A Phase 2b, Randomised, Double-Blind, Active Controlled, Multi Centre Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin Treatment in Patients With Heart Failure and Chronic Kidney Disease
Phase: PHASE2
Conditions: Heart Failure, Chronic Kidney Disease
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
AZD9977 and dapagliflozin
Study Code
D6402C00001
Version
7.0
Date
02 Feb 2022
A Phase 2b, Randomised, Double-Blind, Active-Controlled, 
Multi-Centre Study to Evaluate the Efficacy, Safety and 
Tolerability of Oral AZD9977 and Dapagliflozin Treatment in 
Patients with Heart Failure and Chronic Kidney Disease
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): IND 149932; EudraCT 2020-003126-23
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D6402C00001
Amendment Number: 6
Study Intervention: AZD9977 and dapagliflozin
Study Phase: Phase 2b
Short Title: Efficacy, safety, and tolerability of AZD9977 and dapagliflozin in patients with 
heart failure and chronic kidney disease
Acronym: MIRACLE (MIneRAlocorticoid reCeptor moduLator and sodium-glucosE 
cotransporter-2-inhibitor in HF and CKD trial)
Study Physician Name and Contact Information will be provided separately
International co-ordinating investigators: 
 (University of Glasgow, United 
Kingdom); 
 (Harvard Medical School, United States); 
 
(National Heart Centre, Singapore)
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Version 1.0
25 August 2020
Amendment 1, Version 2.0
06 October 2020
Amendment 2, Version 3.0
26 January 2021
Amendment 3, Version 4.0
19 March 2021
Amendment 4, Version 5.0
15 July 2021
Amendment 5, Version 6.0
20 December 2021
Amendment 6, Version 7.0
02 February 2022
A summary of changes for the previous amendments is provided in Appendix K.
Amendment 6 (02 February 2022)
This amendment is considered to be substantial due to being a correction and clarification of 
CSP Amendment 5/CSP 6.0 which is a substantial amendment based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Rationale for the Amendment
The previous Clinical Study Protocol (CSP) version, version 6.0, dated 20 December 2021 has 
been updated. The updates are summarised below.
Section Number and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of Activities, 
Table 1
Blood samples for 
cardiovascular biomarkers to be 
collected at Follow-Up Visit 11.
Correction of typo to align with 
Section 8.6.1.
Section 1.3 Schedule of Activities, 
Table 1 (footnote)
Section 7.1 Discontinuation of Study 
Intervention
Text added on open label 
dapagliflozin use during Safety 
Follow-Up period.
Clarification of study 
procedures.
Section 2.3.1 Risk Assessment, 
Table 2; Section 11 References
Inclusion of an additional 
literature reference.
To provide the correct literature 
reference.
Section 5.4 Screen Failures
New definition of Screen 
Failures.
Correction of definition to align 
with revised study design.
In addition, the following administrative changes were made:

Tables of Contents updated.

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
Minor editorial changes.
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................. 2
TABLE OF CONTENTS ...................................................................................................... 3
1
PROTOCOL SUMMARY .................................................................................. 7
1.1
Synopsis ............................................................................................................. 7
1.2
Schema............................................................................................................. 12
1.3
Schedule of Activities ....................................................................................... 13
2
INTRODUCTION............................................................................................ 25
2.1
Study Rationale ................................................................................................ 25
2.2
Background ...................................................................................................... 25
2.2.1
Heart Failure with Chronic Kidney Disease ...................................................... 26
2.2.1.1
Prevalence of Heart Failure............................................................................... 26
2.2.1.2
Heart Failure Management................................................................................ 26
2.2.1.3
Mineralocorticoid Receptor Antagonist for Treatment of Heart Failure and 
Chronic Kidney Disease.................................................................................... 27
2.2.1.4
Sodium-glucose Co-transporter 2 Inhibitors in Heart Failure and Chronic 
Kidney Disease................................................................................................. 28
2.3
Benefit/Risk Assessment................................................................................... 29
2.3.1
Risk Assessment ............................................................................................... 29
2.3.2
Benefit Assessment........................................................................................... 33
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 33
3
OBJECTIVES AND ENDPOINTS................................................................... 34
4
STUDY DESIGN ............................................................................................. 37
4.1
Overall Design.................................................................................................. 37
4.1.1
Optional Pre-screening...................................................................................... 38
4.2
Scientific Rationale for Study Design ............................................................... 38
4.3
Justification for Dose........................................................................................ 39
4.4
End of Study Definition.................................................................................... 39
5
STUDY POPULATION.................................................................................... 40
5.1
Inclusion Criteria .............................................................................................. 40
5.2
Exclusion Criteria ............................................................................................. 43
5.3
Lifestyle Considerations ................................................................................... 45
5.3.1
Meals and Dietary Restrictions ......................................................................... 45
5.4
Screen Failures ................................................................................................. 46
6
STUDY INTERVENTION ............................................................................... 47

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6.1
Study Intervention(s) Administered................................................................... 47
6.1.1
Investigational Products.................................................................................... 47
6.1.2
Medical Devices ............................................................................................... 48
6.2
Preparation/Handling/Storage/Accountability ................................................... 49
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 49
6.4
Study Intervention Compliance......................................................................... 50
6.5
Concomitant Therapy........................................................................................ 51
6.5.1
Prohibited Medications ..................................................................................... 51
6.5.2
Background Medications .................................................................................. 52
6.5.3
Medications Inducing Hypoglycaemia .............................................................. 52
6.6
Dose Modification ............................................................................................ 53
6.7
Intervention After the End of the Study............................................................. 53
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 54
7.1
Discontinuation of Study Intervention............................................................... 54
7.1.1
Temporary Discontinuation and Rechallenge .................................................... 55
7.2
Participant Withdrawal from the Study.............................................................. 55
7.3
Lost to Follow-up ............................................................................................. 56
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 57
8.1
Efficacy Assessments........................................................................................ 57
8.1.1
Primary/Secondary Variable:  Urinary Albumin to Creatinine Ratio (UACR).... 57
8.1.2
Exploratory Variables – Not Applicable ............................................................ 58
8.2
Safety Assessments........................................................................................... 58
8.2.1
Physical Examinations...................................................................................... 58
8.2.2
Vital Signs ........................................................................................................ 58
8.2.3
Electrocardiograms........................................................................................... 59
8.2.4
Clinical Safety Laboratory Assessments............................................................ 59
8.3
Adverse Events and Serious Adverse Events..................................................... 62
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 62
8.3.2
Follow-up of AEs and SAEs ............................................................................. 62
8.3.3
Causality Collection.......................................................................................... 63
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 64
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 64
8.3.6
Hy’s Law.......................................................................................................... 64
8.3.7
Reporting of Serious Adverse Events ................................................................ 64
8.3.8
Pregnancy......................................................................................................... 65
8.3.8.1
Maternal Exposure............................................................................................ 65
8.3.8.2
Paternal Exposure............................................................................................. 66
8.3.9
Medication Error............................................................................................... 67
8.3.10
Medical Device Deficiencies............................................................................. 68
8.4
Overdose .......................................................................................................... 68
8.5
Human Biological Samples............................................................................... 68
8.5.1
Pharmacokinetics.............................................................................................. 69

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8.5.1.1
Determination of Drug Concentration ............................................................... 69
8.5.2
Pharmacodynamics........................................................................................... 70
8.5.2.1
Collection of Samples....................................................................................... 70
8.6
Human Biological Sample Biomarkers ............................................................. 71
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 71
8.6.2
Collection of Optional Biomarker Samples ....................................................... 71
8.7
Optional Genomics Initiative Sample................................................................ 71
8.8
Medical Resource Utilisation and Health Economics ........................................ 71
9
STATISTICAL CONSIDERATIONS................................................................ 72
9.1
Statistical Hypotheses....................................................................................... 72
9.2
Sample Size Determination............................................................................... 72
9.3
Populations for Analyses................................................................................... 73
9.4
Statistical Analyses ........................................................................................... 73
9.4.1
General Considerations..................................................................................... 73
9.4.2
Efficacy ............................................................................................................ 74
9.4.2.1
Primary Endpoint.............................................................................................. 74
9.4.2.2
Secondary Endpoint.......................................................................................... 75
9.4.3
Pharmacokinetics.............................................................................................. 75
9.4.4
Pharmacodynamics and Biomarkers.................................................................. 76
9.4.5
Safety ............................................................................................................... 76
9.4.5.1
Adverse Events................................................................................................. 76
9.4.5.2
Vital Signs ........................................................................................................ 77
9.4.5.3
Laboratory........................................................................................................ 77
9.4.5.4
Electrocardiograms........................................................................................... 78
9.4.5.5
Physical Examination........................................................................................ 79
9.4.5.6
Safety Topics of Interest.................................................................................... 79
9.5
Interim Analyses............................................................................................... 79
9.6
Data Monitoring Committee ............................................................................. 79
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ........................................................................................ 81
11
REFERENCES............................................................................................... 133
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 12

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LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 13
Table 2
Risk Assessment...................................................................................... 29
Table 3
Objectives and Endpoints......................................................................... 34
Table 4
Study Treatments..................................................................................... 38
Table 5
Investigational Products........................................................................... 48
Table 6
Laboratory Safety Variables..................................................................... 61
Table 7
Populations for Analysis .......................................................................... 73
Table 8
CYP3A4-Interacting Medication that are Prohibited During the Study... 109
LIST OF APPENDICES
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 82
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 87
Appendix C
Handling of Human Biological Samples .................................................. 92
Appendix D
Optional Genomics Initiative Sample....................................................... 94
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 97
Appendix F
Management of Hyperkalaemia and Deteriorating Renal Function......... 103
Appendix G
COVID-19 Specifics.............................................................................. 106
Appendix H
Strong and Moderate Cytochrome P450 3A4 (CYP3A4) Inhibitors and 
Inducers................................................................................................. 109
Appendix I
Clinical Study Medical Device / Device Constituent Report Form ......... 110
Appendix J
Abbreviations ........................................................................................ 111
Appendix K
Protocol Amendment History................................................................. 116

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b, Randomised, Double-Blind, Active-Controlled, Multi-Centre 
Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin 
Treatment in Patients with Heart Failure and Chronic Kidney Disease
Short Title: Efficacy, safety, and tolerability of AZD9977 and dapagliflozin in patients with 
heart failure and chronic kidney disease
Rationale: Although mineralocorticoid receptor antagonists (MRAs) are an important 
standard therapy for heart failure (HF), they are currently contraindicated in patients with 
estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 and are highly underused in 
patients with eGFR < 60 mL/min/1.73 m2 due to risk of hyperkalaemia. 
AZD9977 is a selective mineralocorticoid receptor (MR) modulator, with a differentiated 
mode of action compared with the currently prescribed MRAs (eg,
spironolactone/eplerenone).
The mechanisms of action of AZD9977 and dapagliflozin are different and outcome of the 
combination treatment is expected to be synergistic since the main biological effects of 
AZD9977 would be to block MR driven oxidative stress, inflammation and fibrosis and of 
dapagliflozin to inhibit sodium-glucose co-transporter-2 (SGLT2)-driven metabolic 
dysfunction, volume overload, and endothelial cell dysfunction. 
The overall clinical evidence suggests that the combination of AZD9977 and dapagliflozin 
would have clinical benefit and an acceptable safety profile in patients with HF and that 
further development is warranted. Hence, a global, randomised, Phase 2b study is planned to 
evaluate the efficacy and safety of AZD9977 and dapagliflozin in patients with HF.
The purpose of the study is to establish a dose-response for effect on urinary albumin to 
creatinine ratio (UACR) and assess the safety of AZD9977 given in combination with 
dapagliflozin 10 mg once daily, considering serum/plasma potassium+ (K+) and safety topics 
of interest (hyperkalaemia, hypotension and deteriorating renal function) in addition to general 
safety.

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Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
UACR

Percent change from baseline in UACR 
at the end of 12 weeks of study 
treatment
Secondary

To assess the dose-response 
relationship of dapagliflozin (10 mg) 
alone and 3 doses of AZD9977 (15, 50, 
or 150 mg) combined with 
dapagliflozin (10 mg) on UACR

Percent change from baseline in UACR 
at the end of 12 weeks of study 
treatment
Safety 

To assess the general safety and 
tolerability of AZD9977 in combination 
with dapagliflozin compared with 
dapagliflozin alone

AE/SAE reporting

Vital signs (BP, pulse rate)

Clinical laboratory tests (clinical 
chemistry, haematology, and urinalysis)

Digital 12-lead safety ECG assessments

Safety topics of interest (hyperkalaemia, 
hypotension and deteriorating renal 
function)

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
serum K+ and eGFR

Absolute value and change from 
baseline in serum K+ and eGFR over 
time
AE=adverse event; BP=blood pressure; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; 
K+=potassium; SAE=serious adverse event; UACR=urinary albumin to creatinine ratio.
For exploratory objectives and endpoints, see Section 3 of the protocol.

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Overall Design: This is a Phase 2b, multi-centre, randomised, double-blind, active-controlled 
parallel group, study to assess the efficacy, safety and tolerability of AZD9977 and 
dapagliflozin administered for 12 weeks in patients with HF (LVEF below 60%) and chronic 
kidney disease (CKD) (eGFR ≥20 and ≤60 mL/min/1.73 m2), with at least 20% of patients 
with eGFR ≥20 to < 30 mL/min/1.73 m2 and a maximum of 35% of patients with 
eGFR ≥45 mL/min/1.73 m2.
The study will be conducted at approximately 150 to 250 sites in approximately 20 countries 
including North America, Asia-Pacific, and European countries.
Patients who meet the eligibility criteria will be randomised to one of the following 
4 treatment groups:

AZD9977 15 mg + dapagliflozin 10 mg 

AZD9977 50 mg + dapagliflozin 10 mg 

AZD9977 150 mg + dapagliflozin 10 mg 

Dapagliflozin 10 mg
Participants will be stratified according to T2DM (yes/no) and eGFR (≥20 to 
< 30 mL/min/1.73 m2; or ≥30 to < 45 mL/min/1.73 m2; or ≥45 mL/min/1.73 m2) based on the 
latest eGFR assessment prior to the start of study treatment (eGFR assessment at Visit 2).
A Safety Unblinded Data Review Committee will be set up for this study for ongoing safety 
monitoring. In addition to general safety/tolerability, the committee will focus on potential 
risks related to hypotension, deteriorating renal function and hyperkalaemia.
An Interim Unblinded Data Review Committee will be set up to review data from the 
pre-planned interim analysis and make recommendations regarding future clinical 
development.
Disclosure Statement: This is a parallel group treatment study with 4 arms that is 
participant- and investigator-blinded.
Number of Participants:
Approximately 500 participants will be randomly assigned to study intervention 
(125 participants per group) such that approximately 476 evaluable participants (119 per 
group) complete the study.
Intervention Groups and Duration:
For each participant, the total duration of participation will be approximately 22 to 24 weeks, 
including a 1-week screening period, followed by up to 7-week run-in period followed by a 

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12-week treatment period (including 6 visits), the end of treatment (EOT) visit, and a 4-week 
safety follow-up after last dose (including 1 visit). An optional pre-screening visit may be 
scheduled. Week and day for pre-screening visit will be at the discretion of the investigator.
After screening, eligible participants currently on treatment with a SGLT2i other than 
dapagliflozin should stop taking the SGLT2i and start on dapagliflozin 10 mg. Participants on 
dapagliflozin treatment will continue on treatment but the medication will be provided. 
Participants will then undergo a 4 to 5-week run-in period to ensure washout of forbidden 
medications and stable doses of allowed background medications.
For participants eligible after screening, and not on treatment with a SGLT2i, treatment with 
dapagliflozin 10 mg will be initiated. Participants will then undergo a 6 to 7-week run-in 
period to ensure washout of forbidden medications and stable doses of allowed background 
medications.
During the treatment period, participants will be randomly assigned in a 1:1:1:1 ratio to 
receive once daily administration of one of the 4 study treatments as described below. To 
ensure blinding, the study treatment will be administered in the form of 3 oral capsules and 
1 oral tablet in the following combinations:
Study Treatment
Capsule 1
Capsule 2
Capsule 3
Tablet
AZD9977 15 mg + 
Dapagliflozin 10 mg
AZD9977 15 mg
Placebo
Placebo
Dapagliflozin 10 mg
AZD9977 50 mg + 
Dapagliflozin 10 mg
Placebo
AZD9977 50 mg
Placebo 
Dapagliflozin 10 mg
AZD9977 150 mg + 
Dapagliflozin 10 mg
Placebo
AZD9977 50 mg
AZD9977 100 mg
Dapagliflozin 10 mg
Dapagliflozin 10 mg 
alone 
Placebo
Placebo
Placebo
Dapagliflozin 10 mg
No dose modifications are allowed during the study.
Data Monitoring Committee: Yes
Statistical Methods
The primary hypothesis for this study is that AZD9977 in combination with dapagliflozin will 
induce a reduction of albuminuria greater than with dapagliflozin alone, as assessed by the 
percent change from baseline in UACR at 12 weeks.
A total of 119 evaluable participants per arm will provide 80% power to detect a 30% 
difference in a AZD9977 dose group combined with dapagliflozin 10 mg compared to 
dapagliflozin 10 mg alone in percent change from baseline in UACR at 12 weeks, assuming a 
standard deviation (SD) of 1.0 on the natural log-scale and alpha = 0.05. To account for 

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approximately 5% drop-out from the study, approximately 500 participants will be randomly 
assigned to study intervention (125 participants per group) such that approximately 
476 evaluable participants (119 per group) complete the study. 
Patients randomised according to CSP versions 1.0 to 5.0 (before dropping placebo and 
AZD9977 150 mg monotherapy arms) will be considered as part of Cohort 1, while patients 
randomised subsequently will be included in the Cohort 2. The primary analysis for remaining 
4 treatment groups will combine data from both cohorts, while the accrued data from 
discontinued treatment groups will be analysed descriptively.
The primary efficacy endpoint for this study is the percent change from baseline in UACR at 
12 weeks. The mean log percent changes in UACR at 12 weeks for each of the 3 doses of 
AZD9977 combined with dapagliflozin 10 mg, and dapagliflozin alone will be estimated in a 
mixed model for repeated measures (Visits 7, 8, 9, and 10). The values will be 
back-transformed onto the original scale to give the geometric mean relative change from 
baseline at 12 weeks. The analysis model will include UACR baseline value, treatment, and 
visit as fixed effect, and the stratifying factors (T2DM [yes/no] and eGFR 
[≥20 to < 30 mL/min/1.73 m2; or ≥30 to < 45 mL/min/1.73 m2; or ≥45 mL/min/1.73 m2]) as 
well as the Cohort variable (1 or 2) as covariates. Moreover, treatment-by-visit interaction will 
also be included in the model. The final analytical approach will be described in detail in the 
Statistical Analysis Plan (SAP).
For the primary analysis, the main treatment comparisons to be evaluated are (in a fixed 
sequence of testing):
1
Overall comparison of the percentage changes from baseline in UACR at week 12 across
all 4 treatment groups
2
Each of the 3 doses of AZD9977 in combination with dapagliflozin 10 mg versus 
dapagliflozin 10 mg in the following order:
1. AZD9977 150 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
2. AZD9977 50 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
3. AZD9977 15 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
For the analysis addressing the secondary objective, the dose-response relationship of percent 
change from baseline in UACR at 12 weeks will be assessed using data from dapagliflozin 
(10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin 
(10 mg).

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1.2
Schema
Figure 1
Study Design
AZD9977 15 mg + dapagliflozin 10 mg
Pre-screening 
informed 
consent and 
local laboratory 
urine sample for 
albumin and 
creatinine
Patients
with 
HF and CKD
Dapagliflozin 
10 mg
Laboratory tests 
for eligibility
Dapa-
gliflozin 
10 mg
AZD9977 50 mg + dapagliflozin 10 mg 
R
AZD9977 150 mg + dapagliflozin 10 mg
Dapagliflozin 10 mg
Pre-screening
Screening
Start Run-in b
Pre-
Randomisation
Baseline
Treatment period
(12 weeks)
EOT/
ET
Safety 
follow-up
(4 weeks)
Visit
Optional
1a
1b
2
3
4
5
6
7
8
9
10
11
Weeks
a
(-8 to -7) c
-6 to -5
(-7 to -6) c
-5 to -4
-1
1
2
3
4
7
10
13
17
Day
a
-56 to -49) c
-42 to -35
(-49 to -42) c
-35 to -28
-10 to -3
1
3
8
15
22
43
64
85
113
CKD=chronic kidney disease; EOT=end of treatment; ET=early termination; HF=heart failure; R=randomisation
Note: Visits at Week 7 and Week 13 (Visits 8 and 10) correspond to visits after completion of 6 weeks and 12 weeks of study treatment, respectively.
a
Week and day for pre-screening will be at the discretion of the investigator.
b
Duration of run-in period for patients on treatment with a SGLT2i: 4 to 5 weeks
Duration of run-in period for patients not on treatment with a SGLT2i: 6 to 7 weeks
c
Applies to SGLT2i naïve patients

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1.3
Schedule of Activities
Table 1
Schedule of Activities
Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Informed 
consent
X
X
Appendix A 3
Local 
laboratory urine 
samples for 
albumin and 
creatinine
X
Sample 
according to 
local clinical 
practice.
Section 8.2.4
Inclusion and 
exclusion 
criteria
X
X
X
Sections
5.1, 5.2
Enrolment in 
RTSM
X
Section 6.3
Demography, 
height, smoking 
history, alcohol 
consumption
X
Sections
5.1, 5.2
Physical 
examination, 
weight
X
X (pre-
dose)
X
X
For site visits 
only.
Section 8.2.1

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Medical/
surgical history 
X
X
Sections
5.1, 5.2
Concomitant 
medication 
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Adverse events
SAEs 
only
SAEs 
only
X
X
X
X
X
X
X
X
X
Section 8.3
Vital signs 
(blood pressure, 
pulse rate)
X
X (pre-
dose)
X
X
X
X
X
X
X
X
Background 
treatment for 
hypertension 
should be 
individually 
optimised and 
stable for 
3 weeks before 
randomisation 
(Visit 3); BP 
assessed for 
eligibility at 
Visit 3.
Sections 
5.1, 6.5.2, 
8.2.2
Digital 12-lead 
safety ECG
X d
X (pre-
dose)
X
X
X
X
ECGs to be 
added as 
clinically 
indicated.
Section 8.2.3

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Local 
echocardio-
graphy
X d
Needed to 
confirm 
eligibility if 
not assessed in 
past 12 months
Section 8.2.3
Local 
laboratory 
blood samples 
for clinical 
chemistry and 
haematology
X d
Section 8.2.4
Local 
laboratory urine 
sample for 
albumin, 
creatinine, and 
urinalysis
X d
Spot urine 
sample
Sections 
8.1.1, 8.2.4
Local 
laboratory 
blood sample 
for NT-proBNP
X d
Section 8.5.2

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Local 
laboratory 
blood sample 
for FSH 
measurement
X d
To confirm 
postmenopausa
l status of 
women (only 
women of non-
child-bearing 
potential will 
be included in 
the study).
Sections
5.1 and 8.2.4
Local 
laboratory 
RT-PCR test 
for 
SARS-CoV-2
X e
Optional.
If available at 
site.
Section 8.2.4

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Local 
laboratory 
serum/plasma 
samples for K+
and Na+
X e
X
X
X
X
X
X
X
X
Results needed 
for eligibility 
and to assess 
discontinuation 
criteria at each 
visit
Section 8.2.4
Local 
laboratory 
serum/plasma 
samples for 
creatinine 
including eGFR 
calculation
X
X
X
X
X
X
X
X
Section 8.2.4
Central 
laboratory 
blood samples 
for clinical 
chemistry and 
haematology; 
and plasma 
sample for K+
measurement
X (pre-
dose)
X
X
X
X
X
X
X
X
Section 8.2.4

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Central 
laboratory 
serum sample 
for creatinine 
for eGFR 
calculation
X e
Section 8.2.4
Central 
laboratory 
serum sample 
for cystatin C 
for eGFR 
calculation
X e
X (pre-
dose)
X
X
X
X
X
X
X
X
Section 8.2.4
Central 
laboratory 
blood samples 
for HbA1c, 
cholesterol, and 
lipids
X (pre-
dose)
X
X
After at least 
8-hour fasting 
for lipids.
Section 8.2.4
Central 
laboratory 
urinalysis
X (pre-
dose)
X
X
X
Section 8.2.4

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Central 
laboratory urine 
samples for 
albumin, 
creatinine (for 
UACR 
calculation), 
Na+, K+, uric 
acid, urea, 
osmolality, 
glucose, and 
cortisol f
X e, f
X
X
X
X
X
X
First morning 
void urine 
sample 
collected at 
home in 
provided vials 
over 
3 consecutive 
days until the 
visit day.
Sections 
8.1.1, 8.5.2, 
8.6.1
Pharmaco-
kinetics
Predose sample 
for AZD9977 
and 
dapagliflozin 
plasma 
concentrations
X
X
X
Collected 
before dose 
intake at site, 
or 1 day after 
last dose for 
the EOT/ET 
visit.
Section 8.5.1

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Optional 
postdose 
plasma samples 
for AZD9977 
and 
dapagliflozin 
concentrations
X
Collected at 
1 (±0.25), 
2 (±0.25), 
4 (±0.5), and 
6 (±1) hours 
postdose.
Section 8.5.1

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Pharmaco-
dynamics 
(Central 
laboratory)
Blood samples 
for 
NT-proBNP, 
aldosterone, 
renin, ACTH, 
cortisol, 
copeptin, and 
FPG
X (pre-
dose)
X
X
X
X
Collected at 
the same time 
of the day.
After at least 
8-hour fasting 
for FPG.
Section 8.5.2
Exploratory 
measurements 
and 
biomarkers
Serum/plasma 
samples for 
cardiovascular 
biomarkers 
X (pre-
dose)
X
X
X
Central 
laboratory.
Section 8.6.1

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Optional 
serum, plasma, 
and urine 
samples for 
exploratory 
assessment of 
biomarkers 
X (pre-
dose)
X
X
Section 8.6.2
Optional 
genetic sample 
for Genomics 
Initiative 
exploratory 
analysis
X (pre-
dose)
Section 8.7, 
Appendix D
Study 
treatments
Randomisation 
in RTSM
X
Section 6.3
Dapagliflozin 
10 mg 
Daily (morning) 
self-administration
Daily (morning) 
self-administration a
Sections 4.1, 
6.1.1, and 6.7

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Procedure
Pre-
scre
enin
g
Screeni
ng
Start 
Run-in
Pre-
rando-
misation
Baseline/ 
Rando 
misation
Treatment Period
EOT/ET 
a
Safety 
Follow-u
p
Notes
Details in CSP 
Section or 
Appendix
Visit b
Opti
onal
1a
1b
2
3
4
5
6
7
8
9
10
11
* Applies to 
SGLT2i naïve 
patients
For details 
on run-in 
period see 
Section 4.1
Week
c
(-8 
to -7)*
-6 to -5
(-7 
to -6)*
-5 to -4
-1
1
1
2
3
4
7
10
13
17
Day
c
(-56 
to -49)*
-42 
to -35
(-49 
to -42)*
-35 
to -28
-10 to -3
1
3 
±
1
8 
±2
15 
±3
22 
±3
43 
±3
64 ±3
85 
±3
113
±4
Study treatment
Daily (morning) self-administration of the assigned 
study treatment
Taken at the 
site on visit 
days, after 
completing all 
predose 
procedures.
Sections
4.1, 6.2, 6.4
Drug 
dispensation
X
X
X
X
X
X
Sections 6.2, 
6.3, and 6.4
Drug
accountability
X
X
X
X
X
X
X
X
X
Sections
6.2, 6.4
ACTH=adrenocorticotropic hormone; BP=blood pressure; BUN=blood urea nitrogen; CKD=chronic kidney disease; CSP=Clinical Study Protocol; 
ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; EOT=end of treatment; ET=early termination; FPG=fasting plasma glucose; FSH=follicle 
stimulating hormone; HbA1c=glycated haemoglobin; HF=heart failure; K+=potassium; Na+=sodium; NT-proBNP=N-terminal natriuretic peptide; 
RT-PCR=reverse transcriptase polymerase chain reaction; RTSM=Randomisation and Trial Supply Management, SAE=serious adverse event; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; UACR=urinary albumin to creatinine ratio.
Note: Visits at Week 7 and Week 13 (Visits 8 and 10) correspond to visits after completion of 6 weeks and 12 weeks of study treatment, respectively.
a
Patients will continue on open label dapagliflozin 10 mg after the EOT visit during the safety follow up period up to Visit 11. Patients who discontinue 
study treatment early may continue on open label dapagliflozin 10 mg after the ET visit during the safety follow up period up to Visit 11, as judged by the 
investigator. Patients who withdraw consent may perform an ET visit but the safety follow-up will not be performed.
b
If site visits are not possible due to local SARS-CoV-2 restrictions, home nursing visits may be considered after discussion with and approval by the 
Sponsor.
c
Week and day for pre-screening will be at the discretion of the investigator.
d
Results from the screening tests are needed to confirm eligibility before the run-in period can start.
e
Results are needed to confirm eligibility before randomisation. Serum/plasma Na+ will be assessed at Visit 2 only. The eGFR-based participant stratification 
will rely on central eGFR assessment at Visit 2.

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f
Phone call will occur prior to the visit to remind the participants to collect the first morning void samples.

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2
INTRODUCTION
2.1
Study Rationale
Although MRAs are an important standard therapy for HF, they are currently contraindicated 
in patients with eGFR < 30 mL/min/1.73 m2 and are highly underused in patients with eGFR 
< 60 mL/min/1.73 m2 due to risk of hyperkalaemia.
AZD9977 is a selective MR modulator, with a differentiated mode of action compared with 
the currently prescribed MRAs (eg, spironolactone/eplerenone).
The mechanism of action for AZD9977 and dapagliflozin are different and outcome of 
treatment is expected to be synergistic since the main biological effects of AZD9977 would be 
to block MR driven oxidative stress, inflammation and fibrosis and dapagliflozin to inhibit 
SGLT2-driven metabolic dysfunction, volume overload, and endothelial cell dysfunction. 
The overall clinical evidence suggests that the combination of AZD9977 and dapagliflozin 
would have clinical benefit and an acceptable safety profile in patients with HF and that 
further development is warranted. Hence, a global, randomised, Phase 2b study is planned to 
evaluate the efficacy and safety of AZD9977 and dapagliflozin in patients with HF.
The purpose of the study is to establish a dose-response for effect on UACR and assess the 
safety of AZD9977 given in combination with dapagliflozin 10 mg once daily, considering 
serum/plasma K+ and safety topics of interest (hyperkalaemia, hypotension and deteriorating 
renal function) in addition to general safety.
2.2
Background
The presence of significant concomitant renal dysfunction in patients with HF severely limits 
the use and the benefits of proven HF medications, such as ACEIs, ARBs, MRAs, and ARNIs. 
In the absence of evidence-based therapies capable of both renal and cardiovascular 
protection, new treatments are warranted. 
Mineralocorticoid receptor antagonists have proven benefits on HF, but use has been limited 
due to risks associated with hyperkalaemia, in particular in patients with reduced renal 
function, although existing evidence suggests that MRAs also provide benefit in HF patients 
with CKD. Sodium-glucose co-transporter-2 inhibitors have proven benefits on HF, as well as 
potential beneficial effects on kidney function. In the recent DAPA-HF trial (D1699C00001) 
the treatment benefit of dapagliflozin was observed in HFrEF patients both with T2DM and 
without diabetes. In that study, approximately 70% of the patients were treated with MRAs 
and effect of dapagliflozin was independent of baseline MRA therapy, suggesting additive 
effects on top of MRA treatment (McMurray et al 2019). In the recent DAPA-CKD trial 
(D169AC00001), among patients with CKD, regardless of the presence or absence of T2DM, 

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the risk of a composite of a sustained decline in the eGFR of at least 50%, end-stage kidney 
disease, or death from renal or cardiovascular causes was significantly lower with 
dapagliflozin than with placebo (Heerspink et al 2020). Combination of AZD9977 with 
dapagliflozin, could have synergistic effects and importantly improve outcomes in HF 
patients, especially those with lower GFR who do not receive MRA treatment. By providing 
differential effects on disease mechanisms related to MR driven inflammation and fibrosis as 
well as SGLT2-driven mechanisms the action of both drugs is anticipated to provide 
significant patient benefit. 
2.2.1
Heart Failure with Chronic Kidney Disease
2.2.1.1
Prevalence of Heart Failure 
Chronic HF continues to be a major cause of mortality, hospitalisations, and suboptimal 
quality of life. Even with the best possible treatment, the 5-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) and will increase dramatically as the population ages.
2.2.1.2
Heart Failure Management
Foundations of HF management rely on volume status with appropriate diuretic dosing, 
control of BP, treatment of contributing risk factors such as sleep apnoea, coronary artery 
disease and valvular disease, alongside with dietary education. The ACCF/AHA guidelines 
(Yancy et al 2017) support the use of beta-blockers, ACEI, ARBs and MRAs. Angiotensin 
receptor-neprilysin inhibitors can replace ACEI or ARB in patients with HF who remain 
symptomatic despite optimal treatment with an ACEI or ARB, a beta-blocker and an MRA. 
Isosorbide dinitrate/hydralazine and the If-channel inhibitor (ivabradine) and digoxin can be 
prescribed in some patients, as appropriate. The European Society of Cardiology guidelines 
now include a Class-1 recommendation for treatment with dapagliflozin or empagliflozin for 
patients with HFrEF to reduce the risk of HF hospitalization and death (ESC Guidelines 
2021). 
Heart failure patients with CKD have even higher risk and fewer treatment options resulting in 
a patient group with high unmet medical need. Studies have indicated that between 20% and 
67% of patients with HF also have CKD (Sarraf et al 2009). Patients with both HF and renal 
insufficiency have approximately 25% to 30% higher risk of mortality compared with patients 
with HF without CKD (Ather et al 2012). However, in patients with poor kidney function 
(eGFR< 30 mL/min/1.73 m2) there are no specific therapies approved for renal impairment 
and recommended treatments for HF are underused because of intolerance and safety concerns 
and may even be contraindicated in some individuals. 

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This type of concern primarily involves inhibitors of the RAAS, including MRAs, and RAAS 
blockers. An additional and related concern is the risk of hyperkalaemia, which is greatest for 
MRAs, with potential risk of or actual hyperkalaemia events being a major cause of underuse 
of this type of therapy. While concerns about worsening renal function and hyperkalaemia 
result in underutilisation of MRAs, there is evidence from randomised clinical trials that 
patients with HF and renal impairment have important clinical benefit from MRA therapy (Pitt 
et al 1999, Zannad et al 2011). Recent data from the FIDELIO-DKD and FIGARO-DKD trials 
assessing the non-steroidal MRA finerenone in patients with CKD and T2DM established that 
MRAs also are reno-protective in the long term and reduce the CV risks in this patient 
population (Bakris et al 2020, Pitt et al 2021).
2.2.1.3
Mineralocorticoid Receptor Antagonist for Treatment of Heart Failure and 
Chronic Kidney Disease
The steroidal MRAs spironolactone and eplerenone reduce mortality and hospitalisations for 
HF in patients with HFrEF (Pitt et al 1999, Zannad et al 2011) and have a class 1A 
recommendation for the treatment of this patient population in international guidelines. In 
patients with CKD, MRA treatment has been shown to reduce albuminuria and may improve 
long-term kidney function (Kato et al 2015, Bakris et al 2015). The mineralocorticoid receptor 
antagonist finerenone was recently shown to prevent the development of cardiovascular 
disease and progression to end-stage kidney disease in patients with CKD and T2DM (Bakris 
et al 2020, Pitt et al 2021).
One of the primary safety concerns related to MRA treatment is the development of 
hyperkalaemia, especially in patients taking concomitant medications associated with K+
retention (such as ACEIs or ARBs), and in patients with diabetes mellitus and/or kidney 
dysfunction (Cooper et al 2017). In placebo-controlled clinical trials with MRAs in HF 
patients, the incidence of hyperkalaemia is approximately 9%, with 54% of these being truly 
attributable to MRA therapy (Vukadinović et al 2017). However, real world data suggest that 
the incidence of hyperkalaemia in patients with HF could be greater than this (Abbas et al
2015). Concern about hyperkalaemia, especially in patients with reduced kidney function 
results in underuse and suboptimal dosing of MRAs in these HF patients (Savarese et al
2018). 
While dose escalation with existing MRA therapies is limited by the risk of hyperkalaemia, 
this may not be the case with novel MR modulators (such as AZD9977), as the dose-response 
relationship for acute effects on urinary electrolyte excretion may differ from that for organ 
protection (Bamberg et al 2018). Novel MR antagonists or modulators should increase the 
therapeutic window by increasing selectivity against other steroid nuclear receptors thereby 
avoiding gynaecomastia (eg, with spironolactone) as well as improving the separation of 
cardiac and kidney protective effects from electrolyte regulation thereby avoiding 
hyperkalaemia (seen with spironolactone and eplerenone) (Capelli et al 2020). Pre-clinical 

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data have demonstrated that AZD9977 at clinically relevant exposures is effective in reducing 
MR-mediated cardiac and renal pathology, as well as reducing the risk of treatment-related 
hyperkalaemia, when compared to currently available MR antagonists. AZD9977 has been 
evaluated in 7 Phase 1 studies involving healthy volunteers at doses up to 1200 mg as a single 
dose and multiple dosing of 300 mg twice daily, with no clinically relevant effect on serum K+
levels (see the Investigator’s Brochure of AZD9977). In addition, a Phase 1b study comparing 
AZD9977 to spironolactone in patients with HF with preserved LVEF > 40%) and CKD with 
eGFR between 40 and 70 mL/min/1.73 m2 was recently completed (NCT 03682497). 
Recently, the novel non-steroidal MRA finerenone was found to be safe and to reduce adverse 
kidney and cardiovascular outcomes in patients with CKD and diabetes (Bakris et al 2020).
2.2.1.4
Sodium-glucose Co-transporter 2 Inhibitors in Heart Failure and Chronic 
Kidney Disease
Recent data from cardiovascular outcome studies of the SGLT2i dapagliflozin and real world 
studies (including patients treated with dapagliflozin) show that treatment with dapagliflozin 
can reduce the risk of cardiovascular death and hospitalisation due to HF in patients with and 
without T2DM (Zinman et al 2015, Ferrannini et al 2016, Fitchett et al 2016, Neal et al 2017, 
Rådholm et al 2018, McMurray et al 2019, Petrie et al 2020). 
It has been postulated that kidney protection along with diuretic and natriuretic effects induced 
by SGLT2i may contribute to the reductions in HF hospitalisation in the EMPA-REG 
OUTCOME, CANVAS, and DECLARE-TIMI 58 trials (Zelniker et al 2019). Moreover, the 
reduction in HF hospitalisation in these trials was greater in patients with worse baseline 
kidney function; a 40% reduction in HF hospitalisation was observed in patients with eGFR 
< 60 mL/min/1.73 m2 compared with 31% in patients with eGFR > 60 to 
< 90 mL/min/1.73 m2 and 12% reduction in patients with eGFR > 90 mL/min/1.73 m2
(Zelniker et al 2019). Dapagliflozin also reduced UACR by 21% in T2DM patients in the 
DELIGHT study (Pollock et al 2019). In the recent DAPA-HF trial (D1699C00001), 
dapagliflozin demonstrated a reassuring safety profile in a population with a broad range of 
kidney function (including patients with eGFR < 45 and a few with eGFR 
< 30 mL/min/1.73 m2). In this study, approximately 70% of the patients were treated with 
MRAs and effect of dapagliflozin was independent of baseline MRA, suggesting additive 
effects on top of MRA treatment. In the DAPA-CKD trial (D169AC00001), an event-driven 
study in patients with CKD (eGFR ≥25 and ≤75 mL/min/1.73 m2) with albuminuria (UACR 
≥200 and ≤5000 mg/g) with T2DM or without diabetes, dapagliflozin was superior to 
placebo in reducing the incidence of the primary composite endpoint of ≥50% sustained 
decline in eGFR, reaching ESRD, cardiovascular or renal death when added to current 
background therapy. Treatment effects on ESRD were driven by reductions in sustained eGFR 
≤15 mL/min/1.73 m2 and chronic dialysis. There were 11 events (3 in dapagliflozin, 8 in 
placebo group) of renal transplants in the study. Treatment effects on the exploratory 
composite endpoint of renal death, renal transplant, and chronic dialysis were consistent with 

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effects on ESRD. In addition, dapagliflozin was superior to placebo for time to first event of 
the composite of ≥50% sustained decline in eGFR, reaching ESRD, and renal death; time to 
first event of the composite of cardiovascular death and hospitalisation for HF; and time to 
death from any cause. Treatment benefit was observed in CKD patients both with T2DM and 
without diabetes (Jongs et al 2021).
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD9977 and 
dapagliflozin is provided in the Investigator’s Brochure of each product.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD9977 and dapagliflozin may be found in their respective Investigator’s Brochures.
2.3.1
Risk Assessment
Table 2
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Dapagliflozin
Diabetic ketoacidosis 
in patients with 
diabetes mellitus
Diabetic ketoacidosis was only observed in patients 
with diabetes mellitus:
•
Type 2 diabetes mellitus:
In the DECLARE study with a median exposure 
time of 48 months, events of DKA were reported 
in 27 out of 8574 patients in the dapagliflozin 
10 mg group and 12 out of 8569 patients in the 
placebo group.
The events were evenly distributed over the study 
period. Of the 27 patients with DKA events in the 
dapagliflozin group, 22 had concomitant insulin 
treatment at the time of the event.
Precipitating factors for DKA were as expected in 
a T2DM population.
In the DAPA-HF study, events of DKA were 
reported in 3 patients with T2DM in the 
dapagliflozin group and none in the placebo 
group.
In the DAPA-CKD study, DKA was not reported 
in any patient in the dapagliflozin group and in 
2 patients with T2DM in the placebo group.
•
Type 1 diabetes mellitus:
In the 2 placebo-controlled clinical trials of 
dapagliflozin in T1DM, patients were advised to 
monitor blood ketones in case of suspected 
symptoms of DKA and seek medical 
advice/attention if their self-measured blood 
ketone reading was ≥0.6 mmol/L. In the pooled 
24-week data, events of DKA were reported in 
11 (1.9%) patients in the dapagliflozin 10 mg 
group and 3 (0.6%) patients in the placebo group. 
DKA events occurred evenly distributed over the 
Patients with uncontrolled diabetes 
mellitus (HbA1c > 10%) and patients 
with T1DM are excluded from the 
study (see exclusion criteria #6 and 
#7).
If ketoacidosis is suspected, 
discontinuation or temporary 
interruption of dapagliflozin/placebo 
should be considered and the patient 
should be promptly evaluated (see 
Section 7.1).

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Table 2
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
study period. Inadequate insulin doses (missed 
insulin dose or insulin pump failure) were the 
most common precipitating factors. Three of the 
11 patients with DKA in the dapagliflozin 10 mg 
group had blood glucose in the euglycemic range 
(< 14 mmol/L or 250 mg/dL). Patients with DKA 
events responded to conventional treatment for 
DKA.
•
In addition, there have been post marketing 
reports of ketoacidosis, including diabetic 
ketoacidosis, in patients with T1DM and T2DM 
taking dapagliflozin or other SGLT2i.
AZD9977 
Hyperkalaemia
The primary safety concern related to the on-target 
effects of MR antagonism is the potential for 
development of hyperkalaemia.
The pre-clinical data generated for AZD9977 suggests 
that the risk of hyperkalaemia will be significantly 
lower than for approved MR antagonist drugs (namely 
spironolactone and eplerenone) due to its different 
mechanism of action.
No clinically significant changes were seen in serum K+
levels in completed healthy volunteer studies.
In the phase 1b study in patients with HFmrEF or 
HFpEF and eGFR ≥40 and ≤70 mL/min/1.73 m2, there 
were generally small increases in serum potassium from 
baseline in the AZD9977 and spironolactone groups 
that were generally similar and not considered clinically 
relevant, and there were no discontinuations due to 
hyperkalaemia (confirmed serum K+ ≥5.6 mmol/L).
Considerations for combination with dapagliflozin:
In the DAPA-HF trial, patients treated with 
dapagliflozin in conjunction with an MRA at baseline 
showed a reduced incidence of mild and 
moderate/severe hyperkalaemia compared to patients 
treated with placebo (McMurray et al 2019).
Patients enrolled in the study should 
have serum/plasma K+ level ≥3.5 and 
< 5.0 mmol/L (see inclusion 
criterion #7).
During the study, changes in 
serum/plasma K+ will be closely 
monitored (see SoA). Specific 
discontinuation criteria and 
instructions for management of 
hyperkalaemia are provided (see 
Section 7.1 and Appendix F 1).
Deteriorating Renal 
Function/Initial 
eGFR decrease 
In HF patients, MRA treatment is associated with an 
early modest decrease in GFR (Rossignol et al 2014).
In healthy volunteer clinical studies with AZD9977, no 
clinically significant changes in GFR or creatinine were 
observed.
In the phase 1b study in patients with HFmrEF or 
HFpEF and eGFR ≥40 and ≤70 mL/min/1.73 m2, there 
were small decreases in eGFR from baseline in the 
AZD9977 and spironolactone groups that were not 
considered clinically relevant and showed improvement 
at follow-up/after last dose.
Considerations for combination with dapagliflozin:  
SGLT2 inhibitor classes (including dapagliflozin) are 
During the study, changes in eGFR 
will be closely monitored (see SoA). 
Specific discontinuation criteria and 
instructions for the management of 
deteriorating renal function are 
provided (see Section 7.1 and 
Appendix F 2).

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Table 2
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
known to be associated with an initial modest decrease 
in eGFR though long-term effects are thought to be 
nephroprotective. 
Hypotension
Treatment with MRAs is associated with a BP lowering 
effect and some MRAs, including spironolactone, are 
used in resistant hypertension.
In dog toxicology studies, tachycardia and decreased 
BP were observed with high AZD9977 doses. 
In healthy volunteer clinical studies, no clinically 
significant effect on BP was observed.
In the phase 1b study in patients with HFmrEF or 
HFpEF and eGFR ≥40 and ≤70 mL/min/1.73 m2, there 
were generally decreases from baseline in systolic and 
diastolic blood pressure in both treatment groups, 
though the reduction in systolic blood pressure was 
numerically larger with AZD9977 than with 
spironolactone. These changes were not considered 
clinically relevant from a safety perspective.
Considerations for combination with dapagliflozin:  
SGLT2 inhibitor classes (including dapagliflozin) are 
known to be associated with modest decreases in BP. 
Monitoring of BP according to the 
SoA.
Cardiovascular 
effects
In dog toxicology studies, increases in HR, decreases in 
BP, and cardiac perivascular proliferation were 
observed with high AZD9977 doses.
A follow-up study in dog and modelling showed that 
cardiac pathology was related to the HR increase and 
that no pathology occurred with a mean HR below 
135 bpm, and HR monitoring was used as a biomarker 
for cardiac pathology in the initial healthy volunteer 
studies.
In healthy volunteer clinical studies and in the Phase 1b 
study in patients with HFmrEF or HFpEF and eGFR 
≥40 and ≤70 mL/min/1.73 m2, no clinically significant 
effects on HR or BP were observed. The cardiac injury 
biomarkers troponin and NT-proBNP were measured in 
the majority of the healthy volunteer studies, including 
multiple ascending dose studies, with no clinically 
significant effects observed. 
Monitoring heart rate, BP, and ECGs 
according to the SoA.
Hepatotoxicity
In both rats and dogs isolated plasma chemistry changes 
in GLDH, AST, ALT and ALP were noted in some 
animals in the non-GLP studies. None had correlating 
histopathological findings and the findings were not 
reproduced in longer term studies up to 6 and 9 months 
in rat and dog, respectively. In healthy volunteer 
clinical studies and in the Phase 1b study in patients 
with HFmrEF or HFpEF and eGFR ≥40 and 
≤70 mL/min/1.73 m2, no clinically relevant trends were 
observed in liver chemistry values.
During the study, changes in AST, 
ALT, ALP and bilirubin and potential 
Hy’s law cases will be monitored (see 
SoA and Appendix E).

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Table 2
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Metabolic control
Increases in HbA1c by 0.4% and 0.6% were noted in 
2 previously published clinical studies with 
spironolactone (Nielsen et al 2012, Matsumoto et al 
2006).
In the 1-month and 6-month rat GLP studies with 
AZD9977, there was a dose-dependent increase in 
blood glucose, but glucose levels remained in the 
normal range at all doses tested In GLP studies up to 
9 months in dogs, once daily administration of 
AZD9977 was not associated with increased blood 
glucose.
In healthy volunteer clinical studies, no clinically 
relevant trends were observed in plasma glucose values.
In addition, there were no clinically relevant effects of 
AZD9977 on glucose control during an OGTT in the 
MAD study.
During the study, changes in HbA1c 
will be monitored (see SoA).
Other
COVID-19 pandemic 
risks
There is currently an outbreak of respiratory disease 
(COVID-19) caused by a novel SARS-CoV-2, for 
which the WHO declared a pandemic situation on 
12 March 2020. 
The mechanism of action of AZD9977 and 
dapagliflozin are unlikely impact the course of infection 
with SARS-CoV-2. Therefore, the risk of the 
participants exposure to SARS-CoV-2 or to suffer from 
COVID-19 is expected to be similar to the background 
population with the same co-morbidities as those in the 
study, in particular CKD and HF. The risk of exposure 
to infected people cannot be completely excluded as the 
participants may need to expose themselves to public 
areas (eg, commute to the site) and have additional 
human contact (eg, with site staff and other participants 
of the clinical study).
Patients with signs or confirmation of 
infection are excluded from the study 
(see exclusion criterion #25). Further 
risk mitigation measures are detailed 
in Appendix G.
ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BP=blood pressure; 
bpm=beats per minute; CKD=chronic kidney disease; COVID-19=coronavirus disease 2019; DKA=diabetic 
ketoacidosis; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; GFR=glomerular filtration 
rate; GLDH=gamma-lactone dehydrogenase; GLP=Good Laboratory Practice; HbA1c=glycated haemoglobin; 
HF=heart failure; HFmrEF=heart failure mid-range ejection fraction; HFpEF=heart failure preserved ejection 
fraction; HR=heart rate; MAD=multiple ascending dose; MR=mineralocorticoid receptor; MRA= 
mineralocorticoid receptor antagonist; NT-proBNP=N-terminal pro-brain natriuretic peptide; OGTT=oral 
glucose tolerance test; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SGLT2i=sodium-glucose 
co-transporter-2 inhibitor; SoA=schedule of activities; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes 
mellitus; WHO=World Health Organization.
The 3-month combination toxicology studies in rats with AZD9977 and dapagliflozin did not 
reveal aggravated or additional effects not seen with the compounds when studied separately.

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2.3.2 Benefit Assessment
Based on available clinical data with MRAs and dapagliflozin, it is expected that patients 
enrolled in the study will benefit from treatment with dapagliflozin and/or AZD9977:

Clinical data from patients with HF and CKD suggest clinical benefit of MRAs in 
preventing the development of cardiovascular disease and progression to end-stage 
kidney disease in patients with CKD (see Section 2.2.1.3).

Recent data from cardiovascular outcome studies of dapagliflozin and real world studies 
(including patients treated with dapagliflozin) show that treatment with dapagliflozin can 
reduce the risk of cardiovascular death and hospitalisation due to HF in patients with and 
without T2DM (also when given in addition to an MRA), and it has been postulated that 
the kidney protection and natriuretic effects induced by SGLT2 inhibitors may account 
for the reductions in HF hospitalisation (see Section 2.2.1.4).

Recent data from an event-driven study with dapagliflozin in patients with CKD show
that treatment with dapagliflozin is superior to placebo in reducing the incidence of the 
primary composite endpoint of ≥50% sustained decline in eGFR, reaching ESRD, 
cardiovascular or renal death when added to current background therapy (see 
Section 2.2.1.4).
2.3.3 Overall Benefit: Risk Conclusion
The overall clinical evidence suggests that the combination of AZD9977 and dapagliflozin 
would have clinical benefit and an acceptable safety profile in patients with HF and that 
further development is warranted.

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3
OBJECTIVES AND ENDPOINTS
Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
UACR

Percent change from baseline in UACR 
at the end of 12 weeks of study 
treatment
Secondary

To assess the dose-response relationship 
of dapagliflozin (10 mg) alone and 
3 doses of AZD9977 (15, 50, or 
150 mg) combined with dapagliflozin 
(10 mg) on UACR

Percent change from baseline in UACR 
at the end of 12 weeks of study 
treatment
Safety 

To assess the general safety and 
tolerability of AZD9977 in combination 
with dapagliflozin compared with 
dapagliflozin alone 

AE/SAE reporting

Vital signs (BP, pulse rate)

Clinical laboratory tests (clinical 
chemistry, haematology, and urinalysis)

Digital 12-lead safety ECG assessments

Safety topics of interest (hyperkalaemia, 
hypotension and deteriorating renal 
function)

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
serum K+ and eGFR

Absolute value and change from 
baseline in serum K+ and eGFR over 
time
Exploratory 

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
serum NT-proBNP levels

Change from baseline in serum 
NT-proBNP over time

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
To assess plasma exposure of AZD9977 
and dapagliflozin

Plasma concentrations of AZD9977 and 
dapagliflozin

To explore the relationships between 
AZD9977 and dapagliflozin 
dose/exposure and 
safety/pharmacodynamic variables

Dose/exposure of AZD9977 and 
dapagliflozin relative to safety and 
pharmacodynamic variables (eg, 
serum/plasma K+, eGFR, aldosterone)

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
blood uric acid, BUN, fasting plasma 
glucose, haematocrit, renin, ACTH, 
cortisol and copeptin levels

Change from baseline in blood uric 
acid, BUN, FPG, haematocrit, renin, 
ACTH, cortisol and copeptin levels over 
time

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
MCV, MCHC, RBC distribution width, 
erythrocyte count

Change from baseline in blood MCV, 
MCHC, RBC distribution width, 
erythrocyte count over time

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
urine Na+, K+, uric acid, urea, 
osmolality, glucose, creatinine, and 
cortisol

Change from baseline in urine Na+, K+, 
uric acid, urea, osmolality, glucose, 
creatinine, and cortisol levels over time

To assess the effect of AZD9977 in 
combination with dapagliflozin 
compared with dapagliflozin alone on 
cardiovascular biomarkers in blood

Evaluation of changes in blood 
biomarkers (including but not limited to 
hsTnT, PIIIP3, GDF-15, ST2, ADMA, 
SDMA, L-Arg, ICAM, NGAL) over 
time

Optional: To collect and store serum, 
plasma, and urine samples for future 
exploratory biomarker research related 
to PK, pharmacodynamics, safety, and 
tolerability of AZD9977 or 
dapagliflozin; or related to cardiorenal 
diseases

Biomarker assessment in serum, 
plasma, and urine samples

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
Optional: To collect and store blood 
samples for genetic research (according 
to each country’s local and ethical 
procedures)

Exploratory research into genes/genetic 
variation that may influence response to 
treatment
ACTH=adrenocorticotropic hormone; ADMA=asymmetric dimethylarginine; AE=adverse event; BP=blood 
pressure; BUN=blood urea nitrogen; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate;
FPG=fasting plasma glucose; GDF-15=growth differentiation factor-15; hsTnT=high sensitivity troponin T; 
ICAM=intercellular adhesion molecule; K+=potassium; L-Arg=l-arginine; MCHC=mean corpuscular 
haemoglobin concentration; MCV=mean corpuscular volume; Na+=sodium; NGAL=neutrophil 
gelatinase-associated lipocalin; NT-proBNP=N-terminal pro-brain natriuretic peptide; PIIIP3=procollagen 
type III N-terminal propeptide; PK=pharmacokinetics; RBC=red blood cell; SAE=serious adverse event; 
SDMA=symmetric dimethylarginine; ST2=suppression of tumourigenicity 2; UACR=urinary albumin to 
creatinine ratio.

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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, multi-centre, randomised, double-blind, active-controlled parallel group, 
study to assess the efficacy, safety and tolerability of AZD9977 and dapagliflozin 
administered for 12 weeks in patients with HF and CKD (eGFR ≥20 and 
≤60 mL/min/1.73 m2, with at least 20 % of patients with eGFR ≥20 to < 30 mL/min/1.73 m2
and a maximum of 35% of patients with eGFR ≥45 mL/min/1.73 m2).
The study will be conducted at approximately 150 to 250 sites in approximately 20 countries 
including North America, Asia/Pacific, and European countries.
For each participant, the total duration of participation will be approximately 22 to 24 weeks, 
including a 1-week screening period, followed by up to 7-week run-in period followed by a 
12-week treatment period (including 6 visits), the EOT visit, and a 4-week safety follow-up 
after last dose (including 1 visit). An optional pre-screening visit may be scheduled. Week and 
day for pre-screening visit will be at the discretion of the investigator.
After screening, eligible participants currently on treatment with a SGLT2i other than 
dapagliflozin should stop taking the SGLT2i and start on dapagliflozin 10 mg. Participants on 
dapagliflozin treatment will continue on treatment but the medication will be provided. 
Participants will then undergo a 4 to 5-week run-in period to ensure washout of forbidden 
medications and stable doses of allowed background medications.
For participants eligible after screening not on treatment with a SGLT2i, treatment with 
dapagliflozin 10 mg will be initiated. Participants will then undergo a 6 to 7-week run-in 
period to ensure washout of forbidden medications and stable doses of allowed background 
medications.
During the treatment period, participants will be randomly assigned in a 1:1:1:1 ratio to 
receive once daily administration of one of the 4 study treatments as described below. To 
ensure blinding, the study treatment will be administered in the form of 3 oral capsules and 
1 oral tablet in the following combinations.

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Table 4
Study Treatments
Study Treatment
Capsule 1
Capsule 2
Capsule 3
Tablet
AZD9977 15 mg + 
Dapagliflozin 10 mg
AZD9977 15 mg
Placebo
Placebo
Dapagliflozin 10 mg
AZD9977 50 mg + 
Dapagliflozin 10 mg
Placebo
AZD9977 50 mg
Placebo 
Dapagliflozin 10 mg
AZD9977 150 mg + 
Dapagliflozin 10 mg
Placebo
AZD9977 50 mg
AZD9977 100 mg
Dapagliflozin 10 mg
Dapagliflozin 10 mg 
alone 
Placebo
Placebo
Placebo
Dapagliflozin 10 mg
Participants will be stratified according to T2DM (yes/no) and eGFR (≥20 to 
< 30 mL/min/1.73 m2; or ≥30 to < 45 mL/min/1.73 m2; or ≥45 mL/min/1.73 m2) based on the 
latest eGFR assessment prior to the start of study treatment (eGFR at Visit 2).
4.1.1
Optional Pre-screening
Patients who perform the optional pre-screening visit to evaluate UACR should sign a 
separate, abbreviated ICF. Samples should be obtained for analysis in a local laboratory. The 
results are to be recorded in the medical records only.
4.2
Scientific Rationale for Study Design
The study is designed to evaluate the effect of AZD9977 in combination with dapagliflozin 
compared with dapagliflozin alone on UACR. The secondary objective is to assess the 
dose-response relationship of dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 
150 mg) combined with dapagliflozin (10 mg) on UACR.
The primary endpoint (percent change from baseline in UACR at 12 weeks) is an established 
key surrogate marker of the MRA mechanism of action. This marker has also shown to be 
predictive for adverse cardiovascular outcomes in patients with HF (Selvaraj et al 2018). 
Reported studies have shown a clear dose-response with UACR for MRAs (eg, finerenone), 
unlike other biomarkers relevant for HF such as the cardiac biomarker NT-proBNP. Clear 
effects on UACR have also been established for dapagliflozin (Pollock et al 2019), while 
dapagliflozin did not significantly reduce NT-proBNP over 12 weeks compared with placebo 
(Nassif et al 2019).
The study will evaluate general safety and tolerability with special focus on serum/plasma K+, 
eGFR, and hypotension of treatment with AZD9977 and dapagliflozin in combination and 
alone. Exploratory objectives include PK, NT-proBNP, biomarkers reflecting cardiac fibrosis, 
endothelial function, and other aspects of cardiovascular function as well as markers of the 
potential mechanisms of action of SGLT2 inhibitors and AZD9977. 

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4.3
Justification for Dose
The doses of AZD9977 for combination therapy were selected to enable characterisation of 
the dose-response for UACR and to evaluate safety in this patient population. 
The wide (10-fold) range of doses for AZD9977 (15 to 150 mg) given in combination with 
dapagliflozin 10 mg and dapagliflozin treatment alone will provide a sufficiently large range 
of AZD9977 exposures to evaluate the dose/exposure response relationship between UACR 
and AZD9977 + dapagliflozin in relation to dapagliflozin alone. About one third of the dose is 
excreted as unchanged AZD9977 in urine suggesting that renal clearance is contributing to the 
overall elimination of AZD9977. The main metabolic enzyme for AZD9977 is CYP3A4 that 
may have changed capacity in patients with low renal function. 
 
. The ongoing PK renal impairment study (D6401C00008) 
will confirm the PK profile of AZD9977 in patients with low renal function including those 
with an eGFR < 30 mL/min/1.73 m2. This data will be available ahead of including patients 
with eGFR< 30 mL/min/1.73 m2 into this study (D6402C00001). The dose selection for 
AZD9977 is based on PK, pharmacodynamic and safety data from previous studies in healthy 
subjects and in patients with HF. Using in vitro and clinical literature data for eplerenone, a 
translational PK/pharmacodynamic model for UACR reduction was developed. This model 
could well predict the UACR reduction for both spironolactone and finerenone assuming the 
same in vitro: in vivo ratio for IC50 and was therefore used to predict the UACR reduction for 
AZD9977. The 3 selected doses of AZD9977 are anticipated to yield an effect on UACR 
covering the whole dose-response curve from approximately 20 to 60% UACR reduction.
Dapagliflozin is currently under investigation in HF patients with LVEF >40% (HFmrEF and 
HFpEF) in the DELIVER◦study (NCT03619213). The dapagliflozin dose of 10 mg once daily 
is approved for treatment of patients with T2DM, for patients with heart failure and reduced 
ejection fraction with or without T2DM, and for patients with chronic kidney disease with or 
without T2DM.
There is a low risk for metabolic drug-drug interactions between AZD9977 and dapagliflozin. 
AZD9977 is mainly eliminated by CYP3A4-mediated metabolism and dapagliflozin is not an 
inhibitor of that metabolic enzyme (Kasichayanula et al 2012). Dapagliflozin is mainly 
eliminated by UGT1A9-mediated metabolism and AZD9977 is not an inhibitor of that 
metabolic enzyme.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the safety follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the study.
CCI

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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply at 
screening (Visit 1a):
Age
1
Participant must be 21 years of age or older, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Documented diagnosis of stable symptomatic HF (NYHA class II-III) at screening 
(Visit 1a), and a medical history of typical symptoms and signs of HF in those who are 
currently receiving loop diuretic treatment.

Typical symptoms associated with HF: breathlessness, orthopnoea, paroxysmal 
nocturnal dyspnoea, reduced exercise tolerance, fatigue, tiredness, increased time to 
recover after exercise.

Signs associated with HF: 
o
More specific: elevated jugular venous pressure, hepatojugular reflex, third heart 
sound (gallop rhythm), laterally displaced apical impulse.
o
Less specific: weight gain (> 2 kg/week), weight loss (in advanced HF), tissue 
wasting (cachexia), cardiac murmur, peripheral oedema (ankle, sacral, scrotal), 
pulmonary crepitations, reduced air entry and dullness to percussion at lung 
bases (pleural effusion), tachycardia, irregular pulse, tachypnoea, Cheyne Stokes 
respiration, hepatomegaly, ascites, cold extremities, oliguria, narrow pulse 
pressure.
3
Left ventricular ejection fraction < 60% documented by the most recent echocardiogram 
2D or 3D or cardiac magnetic resonance imaging within the last 12 months prior to 
screening.
If patient has experienced an acute myocardial event/injury associated with release of 
cardiac troponin within the previous 12 months, then a more recent echocardiogram to 
determine eligibility for participation in the study must be at least 12 weeks after the most 
recent cardiac event.

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4
Patients should be treated for HF, hypertension, T2DM, or renal disease according to 
guidelines.
Note: Background treatment should be in line with locally recognised treatment 
guidelines in each indication, as described in Section 6.5.2. Both patients with or without 
SGLT2i treatment can be included in the study (Section 6.1.1).
5
NT-proBNP ≥300 pg/mL for patients with sinus rhythm at screening; and 
NT proBNP ≥600 pg/mL for patients with atrial fibrillation/flutter at screening, using 
local laboratory sample.
6
eGFR ≥30 and ≤60 mL/min/1.73 m2 (by CKD-EPI formula based on local laboratory 
sample).
Note: Recruitment will start with patients who have eGFR ≥30 mL/min/1.73 m2. During 
the study, the Safety Unblinded Data Review Committee may decide to also include 
patients with eGFR ≥20 to < 30 mL/min/1.73 m2.
7
UACR at screening: spot urine sample analysed at local laboratory ≥30 mg/g 
(3 mg/mmol) and < 3000 mg/g (300 mg/mmol) for participants on SGLT2i; spot urine 
sample analysed at local laboratory ≥50 mg/g (5 mg/mmol) and < 3000 mg/g 
(300 mg/mmol) for participants not on SGLT2i.
Note: The lower limit for participants not on SGLT2i may be increased to ≥60 mg/g 
(6 mg/mmol) in case high proportion of randomisation failures due to UACR (eg, if 
> 50% of participants fail due to UACR < 30 mg/g [3 mg/mmol]) at the discretion of the 
Sponsor. 
Weight
8
Body mass index less than 40 kg/m2.
Sex
9
Male or female of non-childbearing potential.
Reproduction
10 Female patients must be of non-childbearing potential.
Women of non-childbearing potential are defined as women who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Women will be considered postmenopausal if they have been 
amenorrhoeic for 12 months prior to the planned date of randomisation without an 
alternative medical cause. The following age-specific requirements apply:
(a) Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and FSH levels in the postmenopausal range.

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(b) Women ≥50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment.
11 Male patients must be surgically sterile or using, in conjunction with their female partner, 
a highly effective method of contraception for the duration of the study (from the time 
they sign consent) and for 3 months after the last dose of study drug to prevent pregnancy 
in a partner. Male study participants must not donate or bank sperm during this same time 
period.
Informed Consent
12 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
13 Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses.
NOTE: For the optional pre-screening visit there is a separate informed consent. Refer to 
Section 4.1.1.
14 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative.
Participants are eligible to be randomised in the study only if all of the following criteria apply 
at randomisation (Visit 3):
15 eGFR ≥30 mL/min/1.73 m2 (by CKD-EPI formula at central laboratory) based on results 
from pre-randomisation Visit 2.
Note: Recruitment will start with patients who have eGFR ≥30 mL/min/1.73 m2. During 
the study, the Safety Unblinded Data Review Committee may decide to also include 
patients with eGFR ≥20 to < 30 mL/min/1.73 m2
16 UACR ≥30 mg/g (3 mg/mmol) and < 3000 mg/g (300 mg/mmol) based on central 
laboratory samples collected at pre-randomisation Visit 2. Refer to Section 8.1.1.
17 Serum/plasma K+ level ≥3.5 and < 5.0 mmol/L within 10 days prior to randomisation 
(Visit 3) from local laboratory.
18 Serum/plasma sodium (Na+) level within normal reference values within 10 days prior to 
randomisation (Visit 3) from local laboratory.
19 Systolic BP ≥90 and < 150 mmHg (or < 180mmHg if the patient is already receiving 3 or 
more antihypertensive drugs) at randomisation (Visit 3), with no change to 
antihypertensive treatments in previous 3 weeks. Antihypertensive drugs include, but are 
not limited to, a diuretic, ACEI, ARB, beta-blocker and calcium channel blocker.

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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Primary glomerulopathy, vasculitic renal disease (including ANCA-associated vasculitis), 
prior dialysis or unstable rapidly progressing renal disease, autosomal dominant or 
autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated 
vasculitis.
2
Patients with currently decompensated HF requiring hospitalisation for optimisation of 
HF treatment and are not on stable HF therapy at the time of enrolment.
3
HF due to cardiomyopathies that would primarily require specific other treatment such as 
cardiomyopathy due to amyloidosis or infiltrative diseases, primary hypertrophic 
cardiomyopathy, cardiomyopathy related to current toxic or infective conditions (ie, 
ongoing chemotherapy, infective myocarditis, septic cardiomyopathy).
4
High output HF (eg, due to hyperthyroidism or Paget’s disease).
5
HF due to pericardial disease, congenital heart disease or clinically significant 
uncorrected primary cardiac valvular disease or planned cardiac valve repair/replacement.
6
Patients with uncontrolled diabetes mellitus (HbA1c > 10%).
7
Patients with T1DM.
8
Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction 
with clinically significant bradycardia or sinus pauses, not treated with a pacemaker.
9
Known congenital long QT syndrome or history of QT prolongation associated with other 
medications.
10 History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal) or 
uncontrolled ventricular rate in patients with atrial fibrillation or atrial flutter.
11 Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions 
within 3 months prior to randomisation (Visit 3) or is planned to undergo any of these 
procedures during the study.
12 Any major cardiovascular (eg, open chest coronary artery bypass grafting or valvular 
repair/replacement) or major non-cardiovascular surgery as judged by the investigator 
within 3 months prior to randomisation (Visit 3) or is planned to undergo any of these 
procedures during the study.
13 Heart transplantation or left ventricular assist device at any time or if these are planned.
14 Kidney or any organ transplantation or if these are planned.
15 Addison’s disease (a medical conditions associated with development of hyperkalaemia).
16 History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, 
dapagliflozin, empagliflozin).

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17 Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, 
renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical 
impairment) which, as judged by the investigator, might put the patient at risk because of 
participation in the study, or probable alternative primary reason for patient’s symptoms 
in judgement of investigator, including but not limited to:
(a) Isolated pulmonary arterial hypertension (defined as mean PAP ≥25 mmHg at rest) 
or right ventricular failure; in the absence of left-sided HF.
(b) Anaemia defined as haemoglobin level < 100 g/L or < 10 g/dL at time of screening 
(Visit 1a).
(c) Severe chronic obstructive pulmonary disease or other lung disease including but not 
limited to pulmonary fibrosis requiring chronic oxygen therapy, regular nebuliser use 
or oral steroid therapy.
18 Stroke, transient ischaemic attack, carotid surgery, or carotid angioplasty within previous 
3 months prior to randomisation (Visit 3).
19 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas 
of the skin). 
20 Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), 
AST or ALT >2 × ULN; or TBL > 2 × ULN at time of screening (Visit 1a). An isolated 
increase in bilirubin in patients with known Gilbert’s syndrome is not a reason for 
exclusion. 
21 Prior or ongoing drug or alcohol abuse.
22 Patients treated with strong or moderate CYP3A4 inhibitor or inducer (Appendix H).
23 Patients with newly detected pathological laboratory values or an ongoing disease 
condition requiring investigation and/or initiation or adjustment of current treatment (in 
the opinion of the investigator).
24 Any condition outside the renal and cardiovascular disease area, such as but not limited to 
malignancy, with a life expectancy of less than 2 years based on investigator´s clinical 
judgement.
25 Any of the following signs or confirmation of COVID-19 infection:
(a) Optional in case RT-PCR is available at the site with an appropriate turnaround time: 
Patient has a positive test result for SARS-CoV-2 at Visit 2 before randomisation at 
Visit 3.
(b) Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, 
dyspnoea, sore throat, fatigue) or confirmed infection by appropriate laboratory test 
within the last 4 weeks prior to screening (Visit 1a) or at randomisation (Visit 3).
(c) Patient has been previously hospitalised with COVID-19 infection and did not fully 
recover their previous health status.

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Prior/Concomitant Therapy
26 Prior medical treatment with an MRA where the medication was taken within 90 days 
prior to screening (Visit 1a).
27 Treatment with MRA and other prohibited concomitant medications during run-in.
Note: Prohibited medications are listed in Section 6.5.1.
28 Current or prior treatment within 6 months prior to screening (Visit 1a) with cytotoxic 
therapy, immunosuppressive therapy, or other immunotherapy.
29 Participation in another clinical study with an investigational product administered in the 
last 3 months prior to randomisation (Visit 3).
Other Exclusions
30 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
31 Judgement by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
32 Previous randomisation in the present study.
33 Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss 
> 500 mL during the 3 months prior to any visit at the clinic.
Genetic Sampling (Optional)
Exclusion from this genetic research may be for any of the exclusion criteria specified for the 
main study or any of the following:
34 Previous allogeneic bone marrow transplant.
35 Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Patients should fast prior to the collection of blood samples for FPG and lipids, on the days 
specified in the SoA. Fasting is defined as no caloric intake for at least 8 hours prior to the 
collection of the sample.
There are no other specific meals and dietary restrictions.
Study medications should be taken at approximately the same hour each morning, and the 
time recorded by the participant in the diary card (see Section 6.4).
On days when participants will attend the study site for a study visit and assessments, they 
will be asked to not take their study medications prior to attending the study visit. The 

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participant will take the study medication at the site after completing all predose procedures 
and provided they are permitted to continue in the study following assessments.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
fail to be eligible to start Run-in. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the eGFR and/or K+ inclusion/exclusion criteria for participation 
in the study at screening (Visit 1a) and/or pre-randomisation Visit 2, may have their eGFR 
and/or serum/plasma K+ retested later upon investigator's discretion.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Only 1 rescreening is allowed in the study. Rescreened participants should be 
assigned the same participant number as for the initial screening.

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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, intended to be administered to, or medical device(s) intended to be used by a study 
participant according to the CSP.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
After screening, eligible participants currently on treatment with a SGLT2i other than 
dapagliflozin should stop taking the SGLT2i and start on dapagliflozin 10 mg once daily. 
Participants on dapagliflozin treatment will continue on treatment but the medication will be 
provided. Participants will then undergo a 4 to 5-week run-in period to ensure washout of 
forbidden medications and stable doses of allowed background medications.
For participants eligible after screening not on treatment with a SGLT2i, treatment with 
dapagliflozin 10 mg once daily will be initiated. Participants will then undergo a 6 to 7-week 
run-in period to ensure washout of forbidden medications and stable doses of allowed 
background medications.
Participants will be randomly assigned with a 1:1:1:1 ratio to receive once daily 
administration of one of the following study treatments:

AZD9977 15 mg + dapagliflozin 10 mg

AZD9977 50 mg + dapagliflozin 10 mg

AZD9977 150 mg + dapagliflozin 10 mg

Dapagliflozin 10 mg
To ensure blinding to treatment allocation and the AZD9977 dose, daily dosing will consist of 
1 open label dapagliflozin 10 mg tablet and 3 AZD9977 capsules containing respectively 
AZD9977 150 mg or placebo, AZD9977 50 mg or placebo, and AZD9977 15 mg or placebo 
See Table 5 and Section 4.1.

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Table 5
Investigational Products
AZD9977
Dapagliflozin
Intervention 
Name
AZD9977 15 mg 
or placebo
AZD9977 50 mg 
or placebo
AZD9977 
100 mg or 
placebo
Dapagliflozin
10 mg 
Type 
Drug
Drug
Drug
Drug
Dose 
Formulation
Pellets in 
capsule (size 3)
Pellets in 
capsule (size 0)
Pellets in 
capsule (size 0)
Film-coated tablet
Unit Dose 
Strength(s)
15 mg 
50 mg
100 mg
10 mg
Dosage Level(s)
15 mg:
1 AZD9977 15 mg capsule +
1 placebo size 0 capsule +
1 placebo size 0 capsule
10 mg tablet
50 mg:
1 AZD9977 50 mg capsule +
1 placebo size 3 capsule +
1 placebo size 0 capsule
150 mg:
1 AZD9977 50 mg capsule +
1 AZD9977 100 mg capsule +
1 placebo size 3 capsule
Route of 
Administration
oral
oral
oral
oral
IMP and NIMP
IMP
IMP
IMP
IMP, NIMP a
Sourcing
AZD9977, dapagliflozin, and matching placebo treatments will be supplied 
centrally through AstraZeneca.
Packaging and 
Labelling
For each strength, AZD9977 and matching placebo will 
be provided in bottles containing 32 capsules.
Dapagliflozin will be 
supplied in HDPE 
bottles containing 
35 tablets.
All bottles will be labelled in accordance with GMP Annex 13 and per country 
regulatory requirement.
GMP=Good Manufacturing Practice; HDPE=high-density polyethylene; IMP=investigational medicinal product; 
NIMP=non-investigational medicinal product.
a
Dapagliflozin is NIMP during the run-in and safety follow-up, but IMP during the treatment phase.
6.1.2
Medical Devices
1
No AstraZeneca manufactured medical devices (or devices manufactured for AstraZeneca
by a third party) are provided for use in this study.

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2
Other medical devices (not manufactured by or for AstraZeneca) provided for use in this 
study are as follows. 

dECG device: GE MAC 2000 ECG Analysis System (510k and CE marked)
3
All medical device deficiencies (including malfunction, use error and inadequate 
labelling) will be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.10) and appropriately managed by the sponsor.
6.2
Preparation/Handling/Storage/Accountability
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Drug Handling Instructions.
6.3
Measures to Minimise Bias: Randomisation and Blinding
All participants will be centrally assigned to randomised study intervention using an 
IRT/RTSM. Before the study is initiated, the telephone number and call-in directions for the 
IRT and/or the log in information and directions for the RTSM will be provided to each site.
Study intervention will be dispensed at the study visits summarised in SoA. 
Unused returned study intervention must not be re-dispensed to the participants.
The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification 
numbers to be allocated to the participant at the dispensing visit.
Routines for this will be described in the IRT/RTSM user manual that will be provided to each 
centre.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 

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The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented.
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the participant’s condition (eg, antidote available), the investigator 
has the sole responsibility for determining if unblinding of a participants’ intervention 
assignment is warranted. Participant safety must always be the first consideration in making 
such a determination. If a participant’s intervention assignment is unblinded, the sponsor must 
be notified within 24 hours after breaking the blind. The investigator documents and reports 
the action to AstraZeneca, without revealing the treatment given to participant to the 
AstraZeneca staff.
The PK samples will be analysed at Labcorp Drug Development bioanalytical laboratory only 
for patients on active treatment. 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.
6.4
Study Intervention Compliance
Participants will take treatment at the site on visit days and at home between visits.
When participants are dosed at the site, they will receive study treatments directly from the 
investigator or designee, under medical supervision, after checking treatment was not taken at 
home before coming to the study site. The date, and time of dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. 
When participants self-administer study treatments at home, compliance with study treatment 
will be assessed at each visit. Diary Cards will be given to the patients at the randomisation 
visit (Visit 3) and the patients will be asked to fill in the dose intake information (date and 
time) at home. The diary cards will be checked by study site personnel at the study visits and 
data transferred to the eCRF. 
Compliance will be assessed by direct questioning and counting returned tablets/capsules
during the site visits and documented in the source documents and eCRF. Deviation(s) from 
the prescribed dosage regimen should be recorded in the eCRF.

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A record of the number of dapagliflozin tablets and AZD9977/placebo capsules dispensed to 
and taken by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention delays 
will also be recorded in the eCRF. If treatment was taken at home before coming to the study 
site, no new dose should be administered, and the date and time of the dose administered at 
home should be recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of screening (Visit 1a) 
or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Participants may be enrolled and or continue in the study regardless of their choice to be 
vaccinated or not. COVID-19 vaccine received prior to or during the study entry must be 
recorded including the type of vaccine.
The Study Physician should be contacted if there are any questions regarding prior or 
concomitant therapies.
6.5.1
Prohibited Medications
The medications and supplements listed below are prohibited from at least start of run-in and 
for the duration of the study. Patients taking any of these medications at the start of the run-in 
period cannot be included into the study. 

Potassium-sparing diuretics (eg, amiloride, triamterene)

MRAs or aldosterone antagonists (eg, eplerenone, spironolactone)

ACEI and ARB taken in combination

Direct renin inhibitor (eg, Aliskiren)

Cyclosporin or tacrolimus

Strong or moderate CYP3A4 inhibitors or inducers (see Appendix H)

K+ supplements or dietary salt alternatives containing K+ such as Lo-Salt (prohibited 
during run-in unless if serum K+ < 3.5 mmol/L, and can be started during the study as a 
corrective action if hypokalaemia is confirmed)

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
NSAIDs (The use of acetylsalicylic acid as antiplatelet agent is allowed prior and during 
the study as well as the intermittent use of topical NSAIDs if prescribed for a medical 
condition)

Potassium binders (prohibited at screening/randomisation but can be started as a 
corrective action during the study)
Medical treatment with an MRA is exclusionary if the medication was taken within 90 days 
prior to screening (Visit 1a). Cytotoxic therapy, immunosuppressive therapy, and other 
immunotherapy for primary or secondary renal disease are prohibited within 6 months prior to 
screening (Visit 1a) and for the duration of the study.
6.5.2
Background Medications
Background treatment for HF, hypertension, or renal disease should be stable for at least 
3 weeks prior to randomisation (see inclusion criterion #4) and remain stable during the study.
Patients with HF and LVEF ≤40% should receive background standard of care for HFrEF and 
be treated according to locally recognised guidelines with both drugs and devices, as 
appropriate.
Guideline-recommended medications should be used at recommended doses unless 
contraindicated or not tolerated: an ACEI, or ARB or sacubitril/valsartan and a beta-blocker. It 
is advised that other guideline recommendations for management of cardiovascular disease 
and CKD are also followed (except for strong or moderate CYP3A4 inhibitors or inducers).
Patients who are on 10 mg dapagliflozin at screening should remain on the therapy as 
indicated throughout the treatment period of the study. Patients who are on another SGLT2i 
(eg, canagliflozin or empagliflozin) will be switched to 10 mg dapagliflozin starting at the 
start run-in (Visit 1b) after confirmed eligibility and will remain on the therapy throughout the 
treatment period of the study. Patients who are not on a SGLT2i will be started on 10 mg 
dapagliflozin at the start run-in (Visit 1b) after confirmed eligibility and will remain on the 
therapy throughout the safety follow-up period.
Glycaemic control should be performed according to local guidelines.
It is preferable that any background medical therapy (eg, HF, antihypertensive therapy as well 
as therapy with statins) will not be changed during study drug treatment, ie, between the 
screening visit and the last dose of study drug. However, if this is necessary, the participant 
does not need to be withdrawn from study drug.
6.5.3
Medications Inducing Hypoglycaemia
Participants using medications that can cause hypoglycaemia in T2DM patients, including 

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insulin or SU, may be required to reduce insulin by 10 to 20% (total daily dose) and SU by 
25 to 50%. In addition, more frequent blood glucose monitoring may be considered in 
participants receiving insulin and/or SU and with baseline HbA1c ≤7% at randomisation.
6.6
Dose Modification
No dose modifications are allowed during the study.
6.7
Intervention After the End of the Study
Following the EOT visit, participants will stop study drug and continue on open label 
dapagliflozin 10 mg during the safety follow-up period. After the safety follow-up visit,
participants should return to their usual treatments at the discretion of the investigator.

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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. 
Participants may be discontinued from study intervention in the following situations:

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment

An AE that, in the opinion of the Investigator or AstraZeneca, warrants discontinuation 
from further dosing

Severe non-compliance with the CSP

Safety reasons as judged by the investigator and/or sponsor where continued treatment 
may put participant at undue risk
Participants will be discontinued from study intervention in the following situations:

If the participant becomes pregnant during the course of the study

Protocol-defined hyperkalaemia: Study treatments must be discontinued in case of 
confirmed (ie, 2 consecutive samples) serum/plasma K+ > 6.0 mmol/L, or confirmed 
serum/plasma K+ > 5.5 mmol/L (at investigator’s discretion), or serum/plasma
K+ > 5.5 mmol/L with repeat value > 6 mmol/L (see Appendix F 1 for details on the 
monitoring and management of hyperkalaemia)

Protocol-defined deteriorating renal function: Study treatments must be discontinued in 
case of confirmed eGFR reduction from baseline > 50% and/or any confirmed decrease 
below 15 mL/min/1.73 m2 (see Appendix F 2 for details on the monitoring and 
management of deteriorating renal function)

There have been reports of ketoacidosis, including DKA, in patients with T2DM taking 
dapagliflozin and other SGLT2 inhibitors in previous studies. Patients with T2DM on 
investigational treatment who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath 
should be assessed for ketoacidosis, even if blood glucose levels are < 14 mmol/L 
(250 mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of the 
investigational treatment should be considered and the patient should be promptly 
evaluated.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 

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the study.
If study interventions are permanently discontinued, the participant will remain in the study 
for the ET visit and the safety follow-up visit. The participant may continue on open-label 
dapagliflozin during the safety follow-up period as judged by the Investigator taking in 
consideration the reason for the permanent discontinuation of the study intervention.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.1
Temporary Discontinuation and Rechallenge
Temporary discontinuation of study treatments may be considered if hyperkalaemia is 
observed and repeat tests are required to confirm protocol-defined discontinuation criteria (see 
Appendix F 1).
Temporary discontinuation of dapagliflozin should be considered if DKA is suspected and the
patient should be promptly evaluated:

If DKA is confirmed, study treatments should be discontinued permanently.

If DKA is not confirmed, dapagliflozin may be restarted.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, an ET visit should be conducted, as 
shown in the SoA. See SoA for data to be collected at the ET visit.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time. The 4-week safety follow-up after last dose will not be performed.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 

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investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
echocardiography) and obtained before signing of the ICF may be utilised for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 400 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Efficacy Assessments
8.1.1
Primary/Secondary Variable: 
Urinary Albumin to Creatinine Ratio (UACR)
The UACR is calculated as follows:

UACR (mg/mmol) = 10 × urine albumin (mg/dL) / urine creatinine (mmol/L)
Urine samples for the determination of albumin and creatinine and calculation of UACR will 
be collected at the timepoints described in the SoA:

After consent at screening (Visit 1a), a container to collect the spot urine sample will be 
dispensed to the participants. The spot urine sample will be collected at this visit. 

Collection of triplicate urine sampling will start at Visit 2. At Visit 1b and at subsequent 
visits, containers to collect the urine samples will be dispensed to the participants prior to 
the visits described in the SoA. Investigators will perform a phone call prior to the visit to 
remind the participants to collect the first morning void samples. Participants will collect 
first morning void urine samples at home on 3 consecutive days (ideally day of visit and 

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preceding 2 days [refrigerated overnight] which will be returned on the day of visit). 
Samples will be analysed centrally. At each visit, the geometric mean of the triplicate 
measurements will be computed centrally and used for all analyses of UACR. 
Note: The samples collected on visit days will also be used for the determination of 
exploratory urinary parameters (see Section 8.5.2.1 and 8.6.2).
8.1.2
Exploratory Variables – Not Applicable
8.2
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
Physical examination, and measurement of weight and height will be conducted as outlined in 
the SoA.

For weight and height measurements, the participant will be allowed to wear indoor, 
daytime clothing with no shoes and no coats/jackets and removal of heavy objects from 
pockets.

A complete physical examination will be performed and include assessments of general 
appearance, respiratory, cardiovascular, abdominal, and neurological systems, the skin, 
lymph nodes, and an assessment of the presence and extent of peripheral (ankle/leg) 
oedema.
For information on how AEs based on physical examination findings should be recorded and 
reported, see Section 8.3.5.
8.2.2
Vital Signs
Blood pressure and pulse rate will be assessed at the study site, as outlined in the SoA, prior to 
blood collection for laboratory tests with the patient resting in a supine position using a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (eg, television, cell phones) and will consist 
of 1 pulse and 3 BP measurements (3 consecutive BP readings will be recorded at intervals of 
at least 1 minute). The average of the 3 BP readings will be recorded on the eCRF.
For information on how AEs based on vital sign results should be recorded and reported, see 
Section 8.3.5.

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8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained after the patient has been resting in a supine position for 
at least 10 minutes, at the visits outlined in the SoA. A dECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals will be used. 
Interpretation of the clinical safety dECG findings will be reviewed and confirmed by the 
investigator and recorded in the eCRF. Digital ECGs will be collected, cleaned, and stored by 
ERT.
Investigators will assess patients’ eligibility according to the ECG report of Visit 1a. Any 
abnormal finding in the ECG tracing will be evaluated by the investigator and will be 
specifically documented and registered in the CRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal 
findings in the tracing) must be considered an AE and must be recorded in the AE CRF form.
For information on how AEs based on ECG results should be recorded and reported, see 
Section 8.3.5.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the visits indicated in the SoA.
Additional safety samples 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 eCRF.
The clinical chemistry, haematology, and urinalysis will be performed at a local laboratory for 
screening, and at a central laboratory at baseline and subsequent visits, as indicated in the 
SoA.
Measurement of electrolytes (Na+ and K+) and creatinine at local laboratories may be done on
either plasma or serum samples, depending on their capabilities, while these measurements at 
the central laboratory will be done on serum samples. In addition, K+ levels will be measured 
in plasma samples at the central laboratories for exploratory analysis.
The participant’s eGFR (mL/min/1.73 m2) will be calculated based on the standard 
BSA-adjusted CKD-EPI formula using serum/plasma creatinine concentration alone (Levey et 
al 2009) as measured at a local laboratory and using both serum creatinine and serum 
cystatin C concentrations (Inker et al 2012)at a central laboratory. Note that for eGFR 
calculation based on creatinine levels, the calibrated methods provide equivalent results for 
plasma and serum sample types.
eGFR calculation using standard BSA-adjusted CKD-EPI formula using serum/plasma 

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creatinine concentration (Levey et al 2009):
eGFR (mL/min/1.73m2) = 141 × min (SCr/ κ,1) α × max (SCr/ κ,1)-1.209 × 0.993Age × [1.018 if 
female] × [1.159 if black]
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.
eGFR calculation using standard BSA-adjusted CKD-EPI formula using both serum creatinine 
and serum cystatin C concentrations (Inker et al 2012):
eGFR (mL/min/1.73m2) = 135 × min(SCr/κ, 1)α × max(SCr/κ, 1)-0.601 × min(Scys/0.8, 1)-0.375
× max(Scys/0.8, 1) 0.711 × 0.995Age × 0.969 [if female] × 1.08 [if black]
SCr (serum creatinine) = mg/dL, Scys (standardised serum cystatin C) = mg/L, κ = 0.7 
(females) or 0.9 (males), α = -0.248 (females) or -0.207 (males), min(SCr/κ or 1) = indicates 
the minimum of SCr/κ or 1, max(SCr/κ or 1) = indicates the maximum of SCr/κ or 1, 
min(Scys/0.8, 1) = indicates the minimum of Scys/0.8 or 1, max(Scys/0.8, 1) = indicates the 
maximum of Scys/0.8 or 1, age = years

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The following laboratory variables will be measured:
Table 6
Laboratory Safety Variables
Haematology/Haemostasis (whole blood) a
Clinical Chemistry (serum or plasma) a
White blood cell (WBC) count
Na+ b
Red blood cell (RBC) count
K+ b, c
Haemoglobin (Hb)
Blood urea nitrogen (BUN)
Haematocrit (HCT)
Serum creatinine b d
Neutrophils absolute count f
Uric acid f
Lymphocytes absolute count f
Albumin
Monocytes absolute count f
Calcium
Eosinophils absolute count f
Phosphate
Basophils absolute count f
Alkaline phosphatase (ALP)
Platelets
Alanine aminotransferase (ALT)
International normalised ratio (INR) e
Aspartate aminotransferase (AST)
MCV f
Total bilirubin (TBL)
MCHC f
Glutamate dehydrogenase (GLDH) f
RBC distribution width f
Creatine kinase (CK) f
HbA1c
Bicarbonate (HCO3-) f
Urinalysis (urine) a
Chloride (Cl-) f
Protein
Magnesium (Mg+) f
Glucose
Glucose
Blood
Total cholesterol, direct HDL-C, triglycerides, 
LDL-C g, VLDL-C g (fasting, see Section 5.3.1) f
Leukocyte esterase
Other assessments
Specific gravity f
Cystatin C d, h
pH f
RT-PCR test for SARS-CoV-2 (optional, at 
pre-randomisation visit)
Microscopic examination of the sediment if blood or 
leukocyte esterase are positive on dipstick f
Follicle stimulating hormone (FSH) (for confirmation 
of postmenopausal status of women < 50 years old 
only [women who are permanently sterilised are
exempted], at screening)
Note: In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN please refer to 
Appendix E. Actions required in cases of increases in liver biochemistry and evaluation of Hy’s law cases, for 
further instructions.
BSA=body surface area; CKD-EPI=chronic kidney disease epidemiology collaboration; eGFR=estimated 
glomerular filtration rate; HbA1c=glycated haemoglobin; HDL-C= high density lipoprotein cholesterol; 
K+=potassium; LDL-C=low density lipoprotein cholesterol; MCHC=mean corpuscular haemoglobin 
concentration; MCV=mean corpuscular volume; Na+=sodium; RT-PCR=reverse transcriptase polymerase chain 
reaction; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SoA=schedule of activities; 
ULN=upper limit of normal; VLDL-C= very low density lipoprotein cholesterol

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a
Local laboratory at screening and pre-randomisation (if applicable per SoA) and central laboratory at 
subsequent visits, unless specified otherwise.
b
At the local laboratories, electrolytes (Na+ and K+) and creatinine may be measured in plasma samples 
instead of serum samples depending on their capability.
c
Central laboratory measurements for K+ levels will be with serum and plasma samples.
d
eGFR (mL/min/1.73 m2) will be calculated using the BSA-adjusted CKD-EPI formula and including both 
serum creatinine and serum cystatin C for central laboratory assessments; and with serum/plasma creatinine 
alone for local laboratory assessments.
e
The post-randomisation INR measurements may be done at a local laboratory if the necessary material 
provided by the central laboratory is not available; and the measurements may be omitted if the local 
laboratory is not capable of doing the measurements. Refer to Laboratory Manual for details.
f
These tests are not required at screening or pre-randomisation.
g
Per Friedewald equation.
h
Central laboratory for all cystatin C measurements.
Instructions for the collection and handling of the samples will be provided in the study 
specific Laboratory Manual.
8.3
Adverse Events and Serious Adverse Events
The PI 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from randomisation (Visit 3) throughout the treatment period 
and including the follow-up period.
Serious AEs will be recorded from the time of signing of the full ICF for the study (Visit 1a).
No AE or SAE information will be collected after just signing of the optional pre-screening 
ICF.
If the investigator becomes aware of a SAE, with a suspected causal relationship to at least 
1 of the IMP, that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
in the study are followed up by the investigator for as long as medically indicated, but without 

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further recording in the eCRF. AstraZeneca retains the right to request additional information 
for any participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse Event Variables
The following variables will be collected for each AE:

AE (verbatim)

Date and time when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the investigational products (yes or no)

Action taken with regard to investigational products

AE caused participant’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s) and/or other medication

Description of AE
8.3.3
Causality Collection
The investigator should assess causal relationship between each of the investigational products 
and each AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.

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A guide to the interpretation of the causality question is found in Appendix B.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit?’ or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, 
ECG parameters and echocardiography findings should therefore only be reported as AEs if 
they fulfil any of the SAE criteria, are the reason for discontinuation of treatment with the 
investigational product or are considered to be clinically relevant as judged by the investigator 
(which may include but not limited to consideration as to whether treatment or non-planned 
visits were required or other action was taken with the study treatment, eg, dose adjustment or 
drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (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 at a physical examination 
as compared with the baseline assessment will be reported as an AE.
8.3.6
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may
need to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
8.3.7
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.

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If any SAE occurs during the course of the study, then investigators or other site personnel 
inform the appropriate AstraZeneca representatives within one 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 one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for both study treatments. 
8.3.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except when 
the pregnancy is discovered before the study participant has received any study drug.
8.3.8.1
Maternal Exposure
There is no information about effects that AZD9977 could have on the development of the 
foetus in humans. Pre-clinical studies have shown that AZD9977 is not genotoxic, however 
formal pre-clinical reproductive toxicology studies have not yet been completed. 
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.

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Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational products should be discontinued immediately, and 
the pregnancy reported to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomaly/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel informs the appropriate 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.8) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.3.8.2
Paternal Exposure 
It is important that women of childbearing potential, who are the partners of male participants, 
do not become pregnant during the study and for a total period of 3 months after the male 
study participant has received his last dose of IMP.
All male participants should avoid fathering a child by either true abstinence or use together 
with their female partner/spouse a highly effective method of contraception (see definition 
below), starting from the time of IMP administration until 3 months after the last dose of IMP. 
For male participants whose partner is already pregnant, the man should use a condom for the 
duration of the study and for 1 week afterwards.
Male participants should not donate sperm for the duration of the study and for at least 
3 months after the study follow-up visit.
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered highly effective birth control methods such as:

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
Combined (oestrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation:

Oral

Intravaginal

Transdermal

Progesterone-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion of female partner

Male vasectomy

True sexual abstinence: True abstinence refers to: When this is in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, 
symptom-thermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial, and withdrawal are not acceptable methods of contraception.
If the partner of a male participant becomes pregnant during the study, this should be reported 
to the investigator. The investigator should also be notified of pregnancy occurring during the 
study but confirmed after completion of the study. In the event that a participant’s partner is 
subsequently found to be pregnant after the study participant is included in the study, then 
consent will be sought from the partner and if granted any pregnancy will be followed and the 
status of mother and/or child will be reported to the sponsor after delivery.
8.3.9
Medication Error
If a medication error occurs during the course of 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 (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 (see Section 8.3.9) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B. 

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8.3.10
Medical Device Deficiencies
In this study any deficiency observed with a third party medical device will be collected and 
reported to the manufacturer.
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
The AstraZeneca (Appendix I), or manufacturer’s where available, medical device complaint 
report will be used to collect the deficiency.
8.4
Overdose
Dapagliflozin has been well tolerated at doses 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 type 2 diabetes. Only suspected single intake of more than 
500 mg dapagliflozin or repeated intake of more than 100 mg dapagliflozin should be reported 
on the eCRF overdose module. 
Presently there is no information regarding overdose of AZD9977 in man. For this study, any 
dose of AZD9977 greater than 150 mg within 24 hours will be considered an overdose.
If an overdose is suspected, monitoring of vital functions as well as treatment should be 
performed as appropriate.

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.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs during the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see section 8.3.7) and within 30 days 
for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual. Samples should be stored in a secure storage space with 

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adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Sample see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report 
finalisation or 6 months after issuance of the draft Bioanalytical Report (whichever is 
earlier), unless consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR.
8.5.1
Pharmacokinetics

Blood samples will be collected for measurement of plasma concentrations of AZD9977 
and dapagliflozin, including predose samples from all participants and optional postdose 
samples from participants who consent, at the visits and timepoints specified in the SoA.

Samples may be collected at additional timepoints during the study if warranted and 
agreed upon between the investigator and the sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Samples collected for analyses of AZD9977 and dapagliflozin plasma concentrations may 
also be used to evaluate safety or efficacy aspects related to concerns arising during the 
study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be assayed by Labcorp Drug 
Development on behalf of AstraZeneca, using appropriately validated bioanalytical methods. 
Full details of the analytical methods used will be described in a separate Bioanalytical 
Report.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis or additional assay development work, if any, will be 

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performed alongside the bioanalysis of the test samples. The results from the evaluation, if 
performed, will be reported in a separate Bioanalytical Report.
8.5.2
Pharmacodynamics
Urinary and serum/plasma parameters will be measured during the study for the evaluation of 
the exploratory endpoints:

NT-proBNP, aldosterone, renin, ACTH, cortisol, copeptin, and FPG (per the SoA)
The following parameters will be measured from the blood samples collected for safety and 
analysed centrally (see Section 8.2.4): 

Bicarbonate (HCO3-), Na+, K+, creatinine, uric acid, BUN (at Visits 3 to 11) as part of 
clinical chemistry

Haematocrit (at Visits 3 to 11) and MCV, MCHC, RBC distribution width, erythrocyte 
count (at Visits 3, 8, and 10), as part of haematology
8.5.2.1
Collection of Samples
Urine Samples
Urine samples will be collected and analysed at a central laboratory for the determination of 
the exploratory urinary parameters at the timepoints specified in the SoA. 
The urine samples collected on visit days for the analysis of UACR (see Section 8.1.1) will be 
split, so that it can also be used for the determination of Na+, K+, uric acid, urea, osmolality, 
glucose and cortisol levels.
Blood Samples
Blood samples will be collected at the timepoints specified in the SoA and analysed at a 
central laboratory for the determination of the following parameters:

NT-proBNP, aldosterone, active renin, ACTH, cortisol, and copeptin

FPG (for fasting conditions, see Section 5.3.1)
In addition, blood samples will be collected at screening and analysed locally for the 
determination of NT-proBNP to confirm eligibility criteria.
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.
For storage, re-use and destruction of pharmacodynamic samples see Section 8.5 and 
Appendix C. 

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8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study the participant consents to the mandatory research 
components of the study. Mandatory collection of samples for biomarker research is part of 
this study.

Serum/plasma samples for cardiovascular biomarker research will be collected from all 
participants in this study as specified in the SoA. These samples will be used for the 
determination of cardiovascular biomarkers (including but not limited to hsTnT, PIIIP3, 
GDF-15, ST2, ADMA, SDMA, L-Arg, ICAM, NGAL) by a central laboratory.
8.6.2
Collection of Optional Biomarker Samples
Collection of optional samples for biomarker research is also part of this study as specified in 
the SoA and is subject to participant’s optional consent:

Serum, plasma, and urine samples will be collected for future use aimed at exploring 
biomarkers involved in PK, pharmacodynamics, safety and tolerability related to 
AZD9977 and dapagliflozin or related to cardiorenal diseases.
For storage, re-use and destruction of biomarker samples see Section 8.5. 
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA and is subject to participant’s optional consent in the ICF addendum. 
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples see Appendix D.
8.8
Medical Resource Utilisation and Health Economics
Not Applicable.

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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary hypothesis for this study is that AZD9977 in combination with dapagliflozin will 
induce a greater reduction of albuminuria than with dapagliflozin alone, as assessed by the 
percent change from baseline in UACR at 12 weeks.
9.2
Sample Size Determination
A total of 119 evaluable participants per arm will provide 80% power to detect a 30% 
difference in a AZD9977 dose group combined with dapagliflozin 10 mg compared to 
dapagliflozin 10 mg alone in percent change from baseline in UACR at 12 weeks, assuming a 
SD of 1.0 on the natural log-scale and alpha = 0.05. To account for approximately 5% 
drop-out from the study, approximately 500 participants will be randomly assigned to study 
intervention (125 participants per group) such that approximately 476 evaluable participants 
(119 per group) complete the study.
Patients randomised according to CSP versions 1.0 to 5.0 (before dropping placebo and 
AZD9977 150 mg monotherapy arms) will be considered as part of Cohort 1, while patients 
randomised subsequently will be included in Cohort 2. The primary analysis for the remaining 
4 treatment groups will combine data from both cohorts, while the accrued data from 
discontinued treatment groups will be analysed descriptively.

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9.3
Populations for Analyses
The following populations are defined:
Table 7
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who sign the main ICF.
Full Analysis Set (FAS)
All participants who are randomised and either receive or do not receive any 
study intervention. Participants are evaluated according to the treatment 
assigned at randomisation.
The FAS will be used for all analyses of demographic baseline 
characteristics and efficacy data.
Per Protocol Set (PPS)
A subset of the FAS consisting of all participants who do not violate the 
terms of the protocol in a way that may affect the primary efficacy endpoint 
significantly. All decisions to exclude participants from the per protocol 
analysis set will be made and documented prior to the unblinding of the 
study.
Safety Set (SS)
All participants who are randomised and receive any study intervention. 
Participants are evaluated according to the actual treatment they received.
If a participant received a different treatment dose than randomised 
throughout the study, they will be analysed according to the treated dose, 
not the randomisation dose. If a participant received study drug from the 
wrong kit for only part of the treatment duration, they will be analysed 
according to their randomisation dose.
The SS will be used for all safety analyses.
Additional analysis sets, such as PK population may be defined the SAP for exploratory 
analyses.
9.4
Statistical Analyses
The SAP will be finalised prior to database lock for the interim analysis and will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.4.1
General Considerations
All results will be presented by treatment group and overall, with descriptive statistics 
appropriate to the nature of the variables. 
Demographic and baseline characteristics as well as prior and concomitant medication will be 
presented. For continuous variables, the number of non-missing observations, mean, SD, 
median, first and third quartiles, minimum, and maximum will be presented. For categorical 
variables: counts (n) and percentages (%) (where specified) will be presented. These 

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summaries will be provided by timepoint of assessment as appropriate.
When change from baseline will be described, the baseline value will be, in general, the last 
non-missing value prior to administration of the first dose of each treatment period. Further 
details will be described in the SAP.
The SAS® version 9.4 or later will be used for the data analysis.
In general, there will be no imputation of missing data for the safety analyses. Additional 
details will be provided in the SAP.
Deviations from the protocol will be assessed as “important” or “not-important”. Important 
deviations from the protocol may lead to the exclusion of participants from any of the study 
analysis sets. Deviations will be defined before database hard lock. Important deviations will 
include the following:

Violation of inclusion and/or exclusion criteria

Administration of prohibited concomitant medications that are expected to influence the 
measurement of the primary endpoint.
All protocol deviations will be discussed at the data review meeting prior to database hard 
lock in order to define the analysis sets for the study. All the important protocol deviations will 
be listed by participants. Further details will be described in the SAP.
9.4.2
Efficacy
The analysis of all efficacy variables will be performed on the FAS. In addition, the primary 
efficacy endpoint will also be analysed using the PPS, as a sensitivity analysis.
9.4.2.1
Primary Endpoint
The primary efficacy endpoint for this study is the percent change from baseline in UACR at 
12 weeks.
Baseline for UACR will be defined as the geometric mean of 3 UACR values derived from 
samples collected at consecutive days prior to the first dose of study treatment.
As UACR is assumed to follow a log-normal distribution, it will be log transformed for 
statistical analysis purposes. The mean log percent changes in UACR at 12 weeks for each of 
the 3 doses of AZD9977 combined with dapagliflozin 10 mg and dapagliflozin 10 mg alone 
will be estimated in a mixed model for repeated measures (Visits 7, 8, 9, and 10). The values 
will be back-transformed onto the original scale to give the geometric mean relative percent 
change from baseline at 12 weeks.

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Patients randomised according to CSP versions 1.0 to 5.0 (before dropping placebo and 
AZD9977 150 mg monotherapy arms) will be considered as part of Cohort 1, while patients 
randomised subsequently will be included in Cohort 2. The primary analysis for the remaining 
4 treatment groups will combine data from both cohorts, while the accrued data from 
discontinued treatment groups will be analysed descriptively.
The analysis model will include UACR baseline value, treatment, and visit as fixed effect, and 
the stratifying factors (T2DM [yes/no] and eGFR [≥20 to < 30 mL/min/1.73 m2; or ≥30 to 
< 45 mL/min/1.73 m2; or ≥45 mL/min/1.73 m2]) as well as the Cohort variable (1 or 2) as 
covariates. Moreover, treatment-by-visit interaction will also be included in the model. The 
final analytical approach will be described in detail in the SAP. For the primary analysis, the 
main treatment comparisons to be evaluated are (in a fixed-sequence testing):
1
Overall comparison of the percentage changes from baseline in UACR at week 12 across 
all 4 treatment groups
2
Each of the 3 doses of AZD9977 in combination with dapagliflozin 10 mg versus 
dapagliflozin 10 mg in the following order:
1. AZD9977 150 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
2. AZD9977 50 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
3. AZD9977 15 mg + dapagliflozin 10 mg versus dapagliflozin 10 mg
9.4.2.2
Secondary Endpoint
The dose-response relationship of percent change from baseline in UACR at 12 weeks will be 
assessed using data from dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 
150 mg) combined with dapagliflozin (10 mg).
More details of all these models will be provided in the SAP.
9.4.3
Pharmacokinetics
Plasma concentrations of AZD9977 and dapagliflozin will be listed and summarised by 
treatment groups, based on the PK Analysis Set.

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9.4.4
Pharmacodynamics and Biomarkers
The following exploratory pharmacodynamic and biomarker endpoints will be summarised by 
treatment group based on the FAS:

Change from baseline in serum NT-proBNP over time

Change from baseline in blood uric acid, BUN, FPG, haematocrit, renin, ACTH, cortisol 
and copeptin levels over time

Change from baseline in blood MCV, MCHC, RBC distribution width, erythrocyte count 
over time

Change from baseline in urine Na+, K+, uric acid, urea, osmolality, glucose, creatinine, 
and cortisol levels over time

Change from baseline in blood and urine biomarkers over time
The following analyses will not be part of the CSR:

Dose/exposure of AZD9977 and dapagliflozin relative to safety and pharmacodynamic 
variables (eg, serum/plasma K+, eGFR, aldosterone)

Exploratory research into genes/genetic variation that may influence response to 
treatment
Analysis for these exploratory objectives will be described in a separate analysis plan and 
results will be presented separately from the main CSR.
9.4.5
Safety
Safety analyses will be performed using the SS. Safety data will be presented using 
descriptive statistics unless otherwise specified.
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of IMP. Details are described in the SAP.
9.4.5.1
Adverse Events
Adverse events will be coded using the most recent version of the MedDRA that will have 
been released for execution at AstraZeneca or designee. 
AEs will be presented for each treatment group by SOC and/or PT covering number and 
percentage of patients reporting at least 1 event and number of events where appropriate. 
Only AEs occurring with an onset date, or worsening, on or after first dose of IMP and within 
28 days after last dose of IMP will be presented in summary tables. Serious AEs occurring 
prior to start of IMP will be included in data listings.

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An overview of AEs will present for each treatment group the number and percentage of 
patients with any AE, AEs with outcome of death, SAEs, and AEs leading to discontinuation 
of IMP, as well as AEs leading to IMP dose interruptions, and AEs leading to withdrawal from 
study as well as the number of individual occurrences in those categories.
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, maximum intensity, seriousness, death, and AEs leading to discontinuation of 
IMP as well as other action taken related to IMP, other significant AEs, and timing of events.
An additional table will present number and percentage of patients with most common AEs. 
Most common (eg, frequency of > 5%) will be defined in the SAP.
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of patients in any treatment group. 
Key patient information will be presented for patients with AEs with outcome of death, SAEs, 
and AEs leading to discontinuation of IMP.
An AE listing for the SS will cover details for each individual AE; an AE listing for patients 
who were not exposed to IMP is presented separately.
Full details of AE analyses will be provided in the SAP.
9.4.5.2
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, minimum, Q1, median, Q3, and maximum. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline.
Key patient information will be presented for patients with treatment-emergent changes in 
vital sign parameters outside of predefined criteria (see Section 9.4.5.6). 
Supportive vital sign listings cover observed values and changes from baseline as well as 
abnormalities. 
Details of vital sign analyses including definition of abnormality criteria (eg, definition of low, 
normal, high; clinically significant) and project-specific predefined criteria for treatment-
emergent changes in relevant vital sign parameters (eg, systolic and diastolic BP) will be 
provided in the SAP. 
9.4.5.3
Laboratory
Laboratory parameters will be presented for each treatment group. Summary statistics for 

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continuous variables cover n, mean, SD, minimum, Q1, median, Q3, and maximum. 
Frequency tables cover number and percentage of patients in the respective category.
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline. 
A frequency table will present number of patients reporting at least one treatment-emergent 
change in laboratory parameters outside predefined criteria (see Section 9.4.5.6).
Elevation in liver parameters for assessment of Hy’s law will be done and reported 
appropriately if potential cases have been identified during the course of the study. 
Key patient information will be presented for patients with treatment-emergent changes in 
laboratory parameters outside of predefined criteria. 
For urinalysis, a frequency table will present number of patients reporting at least 
1 treatment-emergent increase in baseline category and/or a shift table will present the 
baseline assessment against the maximum on-treatment category. 
Supportive laboratory listings cover observed values and changes from baseline for each 
individual patient as well as abnormalities. 
Details of laboratory analyses including definition of abnormality criteria (eg, definition of 
low, normal, high; clinically significant) and project-specific predefined criteria for 
treatment-emergent changes in relevant laboratory parameters will be provided in the SAP.
9.4.5.4
Electrocardiograms
Descriptive statistics will be produced at each schedule assessment timepoint for all 
quantitative ECG parameters (heart rate, PR, RR, QRS, QT, and QTcF intervals) for both 
observed absolute values and changes from baseline.
Electrocardiogram findings will also be listed. 
An analysis of potentially clinically significant ECG values on QT, QTcF, QRS and PR 
interval, and heart rate will be performed. The number and percentage of patients with 
potentially clinically significant ECG values will be tabulated across time and treatment 
group. The criteria based on severity will be defined in the SAP.
Outliers with respect to QTcF will also be tabulated for the following categories:

Absolute value > 450 ms

Absolute value > 480 ms

Absolute value > 500 ms

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
Increase from baseline > 30 ms

Increase from baseline > 60 ms
9.4.5.5
Physical Examination
The listings of the physical examination will include date of examination and confirmation of 
assessment performed (Yes/No).
9.4.5.6
Safety Topics of Interest
Hyperkalaemia
Hyperkalaemia will be evaluated by the analysis of serum/plasma K+ levels (eg, absolute 
values and change from baseline, values outside predefined ranges, values meeting 
protocol-defined discontinuation criteria for hyperkalaemia). Further details will be provided 
in the SAP.
Hypotension
Symptomatic hypotension/decreased blood pressure will be evaluated by the analysis of BP 
measurements (eg, values outside predefined ranges) and the analysis of pre-defined AE PTs 
related to hypotension, as well as discontinuations due to hypotension. Further details will be 
provided in the SAP.
Deteriorating Renal Function
Deteriorating renal function will be evaluated by analysis of serum creatinine and eGFR 
values (eg, percent change from baseline in eGFR, absolute values and change from baseline, 
values meeting protocol-defined discontinuation criteria for deteriorating renal function) and 
analysis of pre-defined AE PTs related to deteriorating renal function. Further details will be 
provided in the SAP.
9.5
Interim Analyses
An interim analysis will be performed when 300 patients have been treated for 12 weeks, 
unless the planned date of the interim analysis is too close to the expected data base lock date, 
for the complete study. The purpose of the interim analysis is to have the possibility to trigger 
Phase 3 activities; therefore, there will be no alpha spent. The conduct of the study will not be 
impacted by the results of the interim analysis. The decision to conduct an interim analysis 
will be documented.
The SAP will describe the planned interim analyses in greater details.
9.6
Data Monitoring Committee
A Safety Unblinded Data Review Committee will be set up for this study for ongoing safety 
monitoring. In addition to general safety/tolerability, the committee will focus on potential 

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risks related to hypotension, deteriorating renal function and hyperkalaemia. An Interim 
Unblinded Data Review Committee will be set up to review data from the pre-planned interim 
analysis and make recommendations on future clinical development.
For details on the review committee, refer to Appendix A 5.

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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines

Applicable ICH 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 and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements.
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 

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certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

A pre-screening ICF and/or a full ICF have to be signed before any study intervention 
will take place. 

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 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 participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor and its research collaborators will contain the 
identifier only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor and its research collaborators in accordance with local data protection law. 

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The level of disclosure and use of their data must also be explained to the participant in 
the informed consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
A Safety Unblinded Data Review Committee will be set up for this study to monitor general 
safety/tolerability, with a focus on hypotension, deteriorating renal function and 
hyperkalaemia.
An Interim Unblinded Data Review Committee will be set up to review data from the 
pre-planned interim analysis and make recommendations regarding future clinical 
development.
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study 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 study 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 participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee, and its research collaborators, electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 

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non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee, and its research collaborators are responsible for the data 
management of this study including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 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 participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the source data agreement and 
computerised data checklist for electronic source data.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first patient enrolled (ie, who signed consent) and will be the 
study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 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.

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The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multi-centre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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

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

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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 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host, or environmental factors.

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 

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information to make an informed judgement. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an 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.
Medication error includes situations where an error.

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM – including those which lead to one of the 
above listed events that would otherwise have been a medication error

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

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
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
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 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
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 record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives 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 or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented, and study site notified.

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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) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
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, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt – Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content

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Appendix D
Optional Genomics Initiative Sample
D 1
Use/analysis of DNA

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. This 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. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported 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 AZD9977 and dapagliflozin or other 
AstraZeneca study treatments of the same classes or for these indications continues but no 
longer than 15 years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of Genetic Research Population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and: Provide informed consent for the Genomics 
Initiative 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

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Withdrawal of Consent for Genetic Research: 

Participants 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 7.2 of the CSP.
Collection of Samples for Genetic Research

The blood sample for this genetic research will be obtained from the participants at 
Visit 3, at or after randomisation. Although DNA is stable, early sample collection is 
preferred to avoid introducing bias through excluding participants who may withdraw due 
to an AE. If for any reason the sample is not drawn at Visit 3, it may be taken at any visit 
until the last study visit. Only one sample should be collected per participant for genetics 
during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant 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 sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant 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.

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Informed Consent

The genetic component of this study is optional, and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The PI is responsible for ensuring 
that consent is given freely, and that the participant understands that they may freely 
withdrawal from the genetic aspect of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, 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 participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management

Data will be reported will be reported separately from the CSR.

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations 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 only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant 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.

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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 potential Hy’s law (PHL) cases and Hy’s law (HL) cases. 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 participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
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 DILI caused by the IMP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs 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 ALT ≥3 x ULN together with TBL ≥2 x 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 x ULN together with TBL ≥2 x ULN, where no other reason, other than the 
IMP, 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 

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same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 x ULN

AST ≥3 x ULN

TBL ≥2 x ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
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) by the central laboratory without 
delay

Complete the appropriate unscheduled laboratory eCRF module(s) with the 
original local laboratory test result
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:

Determine whether the participant meets PHL criteria (see Section E 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

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
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important Medical Event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting

For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which tests available in 
the Hy’s law lab kit should be used.

Complete the 3 Liver eCRF Modules as information becomes available. 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
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.
As soon as possible 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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 

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date PHL criteria was met. 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.
Where 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 eCRF.

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following 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 IMP:

Send updated 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.

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E 6
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin 
(CD-transferrin) c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
CMV=cytomegalovirus; DNA=deoxyribonucleic acid; EBV=Epstein-Barr virus; GGT=gamma glutamyl 
transferase; HBc=hepatitis B core; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis 
C virus; HEV=hepatitis E virus; HSV=herpes simplex virus; IgG=immunoglobulin G; IgM=immunoglobulin M; 
INR=international normalised ratio; LDH=lactate dehydrogenase; RNA=ribonucleic acid.
a HBV DNA is only recommended when IgG anti-HBc is positive
b HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
c CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 7
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-

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guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

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Appendix F
Management of Hyperkalaemia and Deteriorating Renal 
Function
F 1
Hyperkalaemia
At all baseline and on-treatment visits (according to the SoA) K+ will be measured in either 
serum or plasma samples at a local laboratory depending on the laboratory’s capability and in 
serum samples at a central laboratory. Repeat samples should be sent for both central and local 
laboratory assessment.
Inappropriate sample handling/storage or lengthy transport time to the central laboratory may 
result in falsely elevated serum K+ levels in the centrally analysed blood samples. It is 
expected that local laboratory results (from either serum/plasma samples) will be available 
prior to central laboratory results and expected to take priority for 
decision-making/monitoring:

Serum/plasma K+ >5.5 to ≤6 mmol/L (based on local laboratory samples) should be 
reassessed within 72 hours.

If the repeat local laboratory sample has serum/plasma K+ > 6.0 mmol/L, study 
treatments must be discontinued permanently.

If the repeat local laboratory sample has serum/plasma K+ > 5.5 to ≤6.0 mmol/L, 
consider corrective actions, including dietary changes and/or 
adjustment/discontinuation of non-essential medications that might have caused or 
contributed to hyperkalaemia and reassess within 72 hours:
o
If local serum/plasma K+ remains > 5.5 mmol/L to ≤6 mmol/L, consider 
permanent discontinuation or continue monitoring at the discretion of the 
investigator. Permanently discontinue if repeat local and/or central samples have 
serum/plasma K+ > 6.0 mmol/L.

Serum/plasma K+ > 6 mmol/L (based on local laboratory samples) should be reassessed 
immediately and study treatments should be discontinued temporarily while waiting for 
results:

If the repeat local laboratory sample has serum/plasma K+ > 6.0 mmol/L, study 
treatments must be discontinued permanently. 

If the repeat local laboratory sample has serum/plasma K+ > 5.5 to ≤6.0 mmol/L and 
the central laboratory sample has serum K+ is > 6.0 mmol/L, study treatments must 
be discontinued permanently.

If the repeat local laboratory sample has serum/plasma K+ > 5.5 to ≤6.0 mmol/L and 
the central laboratory sample has serum K+ ≤6.0 mmol/L, based on the discretion of 
the Investigator, consider corrective actions, including dietary changes and/or 
adjustment/discontinuation of non-essential medications that might have caused or 

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contributed to hyperkalaemia; and/or continuation with reassessment; or permanent 
discontinuation.

If the repeat local laboratory sample has serum/plasma K+ ≤5.5 mmol/L, then study 
treatments can be resumed, even if the central laboratory sample has serum 
K+ > 6.0 mmol/L.
If the investigator is aware of any change in the participant’s clinical status that may influence 
serum electrolyte levels or fluid balance (eg, vomiting and/or diarrhoea > 1 day), it is 
recommended to reassess serum/plasma K+ levels as soon as possible after the acute event. In 
case of permanent discontinuation, serum/plasma K+ levels should be monitored until 
resolution or stabilisation.
F 2
Deterioration of Renal Function
Serum creatinine will be measured both at a local laboratory and a central laboratory at all 
baseline and on-treatment visits according to the SoA. Repeat samples should be sent for both 
central and local laboratory assessment. It is expected that local laboratory results will be 
available prior to central laboratory results. As local and central laboratories will calculate 
eGFR using different formulas, central eGFR values should always be compared to central 
eGFR values and local eGFR values should always be compared to local eGFR values. For 
local laboratories, the eGFR assessment at Visit 3 (prior to the start of study treatment) will be 
taken as the baseline eGFR value.

If eGFR shows a 30-50% decline from baseline and an absolute value 
≥15 mL/min/1.73 m2 (based on local and/or central laboratory samples), eGFR should be 
reassessed within 1 week.

If persistent 30-50% decline stabilises upon weekly follow-ups, eGFR monitoring 
may return to the standard SoA, at investigator’s discretion.

If eGFR shows a >50% decline from baseline and/or decreases to an absolute value 
< 15 ml/min/1.73 m2 (based on local and/or central laboratory samples), eGFR should be 
reassessed within 48 hours.

If eGFR shows a 30% to 50% decline from baseline and an absolute value 
≥15 mL/min/1.73 m2, eGFR should be reassessed within 1 week.

If eGFR again shows a >50% reduction from baseline and/or absolute value 
< 15 mL/min/1.73 m2, study treatments must be discontinued immediately and eGFR 
should be followed up within a week and weekly until signs of improvement and 
stabilisation.
If an unexpected, acute decline in kidney function is observed, the patient should be promptly 
evaluated. Volume depletion, hypotension, inter-current medical problems, metabolic 

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derangements, and concomitant drugs may cause increases in blood creatinine. Urinary tract 
infection and urinary obstruction should be considered. Several drugs may cause a decline in 
kidney function, especially NSAID and certain antibiotics such as trimethoprim. If any drug is 
suspected of causing or contributing to worsening kidney function, their use should be 
reconsidered.

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Appendix G
COVID-19 Specifics
G 1
Background to COVID-19
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the WHO to declare a pandemic situation on 
12 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden including new outbreaks, locally or globally, 
will impact the further conduct of clinical studies, appropriate risk assessments and mitigation
measures will need to be taken into consideration in all clinical studies to protect subjects, site 
staff, and society as a whole.
Both EMA and FDA as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at high pace. 
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in future, special attention will be paid to protect subjects 
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline.
G 2
Risk Assessment for COVID-19 Pandemic
Risk of infection with SARS-CoV-2
The 2 study drugs with different mechanisms of action are unlikely to impact on the course of 
infection with SARS-CoV-2. Dapagliflozin is an anti-glycaemic agent and AZD9977 is a 
selective mineralocorticoid receptor modulator; neither is expected to cause immune 
suppression. Therefore, risk of the participants exposure to SARS-CoV-2 or to suffer from 
COVID-19 is expected to be similar to the background population with the same 
co-morbidities, in particular HF and CKD. The risk of exposure to infected people cannot be 
completely excluded as the participants may need to be in public areas (eg, commute to the 
site) and have additional human contact (eg, with site staff and other participants of the 
clinical study).
Measures to mitigate the additional risks caused by COVID-19 are:

This study is going to start enrolling only when the Sponsor and CRO in collaboration 
deem it is safe to start the study. In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic 
imposed by the local authorities are compatible with safe conduct of the study.

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
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.

Participants will be closely monitored for any signs and symptoms of COVID-19, 
including fever, dry cough, dyspnoea, sore throat, and fatigue throughout the study during 
the pandemic. Once clinical signs of infection are reported by participants, the 
Investigator needs to determine whether samples can be collected, and safety data can be 
recorded on site. If not, AEs and concomitant medications will be obtained via phone 
calls. The decision to continue with dosing the participant with the study drugs in the 
event of him/her showing symptoms of COVID-19 infection will be per Investigator’s 
discretion.

The probability of virus transmission will be controlled as much as possible by:

Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory.

Confirmation of COVID-19 infection by optional laboratory assessment will be 
conducted based on availability (test capacity and turnaround time) of approved tests 
and on Investigator’s discretion.

Requesting all participants are contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and are asked not to attend the site in case 
of suspected reports. In addition, participants are asked for any contact with a person 
who has tested positive for SARS-CoV-2. If applicable, participants will be referred 
to the local health care system for further follow-up and treatment.

Physical distancing and person-to-person contact restrictions will be applied during 
site visits. 

Where physical distancing is not possible, personal protective equipment will be used 
by study participants (surgical face mask, gloves) and staff (for example but not 
limited to masks, gloves, protectors, medical suits) if deemed appropriate by the 
Investigators and site staff and guided by local requirements.

Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.

If site visits are not possible due to local restrictions, home nursing visits may be 
considered after discussion with and approval by the Sponsor.
Risk Related to COVID-19 vaccination
The 2 study drugs are predicted to have a low risk of influencing COVID-19 vaccine 
effectiveness and no additional safety concerns are anticipated. Clinical trial participant who 
have already taken the COVID-19 vaccine of any type are permitted to enrol in the study. 
Clinical trial participant who are not yet vaccinated should consider current/local guidelines, 
vaccine availability, and benefit-risk assessment of the COVID-19 vaccine. Ultimately, the 

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decision to vaccinate will be based on the judgment of the treating physician taking into 
account the participant's best interest.
G 3
Restrictions Related to COVID-19
During the COVID-19 pandemic, participants are advised to adhere to local requirements for 
reduction of the public SARS-CoV-2 exposure while ambulatory. If applicable, prior to 
screening (Visit 1a), potential participants should be called to confirm they are not 
experiencing any COVID-19 symptoms and signs and are asked not to attend the site in case 
of suspected infection. If appropriate, participants will be referred to the local health care 
system. Physical distancing and person-to-person contact restrictions will be applied and 
explained to participants while staying at the study site. Where physical distancing is not 
possible, study participants will be asked to use surgical face masks and/or gloves if deemed 
appropriate by the Investigator and site staff and guided by local requirements.
G 4
Data Quality Assurance Related to COVID-19
Monitoring visits at site will be limited to a minimum required as deemed appropriate during 
COVID-19 pandemic, per local regulations.
In addition, where possible, other measures for carrying out protocol related activities, such as 
but not limited to home nursing, may be employed as required.
G 5
References
Guidance on the Management of Clinical Trials during the COVID19 (Coronavirus) 
pandemic, EMA, Version 3 (28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated on June 03, 2020 https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-
products-during-covid-19-public-health-emergency

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Appendix H
Strong and Moderate Cytochrome P450 3A4 (CYP3A4) 
Inhibitors and Inducers
Strong or moderate CYP3A4 inhibitors or inducers are prohibited at least 3 weeks prior to 
randomisation (ie, start of run-in period) and for the duration of the study.
The following list (Table 8) is not intended to be exhaustive and a similar restriction will 
apply to other agents that are known to modulate CYP3A4 activity. Appropriate medical 
judgement is required. Please contact AstraZeneca with any queries you have on this issue.
Table 8
CYP3A4-Interacting Medication that are Prohibited During the Study
Medication
Rationale
Boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and 
ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, 
saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
telithromycin, troleandomycin, voriconazole
Strong CYP3A4 inhibitors which may 
increase AZD9977 concentrations.
Apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort
Strong CYP3A4 inducers which may 
decrease AZD9977 concentrations.
Aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, 
diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, 
imatinib, tofisopam, verapamil
Moderate CYP3A4 inhibitors which may 
increase AZD9977 concentrations.
Bosentan, efavirenz, etravirine, phenobarbital, primidone
Moderate CYP3A4 inducers which may 
decrease AZD9977 concentrations.
H 1
Reference
FDA guidance – Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (content current as of 10 March 2020). Available at https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers. Accessed on 9 June 2020.

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Appendix I
Clinical Study Medical Device / Device Constituent Report 
Form

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Appendix J
Abbreviations
Abbreviation or special 
term
Explanation
2D
2-dimensional
3D
3-dimensional
ABPM
ambulatory blood pressure monitoring
ACCF
American College of Cardiology Foundation
ACEI
angiotensin-converting enzyme inhibitor
ACTH
adrenocorticotropic hormone
ADMA
asymmetric dimethylarginine
AE
adverse event
AHA
American Heart Association
ALP
alkaline phosphatase
ALT
alanine transaminase
ANA
antinuclear antibody
ANCA
anti-neutrophil cytoplasm antibody
ARB
angiotensin II receptor blocker
ARNI
angiotensin receptor-neprilysin inhibitor
AST
aspartate transaminase
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CKD
chronic kidney disease
CKD-EPI
chronic kidney disease epidemiology collaboration
CMV
cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
Case Report Form
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CYP
cytochrome P450

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Abbreviation or special 
term
Explanation
dECG
digital electrocardiogram
DILI
Drug-Induced Liver Injury
DKA
diabetic ketoacidosis
DNA
deoxyribonucleic acid 
EBV
Epstein-Barr virus
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDV
end diastolic volume
E/e’
ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
end of treatment
ET
early termination
ERT
eResearch Technology
ESRD
end-stage renal disease
ESV
end systolic volume
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GDF-15
growth differentiation factor-15
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLDH
gamma-lactone dehydrogenase
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HbA1c
glycated haemoglobin
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus

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Abbreviation or special 
term
Explanation
HCV
hepatitis C virus
HEV
hepatitis E virus
HSV
herpes simplex virus
HCO3-
bicarbonate
HDL-C
high density lipoprotein cholesterol
HDPE
high-density polyethylene
HF
heart failure
HFmrEF
heart failure mid-range ejection fraction
HFpEF
heart failure preserved ejection fraction
HFrEF
heart failure reduced ejection fraction
HIPAA
Health Insurance Portability and Accountability Act
HL
Hy’s law
HR
heart rate
HRQOL
health-related quality of life
hsTnT
high sensitivity troponin T
IATA
International Airline Transportation Association
IC50
concentration required to inhibit 50% of the activity
ICAM
intercellular adhesion molecule
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
Investigational Medicinal Product
INR
international normalised ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
K+
potassium
L-Arg
l-arginine
LAVI
left atrial volume index
LDH
lactate dehydrogenase
LDL-C
low density lipoprotein cholesterol
LV
left ventricular
LVEF
left ventricular ejection fraction
LV-GLS
left ventricular global longitudinal strain

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Abbreviation or special 
term
Explanation
LVM
left ventricle mass
MAD
multiple ascending dose
Max
maximum
MCHC
mean corpuscular haemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Min
minimum
MIRACLE
MIneRAlocorticoid reCeptor moduLator and sodium-glucosE cotransporter-2-
inhibitor in HF and CKD trial
MR
mineralocorticoid receptor
MRA
mineralocorticoid receptor antagonist
Na+
sodium
NGAL
neutrophil gelatinase-associated lipocalin
NIMP
Non-Investigational Medicinal Product
NSAID
non-steroidal anti-inflammatory drug
NT-proBNP
N-terminal-pro-brain natriuretic peptide
NYHA
New York Heart Association
OGTT
oral glucose tolerance test
PAP
pulmonary artery pressure
PHL
potential Hy’s law
PI
Principal Investigator 
PIIIP3
procollagen type III N-terminal propeptide
PK
pharmacokinetic(s)
PPS
Per Protocol Set
PRO
patient-reported outcome
PT
Preferred Term
Q1
first quartile
Q3
third quartile
QTcF
QT interval corrected using Fridericia’s formula
RAAS
renin-angiotensin-aldosterone system
RBC
red blood cell
RNA
ribonucleic acid
RT-PCR
reverse transcriptase polymerase chain reaction
RTSM
Randomisation and Trial Supply Management
SAE
serious adverse event 

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Abbreviation or special 
term
Explanation
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
Scys
standardised serum cystatin C
SD
standard deviation
SDMA
symmetric dimethylarginine
SGLT2
sodium-glucose co-transporter-2
SGLT2i
sodium-glucose co-transporter-2 inhibitor
SoA
Schedule of Activities
SOC
System Organ Class
ST2
suppression of tumourigenicity 2 (biomarker)
SS
Safety Set
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TAPSE
tricuspid annular plane systolic excursion
TBL
total bilirubin
TR Vmax
tricuspid regurgitation maximal velocity
UACR
urinary albumin to creatinine ratio
UGT
uridine diphosphate glycosyltransferase
ULN
upper limit of normal
VLDL-C
very low density lipoprotein cholesterol
WBC
white blood cell
WHO
World Health Organisation

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Appendix K
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment, 
Amendment 6, is located directly before the Table of Contents.
Amendment 5 (20 December 2021)
This amendment was considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Rationale for the Amendment
The previous Clinical Study Protocol (CSP) version, version 5.0, dated 15 July 2021 has been 
updated to adjust the design to heart failure treatment guidelines (ESC Guidelines 2021), by 
dropping the placebo and AZD9977 monotherapy arms to ensure all patients receive SGLT2i 
(dapagliflozin) during the study, as well as to reduce the burden of study assessments on study 
patients. The updates are summarised below.
Section Number and 
Name
Description of Change
Brief Rationale
Cover page
Section 1.1 Synopsis
Section 4 Study Design
Removal of the LVEF criterion 
below 55%
CSP title updated to not include any 
numbers for HF definition.
Cover page
Section 1.1 Synopsis
Section 1.2 Schema
Section 3 Objectives and 
Endpoints
Section 4.1 Overall 
Design
Section 4.2 Scientific 
Rationale for Study 
Design
Section 6.1.1 
Investigational Products
Change of study design details
1) Treatment arms for AZD9977 
150 mg and for placebo were 
removed.
2) Update of study duration 
3) Inclusion of patients with or 
without SGLT2i treatment
To reflect recent changes in heart failure 
guidelines (European Society of 
Cardiology, 2021) and rapid evolving 
uptake and change in clinical practice to 
treat patients with SGLT2i in the 
population, adjustments have been made to 
the design by removal of the placebo 
treatment, thereby changing to active-
controlled treatment. 
Section 1.1 Synopsis
Section 4.1 Overall 
Design
Change of targeted enrolment 
percentages of patients for the 
following cohorts
1. with eGFR ≥20 to 
< 30 mL/min/1.73 m2 and
2.eGFR ≥45 mL/min/1.73 m2
1. To avoid recruitment hurdles that are not 
of clinical relevance.
2. A more appropriate cap based on 
patients randomised so far.

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 9.1 Statistical 
Hypotheses
Update of the primary hypothesis
The primary hypothesis was adjusted
according to the new study design.
Section 1.1 Synopsis
Section 9.2 Sample Size 
Determination
Update for sample size and 
drop-out rate, also for an interim 
analysis
The sample size and the drop-out rate have 
been updated according to the new study 
design.
The expected effect size was reduced due 
to the fact that the new comparator is an 
active drug (dapagliflozin 10 mg).
Section 1.2 Schema
Update of the figure concerning 
the study design
The figure was updated according to the 
new study design.
Section 1.3 Schedule of 
Activities
Time windows for Visits 2 and 5 
to 10 were amended:
Visit 2: -10 to -3 days
Visit 5: ± 2 days
Visits 6, 7, 8, 9 and 10: ± 3 days
Visit 11: ± 4 days
To allow for flexibility in scheduling for 
sites and subjects and adjustment to fit with 
number of tablets in one dapagliflozin 
bottle for the safety follow-up.
Section 1.3 Schedule of 
Activities
Inclusion of central laboratory 
serum/plasma samples for K+, 
creatinine including eGFR 
calculation at Visit 2
To have values from central laboratory 
closer to randomisation Visit 3.
Section 1.3 Schedule of 
Activities
Removal of PK sampling on 
Day 64
Reduction of sampling procedures and 
blood volume to lessen burden on sites and 
subjects.
Section 1.3 Schedule of 
Activities
Reduction of number of PD 
sampling visits (NT-proBNP, 
aldosterone, renin, ACTH, 
cortisol, copeptin, and FPG) from 
9 to 5 visits (visits 3, 5, 7, 10, 11)
Reduction of sampling procedures and 
blood volume to lessen burden on sites and 
subjects.
Section 1.3 Schedule of 
Activities
Inclusion of dapagliflozin 10 mg 
treatment after the EOT visit
To do safety follow-up under the same 
standard of care (dapagliflozin) as during 
run-in.

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section 4.2 Scientific 
Rationale for Study 
Design
Section 8.1.2.1 
Transthoracic 
Echocardiography-derived 
Parameters
Removal of transthoracic 
echocardiography; removal of the 
applicable exploratory objective
Lessen the operational study complexity in 
order to reduce burden on sites and 
subjects. Extensive central echo protocol 
and needed to transfer data for central 
reading. In addition, local 
echocardiography is already being 
conducted at screening to confirm HF 
diagnosis.
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section4.2  Scientific 
Rationale for Study 
Design
Section 8.1.2.2 Patient 
Reported Outcomes
Appendix I Kansas City 
Cardiomyopathy 
Questionnaire
Appendix J Kidney 
Disease and Quality of 
Life
Appendix K Patient 
Global Impression of 
Severity – Heart Failure
Removal of patient-reported 
outcomes questionnaires KCCQ, 
KDQOL-36, and PGIS-HF
Lessen the operational study complexity in 
order to reduce burden on sites and 
participants.
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section 8.1.2.3 
Bioimpedance 
Spectroscopy
Removal of bioimpedance 
spectroscopy; removal of weight 
measurements for bioimpedance at 
Visits 5 and 8, removal of 
applicable footnotes in Section 1.3
Schedule of Activities
Lessen the operational study complexity in 
order to reduce burden on sites and 
subjects.

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section 8.1.2.4 Home 
based Monitoring of 
Activity
Section 9.3 Populations 
for Analyses
Removal of home-based 
monitoring of activity
Lessen the operational study complexity in 
order to reduce burden on sites and 
subjects.
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section 8.1.2.5 
Ambulatory Blood 
Pressure Monitoring
Removal of ambulatory blood 
pressure monitoring in selected 
countries
Lessen the operational study complexity in 
order to reduce burden on sites and 
subjects.
Section 1.3 Schedule of 
Activities
Section 3 Objectives and 
Endpoints
Section 8.6.1 Collection 
of Mandatory Samples for 
Biomarker Analysis
Removal of collection of serum, 
plasma, and urine samples for 
exploratory biomarkers related to 
AZD9977 and dapagliflozin or 
related cardiorenal diseases
Correction of an error.
Section 1.3 Schedule of 
Activities
Section 5.1 Inclusion 
Criteria
Inclusion of an informed consent 
for optional pre-screening
An optional pre-screening visit is 
introduced to reduce screen failures related 
to UACR and all patients who undergo the 
additional visit needs to sign a separate 
informed consent.
Section 1.3 Schedule of 
Activities
Section 8.6.1 Collection 
of Mandatory Samples for 
Biomarker Analysis
Alignment with number of visits 
for PD markers (Visit 3 [Day 1], 
Visit 7 [Day 22], Visit 10 [Day 
85], Visit 11 [Day 113])
Reduction of sampling procedures and 
blood volume to lessen burden on sites and 
subjects.
Section 1.3 Schedule of 
Activities
Section 8.6.2 Collection 
of Optional Biomarker 
Samples
Removal of blood samples for 
RNA expression analysis and 
information regarding unused 
samples of serum, plasma, and 
urine.
Addition of information regarding 
collection of serum, plasma, and 
urine samples for future use
Reduction of sampling procedures and 
blood volume to lessen burden on sites and 
subjects.
Description of exploratory biomarker 
research moved to the correct section.  

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Section Number and 
Name
Description of Change
Brief Rationale
Section 2.2.1.4 Sodium-
glucose Co-transporter 2 
Inhibitors in Heart Failure 
and Chronic Kidney 
Disease
Inclusion of an additional 
literature reference
To provide the correct literature reference 
to a statement in this section.
Section 2.2 Background
Inclusion of additional literature 
references
To add more background to the study.
Section 2.3.1 Risk 
Assessment
Inclusion of data from completed 
combination toxicology study
To reflect new data in the drug 
development program.
Section 4.1 Overall 
Design
Addition of an optional 
pre-screening including timelines
In some clinics UACR is not part of 
clinical practice, introducing an optional 
pre-screening visit for UACR within the 
protocol will facilitate identifying eligible 
patients. 
Section 4.1 Overall 
Design
Section 9.2 Sample Size 
Determination
Update of numbers of participants
Based on new statistical calculations for 
the 4-arm study.
Section 4.3 Justification 
for Dose
Inclusion of further information 
from studies with dapagliflozin
Updated to reflect recent regulatory 
approvals of dapagliflozin 10 mg for the 
treatment of CKD, which is of relevance to 
the patient population being studied.
Section 5.1 Inclusion 
Criteria
Change of the LVEF criterion 
below 55% to below 60%
To broaden patient population by allowing 
additional patients who fall into the HFpEF 
category to enrol into the study in order to 
increase recruitment.
Section 5.1 Inclusion 
Criteria
Reduction of NT-proBNP 
threshold from 600 pg/mL to 
300 pg/mL for sinus rhythm 
patients and from 900 pg/mL to 
600 pg/mL for atrial 
fibrillation/flutter patients 
To broaden the eligible HF population, 
taking into account this is an exploratory 
phase study.
Section 5.1 Inclusion 
Criteria
Removal of UACR values from 
the criterion for eGFR
To have UACR and eGFR as separate 
inclusion criteria.
Section 5.1 Inclusion 
Criteria
Update of the criterion for UACR 
at Visit 2
To have UACR from Visit 2 performed at 
the central laboratory to confirm eligibility 
for randomisation.
Section 5.1 Inclusion 
Criteria
Inclusion of a separate paragraph 
regarding randomisation with all 
applicable criteria for Visit 3
To explain what is required to be eligible 
for randomisation.

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Section Number and 
Name
Description of Change
Brief Rationale
Section 5.1 Inclusion 
Criteria
Section 6.5.2 Background 
Medications
Inclusion of a separate paragraph 
regarding the run-in period with 
all applicable criteria for Visit 2
To explain the addition of open label 
dapagliflozin to all patients during run-in.
Section 5.1 Inclusion 
Criteria
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
Addition of UACR measurement 
at screening including value 
ranges for participants who are 
either on SGLT2i or not on 
SGLT2i
The lower UACR limit at screening will be 
higher for patients naïve to SGLT2i
treatment since UACR is expected to 
decrease during run-in in these patients and 
the UACR limits for eligibility to be 
randomised are the same for all patients. 
Section 5.2 Exclusion 
Criteria
Section 6.5.1 Prohibited 
Medications
Removal of SGLT2i from 
prohibited prior/ concomitant 
therapy
Increasingly difficult to recruit SGLT2i 
naïve patients due to change in HF 
guidelines and rapid inclusion of SGLT2i’s 
in SoC for HF treatment.
Section 6.1.2 Medical 
Devices
Removal of ABPM device, 
bioimpedance spectroscopy 
device, activity tracker, and sleep 
analyser
Simplification for sites and participants.
Section 6.3 Measures to 
Minimise Bias: 
Randomisation and 
Blinding
Section 8.5.1.1 
Determination of Drug 
Concentration
Replacement of Covance with 
Labcorp Drug Development for 
PK samples
Legal entity change.
Section 6.5.2 Background 
Medications
Additional information regarding 
the start for treatment with 
dapagliflozin 10 mg for 
participants being on treatment 
with SGLT2i or not
According to new study design.
Section 6.7 Intervention 
After the End of the Study
Clarification on the use of 
dapagliflozin during the safety 
follow-up period after the blinded 
randomised treatment period in 
the study
All patients will be on open label 
dapagliflozin during run-in up to 
randomisation and after the blinded study 
treatment period during the safety 
follow-up.
Section 7.1 
Discontinuation of Study 
Intervention
Updated text on DKA events
To be aligned with other AstraZeneca 
study protocols involving dapagliflozin.
Section 8 Study 
Assessments and 
Procedures
The maximum amount of blood 
collected from each participant 
over the duration of the study, was 
re-calculated and updated from 
500 mL to 400 mL.
To reflect simplification of blood sampling 
and reduced burden to patients. 

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Section Number and 
Name
Description of Change
Brief Rationale
Section 8.1.1 
Primary/Secondary 
Variable: 
Urinary Albumin to 
Creatinine Ratio (UACR)
Inclusion of details regarding 
procedures 
For clarification on procedures. 
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
Addition of formulas for the 
calculation of eGFR
To provide clarification on the calculation.
Section 9.3 Populations 
for Analyses
Section 9.4.5.1 Adverse 
Events
Replacement of Safety Analysis 
Set (SAF) by Safety Set (SS)
SS is the new AZ standard.
Section  9.4.2.1 Primary 
Endpoint
Removal of AZD9977 alone and 
introduction of dapagliflozin 
10 mg as active comparator
The primary endpoint was updated 
according to the comparison with the active 
comparator.
Section 9.4.2.2 Secondary 
Endpoint
Removal of AZD9977 150 mg 
alone
The dose response relationship was 
modified due to the drop of the placebo and 
AZD9977 alone arm.
Section 9.4.2.3 
Exploratory Endpoints
Removal of exploratory endpoints
The exploratory endpoints have been 
updated according to the removed related 
exploratory variables.
Section 9.4.4 
Pharmacodynamics and 
Biomarkers
Removal of MR-related gene 
transcription
Reduction of sampling procedures and 
blood volume to lessen burden on sites and 
subjects.
Section 9.5 Interim 
Analyses
Section 9.6 Data 
Monitoring Committee
Change in size of interim analysis 
study population
Change in size of interim analysis 
population due to the updated sample size 
of the new study design.
Section 11 
REFERENCES
Addition of literature references
To support the updated study design.
Amendment 4 (15 July 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The previous CSP version, version 4.0, dated 19 March 2021 was updated to implement 
patient-centric measures and improve recruitment. The updates are summarised below.

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Section Number and Name
Description of Change
Brief Rationale
Cover page
Provided the full form of the study 
acronym, MIRACLE.
For clarity.
Section 1.1 Synopsis
Section 4.1 Overall Design
The study will now be conducted at 
approximately 210 sites in 
approximately 20 countries as a change 
from the previously planned 170 sites 
in approximately 18 countries.
To increase potential 
participant pool.
Section 1.2 Schema
Section 1.3 Schedule of Activities
Section 5.1 Inclusion Criteria
Section 5.2 Exclusion Criteria
Time window between Visits 2 and 3 
was widened from −5 to −1 days to −7 
to −1 days. Consequently, text in some 
of the inclusion and exclusion criteria 
was updated to align with this change 
in the time window.
To relieve operational burden 
without compromising 
participant safety or study data 
quality.
Section 5.1 Inclusion Criteria
Section 5.2 Exclusion Criteria
Moved selection criteria regarding use 
of prior and concomitant medications 
from the section on Inclusion criteria to 
the section on Exclusion criteria. 
Corrected because the content 
is appropriate under exclusion 
criteria rather than inclusion 
criteria.  
Section 5.1 Inclusion Criteria
Clarification that 50% of adjustment of 
loop diuretics is allowed
To clarify and improve 
recruitment without 
compromising participant 
safety or study data quality.
Section 5.1 Inclusion Criteria
Change in inclusion criterion of lower 
limit of systolic BP from ≥100 mmHg 
to ≥90 mmHg.
To improve recruitment 
without compromising 
participant safety or study data 
quality.
Section 5.1 Inclusion Criteria
The criterion NT-proBNP ≥900 pg/mL 
applies to patients with atrial 
fibrillation/flutter either at screening 
“or in medical history”.
Clarification that medical 
history is included in this 
criterion.
Section 5.1 Inclusion Criteria
Section 6.5.1 Prohibited 
Medications
The time period during which prior 
treatment with an MRA or SGLT2i is 
not allowed was updated from “for 
> 90 days to 12 months prior to 
screening” to be “within 90 days prior 
to screening”.
To improve recruitment 
without compromising 
participant safety or study data 
quality.
Section 5.2 Exclusion Criteria
The exclusion criterion of prolonged 
QT interval (QTcF > 470 ms) on ECG 
at screening (Visit 1) was removed.
To improve recruitment 
without compromising 
participant safety or study data 
quality.

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Section Number and Name
Description of Change
Brief Rationale
Section 5.4 Screen Failures
Clarification that individuals who do 
not meet the inclusion/exclusion 
criteria regarding eGFR and K+ levels 
may have these blood tests redone once 
after Visit 1 and/or Visit 2 upon 
investigator's discretion.
Clarification for transparency. 
Section 1.3 Schedule of Activities
Section 6.1.2 Medical Devices
Section 8.1.2 Exploratory 
Variables
Section 9.4.2.3 Exploratory 
Endpoints
Appendix A 4 Data Protection
Cancellation of plans to use Eko DUO 
device (stethoscope and integrated 
single-lead electrocardiogram [ECG]). 
Consequently, related text on these 
electrocardiograms and 
phonocardiograms in various sections 
was updated.
Operational issues in
providing the device to all 
sites. 
Section 6.1.2 Medical Devices
Clarification that wearable devices of 
activity tracker and sleep analyser 
should be optional and based on the 
participants’ consent.
Participant-centric approach.
Section 1.1 Synopsis
Section 4.1 Overall Design
Section 8.1.2.4 Home-based 
Monitoring of Activity
Section 9.3 Populations for 
Analyses
The requirement of selecting 
approximately 200 participants for 
home-based monitoring of activity was 
removed.
As use of wearable devices is 
no longer mandatory for the 
participants, the final sample 
size for this subgroup is 
uncertain.
Section 6.5 Concomitant Therapy
Appendix G 2 Risk Assessment 
for COVID-19 Pandemic
Added that COVID-19 vaccination is 
not likely to impact the study 
treatments and that the study treatments 
are not likely to impact COVID-19 
vaccination. Participants may be 
enrolled and or continue in the study 
regardless of their choice to be 
vaccinated or not.
Participant-centric approach 
and transparency.
Section 6.5.1 Prohibited 
Medications
Clarification that dietary K+
supplements or alternatives that are 
prohibited at screening/randomisation 
can be started during the study as a 
corrective action if hypokalaemia is 
confirmed.
Participant-centric approach 
and transparency.
Section 1.3 Schedule of Activities
Section 8.1.1 Primary/Secondary 
Variable: 
Urinary Albumin to Creatinine 
Ratio (UACR)
Clarification that the first morning void 
urine sample should be a full sample 
and not a spot sample.
To ensure that adequate 
sample is available for the 
various analyses.

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Section Number and Name
Description of Change
Brief Rationale
Section 8.1.2.2 Patient-Reported 
Outcomes
Clarified that 2 questions from the 
Kansas City Cardiomyopathy 
Questionnaire will not be applicable in 
this study.
For clarity.
Section 1.3 Schedule of Activities
Section 8.1.2.3 Bioimpedance 
Spectroscopy
Addition of body weight measurement 
at visits that include bioimpedance 
spectroscopy. 
The bioimpedance 
spectroscopy device used in 
this study does not measure 
body weight (required for the 
analysis).
Section 8.1.2.5 Ambulatory Blood 
Pressure Monitoring
Participants will be allowed to visit the 
study site in case required for adjusting 
or fitting the ABPM device. 
Participant-centric approach.
Section 1.3 Schedule of Activities
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Appendix F 1
Data on levels of electrolytes 
(potassium and sodium) and creatinine 
provided by local laboratories may be 
based on plasma or serum samples.
To adapt the study design to 
local laboratory capabilities 
without compromising data 
quality. Data on serum levels 
of electrolytes (potassium and 
sodium) and creatinine will be 
provided by the central 
laboratory.
Section 8.2.4 Clinical Safety 
Laboratory Assessments
The post-randomisation INR 
measurements may be done at a local 
laboratory if the necessary material 
provided by the central laboratory is 
not available; and the measurements 
may be omitted if the local laboratory 
is not capable of doing the 
measurements.
To adapt the study design to 
the central and local 
laboratory capabilities.
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Clarification that microscopic 
examination of urine sample sediments 
will be performed depending on the 
local laboratory’s capability.
To adapt the study design to 
local laboratory capabilities 
without compromising data 
quality.
Section 1.3 Schedule of Activities
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Collection of a plasma sample for K+
measurement at the central laboratory.
Clarification that a separate 
plasma sample should be 
collected for the purpose of 
exploratory pharmacodynamic 
analysis.
Section 8.5.1 Pharmacokinetics
Clarification that samples collected for 
PK assessments may be used, if 
necessary, for safety or efficacy 
assessments only during the study and 
not after the study.
Correction of an error.

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Section Number and Name
Description of Change
Brief Rationale
Section 8.6.2 Collection of 
Optional Biomarker Samples
Added text to clarify that unused 
samples of serum, plasma, and urine 
samples may be stored and used for 
future exploratory analyses if 
participant consents.
To clarify exploratory 
biomarker sample collection 
and use.
Section 8 Study Assessments and 
Procedures
The maximum amount of blood 
collected from each participant over the 
duration of the study, was re-calculated 
and updated from 400 mL to 500 mL.
For transparency.
Section 1.1 Synopsis
Section 4.1 Overall Design
Addition of a table to present the study 
treatment groups.
To improve clarity and 
readability.
Section 1.2 Schema
Section 1.3 Schedule of Activities
Section 3 Objectives and 
Endpoints
Addition of a note that Visits at Week 7 
and Week 13 (Visits 8 and 10) 
correspond to visits after completion of 
6 weeks and 12 weeks of study 
treatment, respectively.
To provide a clarification and 
align with the explanation 
provided in the Statistical 
Analysis Plan.
Section 1.2 Schema
Section 3 Objectives and 
Endpoints
Language updated to clarify that at 
“12 weeks” and other similar usage 
indicates “at the end of 12 weeks” ie, in 
Week 13. 
For clarity.
Section 1.1 Synopsis
Section 4.1 Overall Design
Change in stratification based on eGFR 
in (mL/min/1.73 m2) from: ≥30 to 
≤45; or > 45 to: ≥30 to < 45; or ≥45.
Correction of an error.
Section 1.1 Synopsis
Section 4.1 Overall Design
Appendix F 2
Updated language describing eGFR-
based participant stratification
For clarity
Throughout the document, 
wherever applicable.
Units of eGFR were corrected to 
mL/min/1.73 m2 consistently 
throughout the document.
Correction of an error.
Section 5.1 Inclusion Criteria
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Pregnancy test and lactation status that 
were mentioned for menopausal 
women were deleted. 
Correction of an error.
Section 8.2.4 Clinical Safety 
Laboratory Assessments
The CKD-EPI formula was mentioned 
as “non-BSA adjusted”, which was 
corrected to “BSA-adjusted”. 
Correction to align with the 
standard CKD-EPI formula.
Throughout the document, 
wherever applicable.
Minor language changes. 
To improve readability.
Amendment 3 (19 March 2021)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 

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Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment
Revised CSP, Final 3.0, dated 26 January 2021 was updated to 19 March 2021.
Section Number and Name
Description of Change
Brief Rationale
Protocol Amendment 
Summary of Changes
Correction of rationale for 
change relating to Eko DUO 
device
Eko DUO device is site-based not 
home-based
Correction of typo in
description of change for 
exclusion criterion 6 for 
HBA1c (<10% corrected to 
>10%)
Correction of typo
Section 2.3.1 Risk 
Assessment
Mitigation strategy for 
patients with uncontrolled 
diabetes mellitus corrected in 
line with change to inclusion 
criterion 6 made at Protocol 
Amendment 2 (HbA1c 
changed from >12% to >10%)
Alignment with change to definition of 
uncontrolled diabetes mellitus made in 
previous amendment
Section 6.3 Measures to 
Minimise Bias: 
Randomisation and Blinding
Clarified that unused returned 
study intervention must not be 
re-dispensed to the 
participants
In response to Regulatory Authority in 
Slovakia request
Section 8.1.2.6 Digital 
Cardiac Auscultation and 
Electrocardiogram
Clarified that the Eko DUO 
device will be used in clinic 
not at home
Eko DUO device is site-based not 
home-based
Section 8.3.5
Going forward, any new or 
aggravated clinically relevant 
abnormal medical finding will 
be reported as an AE 
regardless of relationship to 
the disease under study.
Condition that medical findings 
unequivocally related to disease under study 
did not need to be reported as an AE was 
removed in response to Regulatory Authority 
in Germany request|
Section 8.3.8.1 Maternal 
Exposure
Correction to align with 
mandated template text
Aligned with template
Section 9.4.2.3 Exploratory 
Endpoints
Respiratory rate was removed 
from the exploratory endpoint, 
Change from baseline in 
activity, heart rate, respiratory 
rate, body fluid retention, and 
sleep patterns over time
Respiratory rate was included in error; it is 
not collected in the study as per Schedule of 
Activities.

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In addition, the following administrative changes were made:

Tables of Contents updated.

Minor editorial changes.
Amendment 2 (26 January 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
Revised CSP, Final 2.0, dated 06 October 2020 was updated to 26 January 2021.
Section Number and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 4.1 Overall Design
Section 8.1.2.4 Home-based 
Monitoring of Activity
Added text to describe 
secondary randomisation for 
Home-based Monitoring of 
Activity subgroup
To clarify randomisation of subgroups
Section 1.1 Synopsis
Section 9.4.2.1 Primary 
Endpoint
Added text to analysis model 
on stratifying factors as 
covariates
To clarify the analysis model
Section 1.1 Synopsis
Section 4.1 Overall Design, 
Section 9.4.2.1 Primary 
Endpoint
Lower limit of eGFR was 
changed from “<30 mL/min” 
to “≥20 to <30 mL/min”
To clarify that the lower limit of eGFR is 
20 mL/min in this study
Section 1.3 Schedule of 
Assessments
Section 5.1 Inclusion 
Criteria
Section 8.2.4 Clinical Safety 
Laboratory Assessments 
(including Table 5)
Added text on FSH testing and 
adjusted table layout; text on 
LH was removed
To clarify tests regarding female 
reproductive status
Section 1.3 Schedule of 
Assessments; Section 8.1.2.3
Added text to exclude 
participants with pacemakers 
or other implanted devices 
from the bioimpedance 
assessment
The use of bioimpedance devices is 
contraindicated for patients with pacemakers 
or other electronic implanted devices
Section 1.3 Schedule of 
Assessments
Added text on hypertension 
medication; cross-references 
added
To clarify that hypertension treatment can be 
adjusted if needed at the screening visit

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Section Number and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Assessments
Section 3 Objectives and 
Endpoints
Section 6.1.2 Medical 
Devices
Section 8.1.2.6 Digital 
Cardiac Auscultation and 
Electrocardiogram
Section 8.3.10 Medical 
Device Deficiencies
Section 9.4.2.3 Exploratory 
Endpoints
Appendix A4 Data 
Protection
Appendix A7 Data Quality 
Assurance
Added text on the Eko DUO 
device and dECG device; new
sections added 
(Section 8.1.2.6 and 
Section 8.3.10), other 
applicable sections updated, 
SoA revised accordingly, 
cross-references added as 
appropriate
To describe addition of new device to the 
protocol for site-based ECG monitoring
Section 2.2 Background
Section 2.2.1.4 
Sodium-glucose Co-
transporter 2 Inhibitors in 
Heart Failure and Chronic 
Kidney Disease
Section 2.3 Benefit/Risk 
Assessment (Table 2)
Section 2.3.2 Benefit 
Assessment
Section 11 References
Updated introductory text 
according to revised 
Investigator’s Brochure of 
dapagliflozin; redundant 
reference was deleted
To include findings from recent clinical trials 
with dapagliflozin that suggest it has an 
additive treatment effect when given 
concomitantly with MRAs (DAPA-HF trial) 
and to further describe the dapagliflozin risk 
and benefit in patients with chronic kidney 
disease (DAPA-CKD trial)
Section 3 Objectives and 
Endpoints
Section 9.4.2.3 Exploratory 
Endpoints
Corrected typo in alignment 
with Schedule of Assessments
To clarify that the KCCQ must be completed 
at 6 and 12 weeks, not at 8 and 12 weeks

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Section Number and Name
Description of Change
Brief Rationale
Section 5.1 Inclusion 
Criteria
Added “flutter” to criterion 5; 
added timepoints to 
criterion 6; revised the 
timepoint wording at 
criterion 11; corrected the 
cross-reference at criterion 12; 
added age-specific 
requirements to criterion 16 
and revised text according; 
systolic BP inclusion 
criterion 9 clarified and 
diastolic BP inclusion 
criterion 10 removed
To clarify eligibility criteria
Section 5.2 Exclusion 
Criteria
Revised the timepoint wording 
in criteria 11 and 18; 
definition of uncontrolled 
diabetes mellitus changed 
from HBA1c >12% to >10% 
in criterion 6; any major 
cardiovascular surgery 
planned or within 3 months 
added as new criterion 12; 
COVID-19 criterion 25 (c) 
clarified
To clarify eligibility criteria
Section 6.5.1 Prohibited 
Medications
Revised list and added text in 
alignment with Section 5.1 
Inclusion Criteria
To clarify medication restrictions
Section 6.7 Intervention 
After the End of the Study
Edited text
To clarify when patients should return to 
their usual treatments
Section 7.2 Participant 
Withdrawal from the Study
Added text on ET and safety 
follow-up visits
To clarify procedures upon participant 
withdrawal
Section 8 Study 
Assessments and Procedures
Added text on procedures 
performed at another facility
To clarify time frames for procedures 
performed at another facility than the study 
site
Section 8.1.2.4 Home-based 
Monitoring of Activity
Section 8.1.2.5 Ambulatory 
Blood Pressure Monitoring
Section 8.1.2.6 Digital 
Cardiac Auscultation and 
Electrocardiogram
Added text on outcomes of the 
monitoring procedures
To clarify availability of results and handling 
of health-related issues
Section 8.4 Overdose
Added text on dose limit in 
terms of number of capsules
To clarify overdose definition whilst 
maintaining the study blinding

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Section Number and Name
Description of Change
Brief Rationale
Section 8.3.10 Medical 
Device Deficiencies
Appendix L
New section added and 
Clinical Study Medical Device 
/ Device Constituent Report 
Form included as an appendix
Required for studies in which a medical 
device is provided for use in the study
Section 9.3 Populations for 
Analyses
Section 9.4.2 Efficacy
Added text in alignment with 
the SAP
To further describe statistical considerations 
of the study
In addition, the following administrative changes were made:

A duplicate scanned page was removed from Appendix J (Kidney Disease and Quality of 
Life).

Protocol amendment history for previous amendment was moved to a new Appendix 
(Appendix N).

Tables of Contents and the List of Abbreviations were updated.

Minor editorial changes were made throughout.
Amendment 1 (06 October 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the Amendment
The original CSP, Final 1.0, dated 25 August 2020, was updated to include modifications to 
the number of sites and countries and updates to laboratory parameters for clarity. Minor 
editorial updates were made throughout.
Section Number and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 4.1 Overall Design
Update of number of sites and 
countries
To increase potential participant pool
Section 4.1 Overall Design
Update of eGFR strata for 
randomisation
To fix inconsistencies between protocol 
summary and Section 4.1
Section 8.1.1 
Primary/Secondary Variable 
Urinary Albumin to 
Creatinine Ratio (UACR)
Correction of typo in Urinary 
Albumin to Creatinine Ratio 
unit
To fix a typo

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Section Number and Name
Description of Change
Brief Rationale
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Update of local laboratory 
requirements to make 
Glutamate dehydrogenase, 
RBC distribution width, and 
Bicarbonate at screening 
dependent on local capabilities
To account for the fact that some countries 
are not able to perform these tests locally
Section 9.2 Sample Size 
Determination
Addition of alpha value
To align with FDA comments
Section 9.3 Populations for 
Analyses
Clarification of the Full 
Analysis Set including 
participants who both receive 
and do not receive study 
intervention
To align with FDA comments

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11
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2015;373(22):2117-28.

SIGNATURE PAGE
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electronically and this page is the manifestation of the electronic signature
Document Name: d6402c00001-csp-v7
Document Title:
D6402C00001 Clinical Study Protocol version 7
Document ID:
Doc ID-004268198
Version Label:
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