limited = 1
Quite a bit limited = 2
Moderately limited = 3
Slightly limited = 4
Not at all limited = 5
Limited for other reasons or did not do = <missing value>
If at least three of Questions 1a-f are not missing, then compute
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4


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Symptom Stability
Code the response to Question 2 as follows:
Much worse = 1
Slightly worse = 2
Not changed = 3
Slightly better = 4
Much better = 5
I’ve had no symptoms over the last 2 weeks = 3
If Question 2 is not missing, then compute
Symptom Stability Score = 100*[(Question 2) – 1]/4
Symptom Frequency
Code responses to Questions 3, 5, 7 and 9 as follows:
Question 3
Every morning = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5
Questions 5 and 7
All of the time = 1
Several times a day = 2
At least once a day = 3
3 or more times a week but not every day = 4
1-2 times a week = 5
Less than once a week = 6
Never over the past 2 weeks = 7
Question 9
Every night = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5
If at least two of Questions 3, 5, 7 and 9 are not missing, then compute:
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6
S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4


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Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
Symptom Burden
Code responses to each of Questions 4, 6 and 8 as follows:
Extremely bothersome = 1
Quite a bit bothersome = 2
Moderately bothersome = 3
Slightly bothersome = 4
Not at all bothersome = 5
I’ve had no swelling/fatigue/shortness of breath = 5
If at least one of Questions 4, 6 and 8 is not missing, then compute
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4
Total Symptom Score
Total Symptom Score = mean of Symptom Frequency Score and Symptom Burden Score
Self-Efficacy
Code responses to Questions 10 and 11 as follows:
Question 10
Not at all sure = 1
Not very sure = 2
Somewhat sure = 3
Mostly sure = 4
Completely sure = 5
Question 11
Do not understand at all = 1
Do not understand very well = 2
Somewhat understand = 3
Mostly understand = 4
Completely understand = 5
If at least one of Questions 10 and 11 is not missing, then compute
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4
Quality of Life
Code responses to Questions 12, 13 and 14 as follows:
Question 12
It has extremely limited my enjoyment of life = 1
It has limited my enjoyment of life quite a bit = 2
It has moderately limited my enjoyment of life = 3
It has slightly limited my enjoyment of life = 4
It has not limited my enjoyment of life at all = 5


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Question 13
Not at all satisfied = 1
Mostly dissatisfied = 2
Somewhat satisfied = 3
Mostly satisfied = 4
Completely satisfied = 5
Question 14
I felt that way all of the time = 1
I felt that way most of the time = 2
I occasionally felt that way = 3
I rarely felt that way = 4
I never felt that way = 5
If at least one of Questions 12, 13 and 14 is not missing, then compute
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4
Social Limitation
Code responses to each of Questions 15a-d as follows:
Severely limited = 1
Limited quite a bit = 2
Moderately limited = 3
Slightly limited = 4
Did not limit at all = 5
Does not apply or did not do for other reasons = <missing value>
If at least two of Questions 15a-d are not missing, then compute
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4
Overall Summary Score
Overall Summary Score = mean of the following available summary scores:
Physical Limitation Score
Total Symptom Score
Quality of Life Score
Social Limitation Score
Clinical Summary Score
Clinical Summary Score = mean of Physical Limitation Score and Total Symptom Score
For PLS and social limitation domain, the response to the items/questions could be “Limited 
for other reasons or did not do” and “Does not apply or did not do for other reasons”, 
respectively. The response represents the scenario that the question doesn’t apply and the 
score is not calculable (NC). For example, if a patient stays at home, the item “Hurrying or 
jogging (as if to catch a bus)” is not answerable, and the corresponding scale score will be NC. 
If at a time point, at least 4 items in PLS were responded to as “Limited for other reasons or 


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did not do”, or at least 3 items in social limitation were responded to as “Does not apply or did 
not do for other reasons”, the corresponding PLS or social limitation domain at that time point 
will be considered as NC. If the PLS or social limitation score is NC at baseline or visit 5, the 
patient will be excluded from the corresponding analysis. Not calculable at visit 3 is rare and 
only plays a role in the sequential imputations, therefore, it will be treated as missing.


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