Conditions: Chronic Kidney Disease
Keywords: Zibotentan Nephrology Dapagliflozin Sodium-glucose co-transporter 2 sodium-glucose co-transporter 2 inhibitor Kidney diseases Endothelin antagonist
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 542
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess efficacy, safety and tolerability of treatment with zibotentan and dapagliflozin in combination and dapagliflozin 10 mg as monotherapy in participants with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m\^2, and urinary albumin to creatinine ratio (UACR) ≥ 150 mg/g and ≤ 5000 mg/g.

Detailed description:
The study will be conducted in approximately 220 sites in North America, South America, Africa, Asia/Pacific, and European countries.

Participants will be randomized to 12 weeks of treatment plus 2 weeks follow-up.

After screening, eligible participants will be stratified by diabetes (diabetic kidney disease \[DKD\] versus non-diabetes mellitus \[non-DM\] CKD) and baseline eGFR (below or equal versus above 45 mL/min/1.73m\^2).

A total of 495 participants will be randomised into this study, including participants randomised under the earlier study design. Four hundred and fifteen (415) participants will be randomised to have 166 participants in zibotentan Dose A/dapagliflozin 10 mg combination arm and dapagliflozin 10 mg monotherapy arm, and 83 participants in the zibotentan Dose B/dapagliflozin 10 mg combination arm.

* Zibotentan Dose A + Dapagliflozin 10 mg once daily.
* Zibotentan Dose B + Dapagliflozin 10 mg once daily.
* Placebo + Dapagliflozin 10 mg once daily

Participants who were previously randomised cannot be re-randomised.

Arms:
arm 1: Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks. arm 2: Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks. arm 3: Participants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks.

Interventions: intervention 1: Zibotentan intervention 2: Dapagliflozin intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive zibotentan as per the arms they are randomized. intervention 2: Participants will receive 10 mg dapagliflozin as per the arms they are randomized. intervention 3: Participants will receive placebo as per the arms they are randomized to.

Protocol document:
Prot_002.pdf: 
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Clinical Study Protocol
Study Intervention
Zibotentan and Dapagliflozin
Study Code
D4325C00001
Version
Amendment 3
Date
22 Mar 2023
A Phase 2b Multicentre, Randomised, Double-Blind, 
Active-Controlled, Parallel Group Dose-Ranging Study to Assess 
the Efficacy, Safety and Tolerability of Zibotentan and 
Dapagliflozin in Patients with Chronic Kidney Disease with 
Estimated Glomerular Filtration Rate (eGFR) 
≥20 mL/min/1.73 m2
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, SE-15185 Södertälje, Sweden
Regulatory Agency Identifier Numbers
IND 151089
EudraCT 2020-004101-32
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: D4325C00001
Amendment Number: 3


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Study Intervention: Zibotentan and Dapagliflozin
Study Phase: 2b
Brief Title: Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD trial)
PPD
PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
22 Mar 2023
Amendment 2
05 Apr 2022
Amendment 1
03 Dec 2021
Version 1.0
14 Sep 2020
Amendment 3 (22 Mar 2023)
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 Union.
Overall Rationale for the Amendment:
The amended CSP (Amendment 2, dated 05 April 2022) was updated to provide clarification, 
align wording with recent CSP template, and to reflect that some of the exploratory endpoints 
will not be reported in the CSR.


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1
Synopsis
Updated the title to 
“Brief Title” as per the 
recent CSP template
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but 
NOT including a template 
transfer to v7
Non-substantial
Updated the title to 
“Objectives, 
Endpoints and 
Estimands” as per the 
recent CSP template
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but
NOT including a template 
transfer to v7
Non-substantial
Updated the wording 
for secondary 
estimand description / 
endpoint
For clarification since 
endpoints should be defined 
on patient-level
Non-substantial
Updated the wording 
for the second 
administrative interim 
analysis
For clarification
Non-substantial
Deleted information 
about MCP-Mod 
approach to 
investigate the dose 
response.
Updated the wording 
for dose-relationship 
between different 
doses of zibotentan / a 
fixed dose of 
dapagliflozin and 
UACR reduction. 
MCP-Mod analysis is not 
recommended when there
are only 2 active arms
Non-substantial


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial/
Non-substantial
Section 1.2
Figure 1 Study 
Schema
Updated footnote 
wording to the second 
administrative interim 
analysis completion
For clarification
Non-substantial
Section 3
Objectives, 
Endpoints and 
Estimands
Synopsis
Updated the title to 
“Objectives, 
Endpoints and 
Estimands” as per the 
recent CSP template
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but 
NOT including a template 
transfer to v7
Non-substantial
Updated the wording 
for secondary 
estimand description / 
endpoint
For clarification since 
endpoints should be defined 
on patient-level
Non-substantial
Exploratory endpoint 
updated to confirm 
that results for NT-
proBNP, ET-1, ELDP, 
CT-proET-1 and 
copeptin levels will 
not be reported in the 
CSR
For clarification
Non-substantial
Section 4.1
Overall Design
Updated the wording 
to the second 
administrative interim 
analysis
For clarification
Non-substantial
Section 4.4
End of Study 
Definition
Updated the wording 
for a participant 
considered to have 
completed the study
For clarification
Non-substantial
Section 6.1.1
Investigational 
Products
Table 4
Unit Dose Strength for 
Dapagliflozin 10 mg 
was updated to 
remove NA.
For clarification
Non-substantial
Table 4 footnote was 
updated to include and 
expand abbreviation
For clarification
Non-substantial


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial/
Non-substantial
Section 6.1.2
Medical Devices
Instructions for 
medical device 
wording was updated
For clarification
Non-substantial
Section 8.5.3.1
Collection of 
Samples
Included the text that 
results for urine 
cortisol will not be 
reported in the CSR
For clarification
Non-substantial
Section 9.4.2.1
Primary Endpoint
Updated the wording 
to the analysis model 
inclusion criteria
For clarification
Non-substantial
Section 9.4.2.2
Secondary 
Endpoints
Deleted information 
about MCP-Mod 
approach to 
investigate the dose 
response.
Updated the wording 
for dose-relationship 
between different 
doses of zibotentan / a 
fixed dose of 
dapagliflozin and 
UACR reduction
MCP-Mod analysis is not 
recommended when there 
are only 2 active arms
Non-substantial
Section 9.4.4
Other Analyses
Included the analyses 
that will not be 
reported in the CSR
For clarification
Non-substantial
Section 9.5
Interim Analyses
Updated the wording 
to the second 
administrative interim 
analysis completion
For clarification
Non-substantial
Section 10
Appendix A1: 
Regulatory and 
Ethical
Expanded the first use 
of IRB and IEC and 
text updated
For clarification
Non-substantial
A new sub-section 
was added to include 
the mandatory 
wording and section 
for Regulatory 
Reporting 
Requirements for 
Serious Breaches
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but 
Non-substantial


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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial/
Non-substantial
NOT including a template 
transfer to v7
Section 10
Appendix B4: 
Medication Error, 
Drug Abuse and 
Drug Misuse
Updated the title to 
include “Drug Abuse 
and Drug Misuse” as 
per the recent CSP 
template
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but 
NOT including a template 
transfer to v7
Non-substantial
New sub-sections 
were added to include 
the mandatory 
wordings and sections 
for Drug Abuse and 
Drug Misuse
Following a CSP waiver 
from the CSP process 
owner, this report aligns to 
the mandatory 
implementation 
requirement for all 
protocols being updated but 
NOT including a template 
transfer to v7
Non-substantial
Section 10
Appendix H: 
Protocol 
Amendment 
History
Moved Amendment 2 
text to Appendix H
For template alignment
Non-substantial
Section 11
References
Deleted Pinheiro et al, 
2006 from references
To align with the CSP 
amendment
Non-substantial
BNP = B-type natriuretic peptide; CKD = chronic kidney disease; CSP = Clinical Study Protocol; 
CSR = Clinical Study Report; CT-proET-1 = C-terminal pro-endothelin-1; GCP = Good Clinical Practice; 
IA = interim analysis; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; IEC = Independent Ethics 
Committee; IRB = Institutional Review Board; MRA = mineralocorticoid receptor agonist; 
NT-proBNP = N-terminal pro-B-type natriuretic peptide; PK = pharmacokinetic; QTcF = QT interval corrected 
using Fridericia’s formula; SGLT2 = sodium-glucose co-transporter 2; SoA = Schedule of Activities; 
SoC = standard of care; T2DM = type 2 diabetes mellitus; UACR = Urinary Albumin to Creatinine Ratio;
URC = Unblinded Review Committee.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .....................................3
TABLE OF CONTENTS ......................................................................................................8
1
PROTOCOL SUMMARY ................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 17
1.3
Schedule of Activities ....................................................................................... 18
2
INTRODUCTION............................................................................................ 26
2.1
Study Rationale ................................................................................................ 26
2.2
Background ...................................................................................................... 26
2.3
Benefit/Risk Assessment................................................................................... 28
2.3.1
Risk Assessment ............................................................................................... 29
2.3.2
Benefit Assessment........................................................................................... 31
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 31
3
OBJECTIVES AND ENDPOINTS................................................................... 33
4
STUDY DESIGN ............................................................................................. 36
4.1
Overall Design.................................................................................................. 36
4.2
Scientific Rationale for Study Design ............................................................... 37
4.3
Justification for Dose........................................................................................ 38
4.4
End of Study Definition.................................................................................... 38
5
STUDY POPULATION.................................................................................... 38
5.1
Inclusion Criteria .............................................................................................. 39
5.2
Exclusion Criteria ............................................................................................. 41
5.3
Lifestyle Considerations ................................................................................... 43
5.3.1
Meals and Dietary Restrictions ......................................................................... 43
5.3.2
Tobacco ............................................................................................................ 44
5.3.3
Activity............................................................................................................. 44
5.4
Screen Failures ................................................................................................. 44
6
STUDY INTERVENTION ............................................................................... 45
6.1
Study Intervention(s) Administered................................................................... 45
6.1.1
Investigational Products.................................................................................... 45
6.1.2
Medical Devices ............................................................................................... 46
6.2
Preparation/Handling/Storage/Accountability ................................................... 47
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 47
6.4
Study Intervention Compliance......................................................................... 49
6.5
Concomitant Therapy........................................................................................ 49
6.5.1
Prohibited Concomitant Medications ................................................................ 50


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6.5.2
Medications Inducing Hypoglycaemia .............................................................. 50
6.5.3
Background Standard of Care Therapy.............................................................. 50
6.5.4
Rescue Medicine............................................................................................... 50
6.6
Dose Modification ............................................................................................ 51
6.7
Intervention After the End of the Study............................................................. 51
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 51
7.1
Discontinuation of Study Intervention............................................................... 51
7.1.1
Ketoacidosis in Participants with T2DM........................................................... 52
7.2
Participant Withdrawal from the Study.............................................................. 53
7.3
Lost to Follow up.............................................................................................. 53
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 54
8.1
Efficacy Assessments........................................................................................ 55
8.1.1
Primary/Secondary Variable: Urinary Albumin to Creatinine Ratio (UACR)..... 55
8.1.2
Other Secondary Variables................................................................................ 55
8.1.2.1
Office/Clinic Blood Pressure Measurement....................................................... 55
8.1.2.2
Serum Analysis of Creatinine and Cystatin C (eGFR) ....................................... 55
8.1.3
Exploratory Variables........................................................................................ 56
8.1.3.1
Electronic Scale Measurement of Body Weight................................................. 56
8.1.3.2
Bioimpedance Spectroscopy ............................................................................. 56
8.1.3.3
Echocardiography Assessment of Cardiac Structure and Function..................... 57
8.2
Safety Assessments........................................................................................... 57
8.2.1
Physical Examinations...................................................................................... 57
8.2.2
Vital Signs ........................................................................................................ 57
8.2.3
Electrocardiograms........................................................................................... 58
8.2.4
Clinical Safety Laboratory Assessments............................................................ 59
8.3
Adverse Events and Serious Adverse Events..................................................... 60
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 61
8.3.2
Follow-up of AEs and SAEs ............................................................................. 61
8.3.3
Causality Collection.......................................................................................... 62
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 62
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 62
8.3.6
Hy’s Law.......................................................................................................... 63
8.3.7
Reporting of Serious Adverse Events................................................................ 63
8.3.8
Pregnancy......................................................................................................... 64
8.3.8.1
Maternal Exposure............................................................................................ 64
8.3.8.2
Paternal Exposure............................................................................................. 65
8.3.9
Medication Error............................................................................................... 65
8.4
Overdose .......................................................................................................... 66
8.5
Human Biological Samples............................................................................... 66
8.5.1
Pharmacokinetics.............................................................................................. 67
8.5.1.1
PK Sub-Study................................................................................................... 67
8.5.1.2
Determination of Drug Concentration ............................................................... 68


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8.5.2
Immunogenicity Assessments ........................................................................... 68
8.5.3
Pharmacodynamics........................................................................................... 68
8.5.3.1
Collection of Samples....................................................................................... 68
8.6
Human Biological Sample Biomarkers ............................................................. 69
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 69
8.7
Optional Genomics Initiative Sample................................................................ 69
8.8
Health Economics OR Medical Resource Utilisation and Health Economics 
(Not Applicable) ............................................................................................... 70
9
STATISTICAL CONSIDERATIONS................................................................ 70
9.1
Statistical Hypotheses....................................................................................... 70
9.2
Sample Size Determination............................................................................... 70
9.3
Populations for Analyses................................................................................... 71
9.4
Statistical Analyses ........................................................................................... 71
9.4.1
General Considerations..................................................................................... 72
9.4.2
Efficacy ............................................................................................................ 72
9.4.2.1
Primary Endpoint.............................................................................................. 72
9.4.2.2
Secondary Endpoints ........................................................................................ 73
9.4.2.3
Exploratory Endpoints ...................................................................................... 74
9.4.3
Safety ............................................................................................................... 74
9.4.3.1
Adverse Events................................................................................................. 74
9.4.3.2
Vital Signs ........................................................................................................ 75
9.4.3.3
Laboratory Assessments.................................................................................... 75
9.4.3.4
Electrocardiograms........................................................................................... 76
9.4.4
Other Analyses.................................................................................................. 76
9.4.4.1
Exploratory PK Endpoints ................................................................................ 76
9.4.4.2
Exploratory PD and Biomarker Endpoints ........................................................ 77
9.4.4.3
Potential Future Exploratory Research and Optional Genetic Research ............. 77
9.5
Interim Analyses............................................................................................... 77
9.6
Data Monitoring Committee ............................................................................. 78
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 79
11
REFERENCES............................................................................................... 124
LIST OF FIGURES
Figure 1
Study Schema.......................................................................................... 17
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 18
Table 2
Risk Assessment...................................................................................... 29


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Table 3
Objectives and Endpoints......................................................................... 33
Table 4
Investigational Products........................................................................... 45
Table 5
Laboratory Safety Variables..................................................................... 59
Table 6
Populations for Analysis .......................................................................... 71
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 79
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 85
Appendix C
Handling of Human Biological Samples .................................................. 91
Appendix D
Optional Genomics Initiative Sample....................................................... 93
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 96
Appendix F
COVID-19 Specifics.............................................................................. 101
Appendix G
Abbreviations ........................................................................................ 104
Appendix H
Protocol Amendment History................................................................. 107


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b Multicentre, Randomised, Double-Blind, Active-Controlled, 
Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of 
Zibotentan and Dapagliflozin in Patients with Chronic Kidney Disease with Estimated 
Glomerular Filtration Rate (eGFR) ≥20 mL/min/1.73 m2
Brief Title: Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD trial)
Rationale: Patients with chronic kidney disease (CKD) have limited treatment options with 
current standard of care (SoC). The mechanisms of action of zibotentan and dapagliflozin are 
different and the outcome of combined treatment is expected to be synergistic, since the main 
biological effects of zibotentan are to block endothelin-1-dependent vasoconstriction and 
hypertension, to increase renal blood flow, and to reduce podocyte loss, vascular stiffness, 
endothelial dysfunction, fibrosis and inflammation; and of dapagliflozin are to inhibit 
sodium-glucose co-transporter 2 (SGLT2) to increase urinary excretion of glucose, sodium 
and water, to improve metabolic health, decrease vascular stiffness, improve endothelial 
function, and decrease oxidative stress and inflammation. Both mechanisms show efficacy in 
reducing albuminuria in CKD. However, unlocking the renal benefit of endothelin antagonists 
requires mitigation of their potential to cause fluid retention and to increase the risk of 
developing heart failure (HF) in some patients.
Objectives, Endpoints and Estimands:
Objectives
Estimand Description/Endpoints
Primary
!
To evaluate the effect of zibotentan 
1.5 mg/dapagliflozin 10 mg versus dapagliflozin 
10 mg monotherapy on UACR.
!
Change in log-transformed UACR from 
baseline to Week 12.
The primary estimand is a hypothetical estimand such 
that the treatment effect is quantified in the optimal 
situation where any potential confounder is avoided. 
The population of interest is the Full Analysis 
population. Participants will be included in the 
analysis if they have a non-missing baseline and at 
least one post-treatment visit UACR measurement.
For the intercurrent events, if a participant is lost to 
follow up, prematurely discontinues study treatment,
or uses a prohibited medication, the UACR data are 
treated as missing after the event and no imputation is 
performed. The summary measure being evaluated is 
the geometric mean reduction of UACR from 
baseline to Week 12.


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Objectives
Estimand Description/Endpoints
Secondarya
!
To evaluate the effect of zibotentan 
0.25 mg/dapagliflozin 10 mg versus 
dapagliflozin 10 mg on UACR.
!
Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the change in office systolic and 
diastolic BP for doses of zibotentan combined 
with dapagliflozin 10 mg versus dapagliflozin 
10 mg monotherapy.
!
Change in BP from baseline (Visit 2) to 
Week 12.
!
To characterise the dose-response relationship 
(relationship between different doses of 
zibotentan/a fixed dose of dapagliflozin and 
UACR reduction).
!
Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the effect of different doses of 
zibotentan and dapagliflozin 10 mg in 
combination versus dapagliflozin 10 mg 
monotherapy on eGFR.
!
Change in eGFR from baseline to Week 1.
!
Change in eGFR from baseline to Week 12.
!
Change in eGFR from baseline to Week 14.
!
Change in eGFR from Week 1 to Week 12.
Safety
!
To assess the safety and tolerability of all doses 
of zibotentan combined with dapagliflozin 
10 mg and dapagliflozin 10 mg monotherapy.
!
AEs/SAEs/DAEs.
!
Vital signs.
!
Clinical laboratory tests.
!
12-lead ECG assessment.
!
Event of special interest (changes in 
fluid-related measures).
AE = adverse event; BP = blood pressure; DAE = adverse event leading to the discontinuation of study 
intervention; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; SAE = serious adverse 
event; UACR = urinary albumin to creatinine ratio.
a
The estimand for the secondary objectives is defined with the same approach as for the primary objectives.
For exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design:
This is a Phase 2b, multicentre, randomised, double-blind, active-controlled, parallel group 
dose-ranging study to assess the efficacy, safety and tolerability of zibotentan and 
dapagliflozin in participants with CKD with eGFR ≥20 mL/min/1.73 m2, and UACR
≥150 mg/g and ≤5000 mg/g.
The study will be conducted in approximately 220 sites in North America, South America, 


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Africa, Asia/Pacific, and European countries.
An internal Unblinded Review Committee (URC) of AstraZeneca representatives is set up for 
this study for ongoing safety monitoring and reviewing the unblinded interim results. In 
addition to general safety/tolerability, the URC will focus on potential risks related to 
hypotension and hospitalisations due to HF. Changes in fluid-related measures (weight gain or 
B-type natriuretic peptide [BNP]) that meet the defined threshold will be reported as an event 
of special interest.
Participants will be randomised to 12 weeks of treatment plus 2 weeks follow-up.
Participants who meet the eligibility criteria will be randomised to study treatments in addition 
to receiving background local SoC therapy. Participants who were previously randomised
cannot be re-randomised.
Participants will be stratified by diabetes (diabetic kidney disease [DKD] versus non-diabetes 
mellitus [non-DM] CKD) and baseline eGFR (below or equal versus above 
45 mL/min/1.73m2) at the time of randomisation to ensure an approximate balance between 
treatment arms within each sub-population. The number of randomised participants in each 
stratum will be monitored to ensure the non-DM CKD sub-population is approximately a 
minimum of 30% and a maximum of 50% of the total number of participants randomised.
Disclosure Statement:
The study is participant, investigator, and Sponsor (with the exception of the URC) blinded.
Participants will be randomised into one of the three arms (zibotentan 1.5 mg/dapagliflozin 
10 mg combination arm, zibotentan 0.25 mg/dapagliflozin 10 mg combination arm or 
dapagliflozin 10 mg monotherapy arm) in a 2:1:2 allocation.
Number of Participants:
A total of 495 participants will be randomised into this study, including participants 
randomised under the earlier design. Four hundred and fifteen (415) participants will be 
randomised to have 166 participants in the zibotentan 1.5 mg/dapagliflozin 10 mg 
combination arm and dapagliflozin 10 mg monotherapy arm, and 83 participants in the 
zibotentan 0.25 mg/dapagliflozin 10 mg combination arm. 
Intervention Groups and Duration:
Eligible participants will be randomised to either of the following treatments, in addition to 
receiving background local SoC therapy:
!
Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily.
!
Zibotentan 1.5 mg + Dapagliflozin 10 mg once daily.


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!
Dapagliflozin 10 mg once daily.
To ensure blinding to treatment and zibotentan dose, daily dosing will consist of one 
dapagliflozin tablet, containing dapagliflozin 10 mg and one zibotentan capsule containing 
zibotentan 1.5 mg, zibotentan 0.25 mg or placebo.
For each participant, the total duration of participation will be approximately 17 to 19 weeks. 
The screening period can be up to approximately 4 weeks in duration prior to randomisation. 
The first dose will be taken after randomisation at the baseline visit on Day 1. In addition to 
the baseline visit, the participant will visit the clinic 5 times during the following 12 weeks of 
treatment. Approximately 2 weeks after the last dose, the participant will visit the clinic again 
for a follow-up assessment.
Data Monitoring Committee:
An internal URC of AstraZeneca representatives is set up for this study for ongoing safety 
monitoring and reviewing the unblinded interim results.
Statistical Methods:
The primary hypothesis for this study is that zibotentan 1.5 mg and dapagliflozin 10 mg in 
combination will reduce UACR compared with dapagliflozin 10 mg monotherapy. The 
secondary hypothesis for this study is that zibotentan 0.25 mg combined with dapagliflozin
10 mg will reduce UACR compared with dapagliflozin 10 mg monotherapy. Dose-response 
for the reduction in UACR, as a function of the zibotentan dose, as combined with 
dapagliflozin, will be evaluated.
With a 1-sided 5% type I error, 150 evaluable participants in the zibotentan 1.5 mg and 
dapagliflozin 10 mg arm and dapagliflozin 10 mg monotherapy arm will have approximately 
% power to detect a dapagliflozin-corrected UACR reduction of 
% or more assuming a 
SD of 
 on the natural log-scale. In the DKD sub-population (which will be about 70% of 
the total population), the power to detect the same reduction is estimated to be 
%.
For the dose-response models, the sample size below will have at least 
% power across 
multiple dose-response models to detect dose-response significance. This assumes a 1-sided 
type I error of 5% and a maximum UACR reduction of 
% for the zibotentan 1.5 mg and 
dapagliflozin 10 mg combination arm relative to dapagliflozin.
!
Zibotentan/Dapagliflozin dose = 0/10 mg: n = 150.
!
Zibotentan/Dapagliflozin dose = 0.25/10 mg: n = 77.
!
Zibotentan/Dapagliflozin dose = 1.5/10 mg: n = 150.
CCI
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A first administrative interim analysis will be performed when 50% of participants have 
completed 6 weeks of treatment of the study. A second administrative interim analysis will be 
performed after 100% of participants have completed the 6 weeks treatment or at a time 
selected by sponsor / percentage of participants with a planned week 6 visit before data cut 
selected by sponsor. The objective of the administrative interim analyses will be to decide if 
an 
 zibotentan/dapagliflozin project activities is 
 
 on the interim data.
The analysis of all efficacy variables will be performed on the Full Analysis Set (FAS) with a 
hypothetical estimand. In addition, the primary efficacy endpoint will also be analysed using 
the Per Protocol Analysis Set (PPS), and a treatment policy estimand as sensitivity analyses.
The primary efficacy endpoint for this study is the change in log-transformed UACR from 
baseline to Week 12 for zibotentan 1.5 mg combined with dapagliflozin 10 mg versus 
dapagliflozin 10 mg monotherapy. UACR will be log-transformed and analysed using a mixed 
model repeated measures (MMRM) method. The values will be back transformed onto the 
original scale to give the geometric mean relative change from baseline to Week 12. The 
analysis model will include the fixed categorical effects of stratification factor, treatment, 
visit, and treatment-by-visit interaction, plus the continuous covariates of baseline log(UACR) 
and baseline log(UACR)-by-visit interaction. An unstructured covariance structure will be 
used for the within-participant errors.
As a secondary efficacy endpoint for this study, the change in UACR for doses of 0.25 mg 
zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy from 
baseline (Visit 2) to Week 12 (Visit 7) will be assessed. A MMRM model similar to that 
described for the primary endpoints will be fitted.
The dose-response relationship between different doses of zibotentan/a fixed dose of
dapagliflozin and UACR reduction will be characterised by assessing the UACR reduction 
analysed in primary and first secondary objective.
The change from baseline (Visit 2) to Week 12 (Visit 7) in office systolic and diastolic blood 
pressure (BP) will be assessed for doses of zibotentan combined with dapagliflozin 10 mg
versus dapagliflozin 10 mg monotherapy.
The effect of different doses of zibotentan and dapagliflozin in combination versus 
dapagliflozin 10 mg monotherapy on eGFR will be determined from the change in eGFR from 
baseline to Week 1, Week 12, and Week 14, and from Week 1 to Week 12.
These secondary variables of BP and eGFR will be analysed using ANCOVA, adjusting for 
stratification factors, treatment arm, and baseline. The FAS will be used for these analyses.
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1.2
Schema
Figure 1
Study Schema
DAPA = dapagliflozin; N = numbers of participants; QD = once daily; R = randomisation; SAP = Statistical 
Analysis Plan; W = week; ZIBO = zibotentan.
Four hundred and fifteen (415) participants will be randomised to have 166 participants in the 
zibotentan 1.5 mg/dapagliflozin 10 mg combination arm and dapagliflozin 10 mg monotherapy arm, and 
83 participants in the zibotantan 0.25 mg/dapagliflozin 10 mg combination arm.
First administrative interim analysis at 6 weeks of treatment (n = 50% of participants).
Second administrative interim analysis at 6 weeks of treatment (n = 100% of participants, or at a time selected by 
sponsor / percentage of participants with a planned week 6 visit before data cut selected by sponsor).
Details described in the SAP.


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1.3
Schedule of Activities
Table 1
Schedule of Activities
Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Informed consent
X
Section 5.1; 
Appendix A 3
Inclusion and exclusion criteria
X
X
Recheck clinical status before 
randomisation.
Sections 5.1 and 5.2
Screening in IRT/RTSM
X
Section 6.3
Randomisation in IRT/RTSM
X
Diaries will be given to the participants and 
they will be asked to fill in the dose intake 
information (date and time) at home.
Section 6.3 and 6.4
Routine clinical procedures
Demography and baseline 
characteristics (smoking history and 
alcohol consumption included)
X
Sections 5.1 and 5.2
Physical examination
X
X
X
X
X
X
X
X
A complete physical examination will be 
done at screening, randomisation and 
Week 12.
A brief physical examination will be done 
at Weeks 1, 3, 6, 9, 14.
Section 8.2.1


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Medical/ surgical history, which
includes substance usage and family 
history of premature cardiovascular 
disease
X
Substances: drugs, alcohol, tobacco, and 
caffeine
Sections 5.1 and 5.2
Height
X
Sections 5.1, 5.2
and 8.2.1
Serology (HIV I and II, Hepatitis B 
surface antigen, Hepatitis C virus 
antibody, central laboratory)
X
Results need to be available before 
randomisation.
Section 8.2.4
FSH/LH and serum pregnancy test 
(females only, central laboratory)
X
Results need to be available before 
randomisation.
Section 8.2.4
Local test for SARS-CoV-2
X
Testing is also required if participants show 
COVID-19 symptoms during the study.
Section 8.2.4
Concomitant medication
X
X
X
X
X
X
X
X
Section 6.5
Efficacy assessments
Spot urine from first morning void: 
albumin and creatinine (central 
laboratory)
X
Results need to be available before 
randomisation. A single sample for analysis 
is sufficient at screening.
Section 8.1.1


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Spot urine from first morning void over 
3 consecutive days: albumin, creatinine 
(central laboratory) 
X
X
X
X
X
X
Spot urine from first morning void over 
3 consecutive days, ideally on day of clinic 
visit and preceding 2 days, collected at 
home in provided vials. Analysis will be 
done in all 3 samples at central laboratory 
and averaged.
Section 8.1.1
Spot urine from first morning void: 
Na+, K+, uric acid, urea, glucose, 
creatinine, osmolality, and cortisol 
(central laboratory)
X
X
X
X
X
X
Spot urine from first morning void, only 
from the third day sample (day of clinic 
visit), collected at home in provided vial. 
Analysis will be done at central laboratory.
Sections 8.5.3 and 
8.5.3.1
Body weight
X
X
X
X
X
X
X
X
Body weight must be taken and reviewed 
before treatment at each dosing visit.
Sections 8.2.2 and 
5.1
Echocardiography
X
X
Screening and Week 12 only. ECHO will 
be performed locally and sent to central 
reader. Results need to be available before 
randomisation.
Section 8.1.3.3
Bioimpedance spectroscopy
X
X
X
X
X
X
X
Section 8.1.3.2
Home-based monitoring
Daily digital body weight measurement
Daily home measurement using a digital device from 
randomisation to end of follow up.
Home body weight measurements should 
start 2 days before randomisation (same as 
for spot urine).
Section 8.1.3 and 
Section 8.2.1


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Pharmacodynamics
Plasma/serum K+, Na+, uric acid, BUN, 
fasting plasma glucose, cystatin C, 
haematocrit, haemoglobin, ET-1, 
ELDP, CT-proET-1, copeptin, 
NT-proBNP, and BNP (central 
laboratory)
X
X
X
X
X
X
X
X
Results for central BNP testing must be 
reviewed within 24 hours of receipt by the 
investigator.
Section 8.2.4 and 
8.5.3.1
BNP or NT-proBNP (local laboratory)
X
Results need to be available before 
randomisation.
Section 8.2.4
Safety assessments
Adverse event review
X
SAEs 
only
X
X
X
X
X
X
X
Section 8.3
Vital signs (blood pressure, pulse, 
respiratory rate)
X
X
X
X
X
X
X
X
Vital signs at Visit 2 need to be performed 
and the results reviewed before 
randomisation in IWRS.
Section 8.2.2 and 
8.1.2.1
Digital 12-lead safety ECG
X
X
X
X
X
X
X
X
ECGs will be centrally read. ECG read out 
from Visit 2 to be reviewed by the 
investigator before randomisation as central 
report will not be available on the day.
Unscheduled ECGs may be added if 
clinically indicated.
Section 8.2.3


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Clinical chemistry and haematology 
(central laboratory)
X
X
X
X
X
X
X
X
Central laboratory results must be reviewed 
by investigator within 48 hours from receipt 
of result, and eGFR and creatinine 
calculations made, and participant 
discontinued if required.
Clinical chemistry includes creatinine and 
eGFR calculation using the CKD-EPI 
formula in both ways: based on cystatin C 
and based on creatinine.
Sections 8.1.2.2 and 
8.2.4
Urinalysis (central laboratory)
X
X
X
X
X
Section 8.2.4
HbA1c, cholesterol and lipids (central 
laboratory)
X
X
X
X
Section 8.2.4
Study intervention
Study intervention dispensed
X
X
X
X
Section 6.2, 6.3, 6.4
Study intervention account
X
X
X
X
Section 6.2, 6.4
Study intervention intake at the clinic
X
X
X
Between the clinic visits and at Visits 3, 5 
and 7, participants will take their study 
intervention at home. At Visits 4 and 6, 
study intervention will be taken in the clinic 
irrespective of participation in the PK 
sub-study.
Section 6.2, 6.3, 6.4


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Pharmacokinetics
4-hour PK blood sample profile
X
Total of 5 samples, spread over 5 time 
points: Pre-dose, 0.5-1.0 h, 1.5-2.0 h, 
2.5-3.0 h, 3.5-4.5 h post-dose.
Performed in the morning. Dose taken at 
clinic. Participants to arrive fasted at clinic 
(light breakfast provided). Participants to 
stay at clinic until last PK post-dose sample 
has been taken.
Zibotentan and dapagliflozin plasma 
concentrations will be measured separately.
If participants or investigators do not wish 
to participate in this sub-study, only one 
pre-dose sample (separate tubes for 
zibotentan and dapagliflozin) will be taken 
instead of the whole profile.
Section 8.5.1.1
Post-dose PK plasma sample for all 
participants at a convenient day, time
X
X
X
Dose at home, sampling at clinic (any day, 
time). Zibotentan and dapagliflozin plasma 
concentrations will be measured separately.
Document actual clock times of dosing at 
home and of sampling at clinic.
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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Pre-dose PK plasma sample for all 
participants
X
Perform in the first half of the day. Dose 
taken at clinic, sampling before dose.
Zibotentan and dapagliflozin plasma 
concentrations will be measured separately.
Document actual clock times of dosing and 
sampling at clinic.
Section 8.5.1
Exploratory metabolite evaluation for 
all participants
X
Pre-dose plasma sample. Dose taken at 
clinic. Samples to be sent to AstraZeneca
Gothenburg for exploratory zibotentan 
metabolite evaluation.
Section 8.5.1
Exploratory biomarkers
Collect and store serum and plasma 
samples for future exploratory 
assessment of biomarkers
X
X
X
X
X
X
Section 8.6
Collect and store urine samples for 
future exploratory assessment of 
biomarkers
X
X
X
X
X
X
Section 8.6


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Procedure
Scree
ning
Interventional period
Follow-
up
Notes
Details in CSP 
Section/Appendix
Visit
1
2
3
4
5
6
7 
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Optional genetic sample
Optional genetic sampling (blood)
X
Section 8.7
BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CKD-EPI = chronic kidney disease epidemiology collaboration; COVID-19 = coronavirus disease 
2019; CSP = Clinical Study Protocol; CT-proET-1 = C-terminal pro-endothelin-1; ECG = electrocardiogram; ECHO = echocardiogram; ED = Early 
Discontinuation; eGFR = estimated glomerular filtration rate; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; FSH = follicle stimulating hormone; 
HbA1c = glycated haemoglobin; HIV = human immunodeficiency virus; IRT = Interactive Response Technology; IWRS = interactive web response system;
K+ = potassium; LH = luteinising hormone; Na+ = sodium; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PK = pharmacokinetic; 
RTSM = Randomisation and Trial Supply Management, SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.


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2
INTRODUCTION
Zibotentan is a selective ETA receptor antagonist, originally investigated for cardiovascular 
and oncology indications. Zibotentan is currently being investigated as a treatment for CKD in 
combination with dapagliflozin.
Dapagliflozin is a highly potent, selective, and reversible inhibitor of SGLT2 that improves 
glycaemic control in patients with diabetes mellitus and provides cardiorenal benefits in 
patients with T2DM and without diabetes. Dapagliflozin is orally available and requires 
once daily dosing.
2.1
Study Rationale
Patients with CKD have limited treatment options with current SoC.
The mechanisms of action (MoA) of zibotentan and dapagliflozin are different and the 
outcome of combined treatment is expected to be synergistic, since the main biological effects 
of zibotentan are to block endothelin-1-dependent vasoconstriction and hypertension, to 
increase renal blood flow, and to reduce podocyte loss, vascular stiffness, endothelial 
dysfunction, fibrosis and inflammation; and of dapagliflozin are to inhibit SGLT2 to increase 
urinary excretion of glucose, sodium and water, to improve metabolic health, decrease 
vascular stiffness, improve endothelial function, and decrease oxidative stress and 
inflammation. Both mechanisms show efficacy in reducing albuminuria in CKD. However, 
unlocking the renal benefit of endothelin antagonists requires mitigation of their potential to 
cause fluid retention and to increase the risk of developing HF in some patients.
2.2
Background
Chronic Kidney Disease
CKD is a serious progressive condition defined by decreased kidney function (shown by 
reduced eGFR), or markers of kidney damage (eg, albuminuria), or both, for at least 3 months. 
CKD is associated with increased risk of HF (Dhingra et al, 2011), CV and all-cause death 
(Munter et al, 2002; Webster et al, 2017), therapy resistant hypertension (Tanner et al, 2013), 
and chronic fluid overload (Agarwal, 2012). Most patients with CKD stages 3-4 will die of 
CV causes rather than progress to ESKD and die of renal failure; when a patient does progress 
to ESKD, decline of kidney function has progressed to a point where dialysis or 
transplantation is required. The most common causes of CKD are diabetes (42%) and 
hypertension (17%); glomerulonephritis of varying aetiologies accounts for a further 18% of 
cases (Xie et al, 2018).
Potential for SGLT2 Inhibitors (SGLT2i) in CKD
Guidelines are starting to adopt SGLT2i as SoC. Kidney Disease Improving Global Outcomes 
guidelines will recommend SGLT2 inhibitors as SoC for patients with type 2 diabetes mellitus 


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(T2DM) and CKD (KDIGO, 2022). National Institute for Health and Care Excellence 
guidelines will recommend dapagliflozin be used as an add-on to optimised standard care 
(NICE, 2022). Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor 
blockers (ARB) have been used as SoC for decades but confer incomplete protection. 
Sodium-glucose co-transporter 2 inhibitors also slow CKD progression, in part by lowering 
intraglomerular pressure (Wanner et al, 2016). It has been postulated that the kidney 
protection and natriuretic effects induced by SGLT2i may account for the reductions in HF 
hospitalisation in the EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 studies
(Zelniker et al, 2019). Moreover, the reduction in HF hospitalisation in these studies was 
greater in patients with worse baseline renal 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 between 60 to 90 mL/min/1.73 m2 and 12% 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 study, 
dapagliflozin demonstrated a reassuring safety profile over a broad range of renal functions
(including patients with eGFR < 45 and a few < 30 mL/min/1.73 m2). Dapagliflozin was
investigated in patients with CKD in the DAPA-CKD study (NCT03036150) which 
demonstrated a 39% reduction in the primary outcome: a composite of a sustained decline in 
estimated GFR of at least 50%, end-stage kidney disease, or death from renal or 
cardiovascular causes (Heerspink et al, 2020).
Hypertension and Endothelial Dysfunction in CKD
Hypertension is common in CKD and is an independent risk factor for CKD progression: 75% 
of patients with eGFR < 30 mL/min/1.73 m2 have BP values > 140/90 mmHg
(Bakris et al, 2000). The majority of CKD patients fail to reach target BP (NICE, 2022) 
despite a predominantly antihypertensive MoA with current SoC (ACEi or ARB).
Endothelial dysfunction makes a significant contribution to cardiovascular risk in CKD 
(Linden et al, 2008) and can be linked to production of the potent vasoconstrictor endothelin-1 
(ET-1). Plasma ET-1 levels are inversely correlated with eGFR (Dhaun et al, 2015). ET-1 
signals through the ETA and ETB receptors. ETA receptor blockade lowers BP, increases renal 
perfusion, reduces intraglomerular pressure, and also has an anti-inflammatory effect in the 
kidney. ETB blockade is less desirable because this receptor has an important and beneficial 
effect in clearing circulating ET-1 via the lungs. Furthermore, preclinical and clinical data 
have identified a likely class effect of both ETA and ETB antagonists to reduce the natriuretic 
effect of ET-1 in the renal collecting duct.
Rationale for the Development of Zibotentan
Endothelin-1, an agonist of the ETA and ETB receptors synthesised by vascular endothelial 
cells, is one of the most potent vasoconstrictors in humans and can worsen renal function in 
CKD (De Miguel et al, 2016). ETA receptor antagonists have shown efficacy for urine 


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albumin to creatinine ratio reduction in patients with CKD (Heerspink et al, 2019, 
Mann et al, 2010, De Zeeuw et al, 2014). Recently, the ETA receptor antagonist atrasentan 
reported a 35% reduction in a renal composite endpoint in the SONAR trial, although the trial 
was stopped due to too few renal endpoint events (Heerspink et al, 2019). The main biological 
effects of zibotentan relevant for treatment of CKD would be to block ETA-driven 
hypertension, reduce vascular stiffness, improve renal blood flow and endothelial function, 
and decrease podocyte loss, inflammation, and fibrosis.
However, unlocking the potential of ETA receptor antagonists in the treatment of CKD 
requires mitigation of their potential sodium and fluid retention risk. The zibotentan CKD 
development programme is investigating zibotentan in combination with dapagliflozin. 
Coadministration of dapagliflozin with zibotentan is expected to mitigate zibotentan’s 
potential sodium and fluid retention due to the intrinsic diuretic and natriuretic effects of 
SGLT2 inhibition. Further, dapagliflozin and other SGLT2i have demonstrated 
nephroprotective effects (Mosenzon et al, 2019, Perkovic et al, 2019, Scholtes et al, 2020); 
SGLT2 inhibition leads to a physiological adaptation in the kidney due to altered glucose, 
sodium, and water handling, and improved metabolic flexibility, mitochondrial function, and 
overall fluid balance. The combination of zibotentan and dapagliflozin for treatment of CKD 
is expected to be additive, since their mechanisms of action are different.
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of zibotentan and 
dapagliflozin are provided in the respective Investigator’s Brochures.
2.3
Benefit/Risk Assessment
Fluid retention is believed to be a class effect of endothelin receptor antagonists that limits 
their potential use as monotherapy. Clinical data and scientific rationale support a 
zibotentan/dapagliflozin fixed dose combination (FDC) that combines 2 different and 
complementary MoAs targeting the underlining mechanisms of CKD progression. The 
potential fluid retention risk from zibotentan is believed to be mitigated by a lower dose than 
5 mg zibotentan, combined with the diuretic and natriuretic effects of dapagliflozin. The
interim analyses and frequent site visits will also mitigate the known risks of zibotentan.
An internal Unblinded Review Committee (URC) of AstraZeneca representatives is set up for 
this study for ongoing safety monitoring and reviewing the unblinded interim results. In 
addition to general safety/tolerability, the URC will focus on potential risks related to 
hypotension and hospitalisations due to HF. Changes in fluid-related measures (weight gain or 
BNP) that meet the defined threshold (Section 7.1) will be reported as an event of special 
interest.
More detailed information about the known and expected benefits and potential risks of
zibotentan and dapagliflozin may be found in the respective Investigator’s Brochures.


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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 cardiovascular outcome study DECLARE
TIMI-58 in T2DM, 8574 patients received 
dapagliflozin 10 mg and 8569 patients received 
placebo, for a median exposure time of 48 months. 
Events of DKA were reported in 27 patients in the 
dapagliflozin 10 mg group and 12 patients in the 
placebo group. The events occurred 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 clinical trials in subjects with heart failure 
(DAPA-HF) or chronic kidney disease 
(DAPA-CKD) with and without T2DM, events of 
ketoacidosis were only observed in subjects with 
T2DM. 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, events of DKA were 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 type 1 diabetes mellitus, 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 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.
Patients with T1DM are excluded 
from the study (see exclusion 
criteria #10).
DKA including euglycemic DKA 
have been reported with use of 
dapagliflozin. Consider temporary 
interrupting study treatment if DKA 
is suspected. The participant should 
be promptly evaluated.
If diabetic ketoacidosis is 
confirmed, study intervention
should be discontinued 
permanently. If diabetic 
ketoacidosis is not confirmed, 
restart of study intervention should 
be considered (see Section 7.1).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Zibotentan (in context of dapagliflozin combination treatment)
Fluid retention
Peripheral oedema has been very commonly reported in 
patients receiving zibotentan and tend to develop within a 
month of commencing the drug. Most cases are mild 
(CTC Grade 1/2) and tend to resolve with continued 
dosing.
The potential fluid retention risk 
from zibotentan will be mitigated by 
administering a dose lower than 
5 mg of zibotentan, combined with 
the diuretic and natriuretic effects of 
dapagliflozin.
Interim analyses are performed to 
assess changes in fluid-related 
measures (weight gain or BNP).
Changes in fluid-related measures 
that meet the defined threshold will 
be reported as an event of special 
interest.
Discontinuation from study 
intervention if fluid retention 
criteria are met (see criteria for 
weight or BNP in Section 7.1).
Heart failure
Endothelin receptor antagonists have the potential to 
cause fluid retention and risk of increased incidence of 
HF.
Exclusion criteria related to 
presence or risk of HF (see 
Section 5.2, exclusion criteria #3 to 
#8 and #30).
Administration of a dose lower than 
5 mg of zibotentan, combined with 
the diuretic and natriuretic effects of 
dapagliflozin.
An internal URC of AstraZeneca 
representatives is set up for this 
study for ongoing safety monitoring 
and reviewing the unblinded interim 
results. In addition to general 
safety/tolerability, the URC will 
focus on potential risks related to 
hospitalisations due to HF.
Discontinuation based on heart 
failure or the defined BNP elevation
criteria (see Section 7.1).
Hypotension
Adverse clinical effect of hypotension is largely due to 
zibotentan’s pharmacologically mediated effects of ET 
receptor antagonism resulting in vasodilation. 
Hypotension (small reductions in systolic and diastolic 
BP of approximately 5 mmHg) has been reported with 
zibotentan but this has usually been asymptomatic.
Monitoring of BP according to the 
SoA. The URC will focus on 
potential risks related to 
hypotension.
Discontinuation from study 
intervention if criteria for
symptomatic hypotension is met 
(systolic BP < 90 mmHg and/or 
diastolic BP < 60 with symptoms).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 World Health Organization declared a pandemic 
situation on 12 March 2020.
The mechanism of action of either zibotentan and/or
dapagliflozin are unlikely to impact the course of 
infection with SARS-CoV-2. Therefore, the risk to
participants of exposure to SARS-CoV-2 or of suffering
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. 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).
Exclusion of participants with 
COVID-19 infections.
Further risk mitigation measures are 
detailed in Appendix F.
BNP = B-type natriuretic peptide; BP = blood pressure; COVID -19 = corona virus disease-2019; 
CTC = Common Toxicity Criteria; DAPA-CKD = dapagliflozin chronic kidney disease; 
DAPA-HF = dapagliflozin heart failure; DKA = diabetic ketoacidosis; HF = heart failure; 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; URC = Unblinded Review 
Committee.
2.3.2 Benefit Assessment
Based on available clinical data with zibotentan and dapagliflozin, it is expected that 
participants in this study will benefit from treatment with dapagliflozin and zibotentan:
!
Recently, a member of the SGLT2i class, canagliflozin, demonstrated efficacy in patients 
with diabetic nephropathy (Perkovic et al, 2019) and received indications for reductions 
of renal outcomes in adults with T2DM and diabetic nephropathy and albuminuria. 
Nephroprotective effects were reported for dapagliflozin (Mosenzon et al, 2019, 
Scholtes et al, 2020). New clinical guidelines on the management of CKD have 
established SGLT2 inhibitors as a SoC.
!
Coadministration of dapagliflozin with zibotentan is expected to mitigate zibotentan’s 
potential sodium and fluid retention, and the combination as a treatment for CKD is 
expected to have additive nephroprotective effects, since their mechanisms of action are 
different.
2.3.3 Overall Benefit: Risk Conclusion
The overall clinical evidence suggests that the combination of zibotentan and dapagliflozin 
would have clinical benefit, and an acceptable safety profile in patients with CKD and that 


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further drug development, with appropriate risk mitigation strategies for any potential for 
excess fluid retention, is warranted.


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3
OBJECTIVES, ENDPOINTS AND ESTIMANDS
Table 3
Objectives and Endpoints
Objectives
Estimand Description/Endpoints
Primary
!
To evaluate the effect of zibotentan 
1.5 mg/dapagliflozin 10 mg versus dapagliflozin 
10 mg monotherapy on UACR.
!
Change in log-transformed UACR from 
baseline to Week 12.
The primary estimand is a hypothetical estimand such 
that the treatment effect is quantified in the optimal 
situation where any potential confounder is avoided. 
The population of interest is the Full Analysis 
population. Participants will be included in the 
analysis if they have a non-missing baseline and at
least one post-treatment visit UACR measurement.
For the intercurrent events, if a participant is lost to 
follow up, prematurely discontinues study treatment, 
or uses prohibited medication, the UACR data are 
treated as missing after the event and no imputation is 
performed. The summary measure being evaluated is 
the geometric mean reduction of UACR from 
baseline to Week 12.
Secondarya
!
To evaluate the effect of zibotentan
0.25 mg/dapagliflozin 10 mg versus
dapagliflozin 10 mg monotherapy on UACR.
!
Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the change in office systolic and 
diastolic BP for doses of zibotentan combined 
with dapagliflozin 10 mg versus dapagliflozin 
10 mg monotherapy.
!
Change in BP from baseline (Visit 2) to 
Week 12.
!
To characterise the dose-response relationship
(relationship between different doses of 
zibotentan/a fixed dose of dapagliflozin and 
UACR reduction).
!
Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the effect of different doses of 
zibotentan and dapagliflozin 10 mg in 
combination versus dapagliflozin 10 mg 
monotherapy on eGFR.
!
Change in eGFR from baseline to Week 1.
!
Change in eGFR from baseline to Week 12.
!
Change in eGFR from baseline to Week 14.
!
Change in eGFR from Week 1 to Week 12.


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Objectives
Estimand Description/Endpoints
Safety
!
To assess the safety and tolerability of all doses 
of zibotentan combined with dapagliflozin 
10 mg and dapagliflozin 10 mg monotherapy.
!
AEs/SAEs/DAEs.
!
Vital signs.
!
Clinical laboratory tests.
!
12-lead ECG assessment.
!
Event of special interest (changes in 
fluid-related measures).
Exploratory
!
To assess the pharmacokinetics of different 
doses of zibotentan and of dapagliflozin 10 mg
in plasma.
!
Plasma concentrations of zibotentan and 
dapagliflozin.
!
Exploratory analysis of zibotentan metabolites.
!
Plasma concentration of zibotentan metabolites.
Results from this analysis may not be reported in the 
CSR.
!
To assess body weight changes in response to
different doses of zibotentan and dapagliflozin
10 mg in combination versus dapagliflozin 
10 mg monotherapy.
!
Change in body weight throughout the 
interventional period.
!
To explore the relationships between zibotentan 
dose/exposure and safety/PD variables.
!
Dose/exposure of zibotentan relative to safety 
and PD variables.
Safety/PD variables include blood assessment for 
NT-proBNP, BNP, creatinine, and cystatin C, and 
urine assessment of albumin and creatinine.
Results for NT-proBNP will not be reported in the 
CSR.
!
To assess the effect of zibotentan and 
dapagliflozin in combination versus
dapagliflozin 10 mg monotherapy on 
plasma/serum K+, Na+, uric acid, BUN, fasting 
plasma glucose, haematocrit, haemoglobin, 
ET-1, ELDP, CT-proET-1, and copeptin levels.
!
Change in plasma/serum concentrations of K+, 
Na+, uric acid, BUN, fasting plasma glucose, 
haematocrit, haemoglobin, ET-1, ELDP, 
CT-proET-1, and copeptin levels over time 
during the study.
Results for ET-1, ELDP, CT-proET-1 and copeptin 
levels will not be reported in the CSR.
!
To assess the effect of zibotentan and 
dapagliflozin in combination versus 
dapagliflozin 10 mg monotherapy on 
cardiovascular biomarkers in blood.
!
Evaluation of changes in cardiovascular
biomarkers in blood over time during the study.
Results for NT-proBNP will not be reported in the 
CSR.


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Objectives
Estimand Description/Endpoints
!
To assess the effect of zibotentan and 
dapagliflozin in combination versus
dapagliflozin 10 mg monotherapy on body fluid 
volume and distribution status.
!
Evaluation of changes in body fluid volume and 
distribution over the time course of the study. 
Change in total body water, extracellular water 
and intracellular water volumes.
Results will be obtained from using bioimpedance 
spectroscopy.
!
Optional: collect and store plasma, serum, and 
urine samples for potential future exploratory 
research aimed at exploring biomarkers 
involved in PK, PD, safety and tolerability 
related to zibotentan and dapagliflozin in 
combination versus dapagliflozin monotherapy
or related to cardiorenal diseases.
!
Evaluation of changes in blood and urine 
biomarkers relevant to cardiorenal mechanisms, 
inflammation, and fibrosis over the time course 
of the study.
Results from this future analysis will not be reported 
in the CSR.
!
Optional: 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.
Results from this optional genetic research will not be 
reported in the CSR.
AE = adverse event; BNP = B-type natriuretic peptide; BP = blood pressure; BUN = blood urea nitrogen; 
CSR = Clinical Study Report; CT-proET-1 = C-terminal pro-endothelin-1; DAE = adverse event leading to the 
discontinuation of study intervention; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; K+ = potassium; Na+ = sodium; 
NT-proBNP = N-terminal pro-B-type natriuretic peptide; PD = pharmacodynamic; PK = pharmacokinetic; 
SAE = serious adverse event; UACR = urinary albumin to creatinine ratio.
a
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, multicentre, randomised, double-blind, active-controlled, parallel group 
dose-ranging study to assess the efficacy, safety and tolerability of zibotentan and 
dapagliflozin in participants with CKD with eGFR ≥20 mL/min/1.73 m2, and UACR
≥150 mg/g and ≤5000 mg/g.
The study will be conducted in approximately 220 sites in North America, South America, 
Africa, Asia/Pacific, and European countries.
Participants will be randomised to 12 weeks of treatment plus 2 weeks follow-up. All the 
variables will be collected to verify the inclusion criteria and additional demographic data 
such as race/ethnicity, serum creatinine, and height.
Participants who meet the eligibility criteria will be randomised to study treatments in addition 
to receiving background local SoC therapy. To ensure blinding to treatment and zibotentan 
dose, daily dosing will consist of one dapagliflozin tablet, containing dapagliflozin 10 mg and 
one zibotentan capsule containing zibotentan 1.5 mg, zibotentan 0.25 mg or placebo.
A total of 495 participants will be randomised into this study, including participants
randomised under the earlier study design. Four hundred and fifteen (415) participants will be 
randomised to have 166 participants in zibotentan 1.5 mg/dapagliflozin 10 mg combination 
arm and dapagliflozin 10 mg monotherapy arm, and 83 participants in the zibotentan 
0.25 mg/dapagliflozin 10 mg combination arm.
!
Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily.
!
Zibotentan 1.5 mg + Dapagliflozin 10 mg once daily.
!
Dapagliflozin 10 mg once daily.
Participants who were previously randomised cannot be re-randomised.
Participants will be stratified by diabetes (DKD versus non-DM CKD) and baseline eGFR 
(below or equal versus above 45 mL/min/1.73m2) at the time of randomisation to ensure an 
approximate balance between treatment arms within each sub-population. The number of 
randomised participants in each stratum will be monitored to ensure the non-DM CKD 
sub-population is approximately a minimum of 30% and a maximum of 50% of the total 
number of participants randomised.
A first administrative interim analysis will be performed when 50% of participants have 
completed 6 weeks of treatment. A second administrative interim analysis will be performed 


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after 100% of participants have completed the 6 weeks treatment or at a time selected by 
sponsor / percentage of participants with a planned week 6 visit before data cut selected by 
sponsor.
For each participant, the total duration of participation will be approximately 17 to 19 weeks. 
The screening period can be up to approximately 4 weeks in duration prior to randomisation. 
The first dose will be taken after randomisation at the baseline visit on Day 1. In addition to 
the baseline visit, the participant will visit the clinic 5 times during the following 12 weeks of 
treatment. Approximately 2 weeks after the last dose, the participant will visit the clinic again 
for a follow-up assessment.
4.2
Scientific Rationale for Study Design
The primary objective of this study is to evaluate the effect of zibotentan 1.5 mg and 
dapagliflozin 10 mg in combination, compared to dapagliflozin 10 mg monotherapy, on 
UACR. The secondary objectives are to determine the change in UACR for zibotentan
0.25 mg combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy, and the 
change in office systolic and diastolic BP for doses of zibotentan combined with dapagliflozin
10 mg versus dapagliflozin 10 mg monotherapy, to characterise the dose-response relationship 
of the different zibotentan/dapagliflozin doses and the UACR reduction, and to determine the 
effect of zibotentan and dapagliflozin in combination versus dapagliflozin 10 mg on eGFR.
UACR was chosen as a surrogate for renal outcomes based on the analyses presented at the 
2018 National Kidney Foundation (NKF)/FDA workshop on endpoints in CKD, which noted 
a strong and consistent relationship between change in UACR and the clinical outcome of 
kidney disease progression (Levey et al, 2020).
The study will evaluate general safety and tolerability of treatment with zibotentan and 
dapagliflozin in combination, compared with dapagliflozin monotherapy, with special focus 
on hypotension and hospitalisations due to HF. Changes in fluid-related measures (weight gain
or BNP) that meet the defined threshold (Section 7.1) will be reported as an event of special 
interest.
Exploratory objectives include assessment of PK, change in body weight, dose/exposure of
zibotentan relative to safety and PD variables, change in plasma/serum concentrations of K+, 
Na+, uric acid, BUN, fasting plasma glucose, haematocrit, haemoglobin, ET-1, ELDP, 
CT-proET-1, and copeptin levels, change in cardiovascular biomarkers in blood (NT-pro-BNP, 
BNP), and change in body fluid volume and distribution status. In addition, plasma, serum and 
urine samples will be collected and stored for potential future exploratory research aimed at 
exploring biomarkers relevant to cardiorenal mechanisms, inflammation, and fibrosis. 
Optional blood samples will be collected and stored for genetic research (according to each 
country’s local and ethical procedures).


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This study is randomised and double-blinded to prevent bias in treatment allocation and in the
subjective assessment of effect of the study intervention in the intended study population. A
randomised, blinded, multicentre, active-controlled study design is considered the best design 
to achieve the objectives of the study, from both safety and efficacy perspectives.
4.3
Justification for Dose
Zibotentan
Zibotentan doses of 0.25, 1.5, and 5 mg (hereafter referred to as low, intermediate, and high 
dose, respectively) were initially selected to characterise the dose-UACR response 
relationship for zibotentan. Predictions were made using an exposure-UACR response model 
of clinical data from other ETA receptor antagonists, taking into account differences in PK and 
potency between the different compounds. Based on this model, 5 mg zibotentan was 
predicted to achieve a maximal UACR response. In participants with severe renal impairment, 
a dose of 5 mg will result in plasma exposure similar to that of 10 mg in subjects with normal 
renal function. Since 10 mg was associated with an increased fluid retention risk in earlier 
clinical studies, 5 mg was initially selected to be the highest dose used in this study involving 
a participant population with renal impairment. Based on the rate of fluid retention observed 
in an ad hoc safety interim analysis, randomisation to 5 mg zibotentan (both monotherapy and 
in combination with dapagliflozin) has been discontinued. The zibotentan 1.5 mg dose is 
predicted to cause less fluid retention than 5 mg, while at the same time producing meaningful 
UACR response, according to the model predictions. The zibotentan 0.25 mg dose was 
selected to be a minimally clinically relevant dose because it is predicted to produce a 20% or 
less reduction in UACR in addition to that with dapagliflozin.
Dapagliflozin
Dapagliflozin 10 mg is the approved dose for T2DM, CKD, and HF. 10 mg is the dose tested 
in DAPA-CKD for patients with CKD and an eGFR > 25 mL/min/1.73m2 (NCT03036150).
Based on available preclinical and clinical data, the risk for metabolic drug-drug interactions 
between zibotentan and dapagliflozin is regarded as low.
4.4
End of Study Definition
Participants are considered to have completed the study if they have completed all phases of 
the study including the follow-up visit as shown in the SoA (Table 1).
The end of the study is defined as the date of the last visit of the last participant in the study.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and screening criteria, also known 
as protocol waivers or exemptions, is not permitted.


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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be 18 years of age or older at the time of signing the informed consent.
Type of Participant and Disease Characteristics / Laboratory Parameters
2
Diagnosis of CKD, defined as:
(a) eGFR (CKD-EPI) ≥20 mL/min/1.73 m2 (by CKD-EPI formula, see Section 8.1.2.2)
AND
(b) Urine albumin to creatinine ratio (UACR) ≥150 and ≤5000 mg albumin/g creatinine, 
based on a single first morning void spot urine sample at screening.
Medical Treatment
3
No current or prior (within 1 month of screening) medical treatment with an SGLT2i or 
any FDC with SGLT2i (such as SGLT2i + metformin).
4
If ACEi and/or ARB and/or MRA are prescribed, the dose must be stable ≥4 weeks
before screening. Participants who have been deemed unable to tolerate ACEi or ARB 
therapy due to allergy or complications can be enrolled.
5
No current or prior treatment within 6 months prior to screening with cytotoxic therapy, 
immunosuppressive therapy or other immunotherapy for primary or secondary kidney 
disease.
Weight
6
Body mass index (BMI) ≤40 kg/m2.
Sex
7
Male or female of non-childbearing potential.
Reproduction
8
Female participants must have a negative pregnancy test at screening, must not be 
lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling 
one of the following criteria:
(a) Postmenopausal defined as amenorrhoea for at least 12 months or more following 
cessation of all exogenous hormonal treatments and FSH and LH levels in the 
postmenopausal range.


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(b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy but not tubal ligation.
9
Male participants must be surgically sterile, abstinent, or in conjunction with a female 
sexual partner, using 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 
investigational product to prevent any pregnancies. Male study participants must not 
donate or bank sperm during this same time period (see Section 8.3.8.2).
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:
!
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 (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
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 
participant. 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.
Informed Consent
10 Capable of giving signed informed consent, as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
11 Provision of signed and dated, written ICF prior to any mandatory study-specific 
procedures, sampling, and analyses.


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12 Provision of signed and dated written Genetic informed consent prior to collection of 
samples (optional) for genetic analysis.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease 
requiring significant immunosuppression, autosomal dominant or autosomal recessive 
polycystic kidney disease.
2
Participants with NYHA functional HF class III or IV.
3
Acute coronary syndrome (ACS) events within 3 months prior to screening.
4
Participants with a BNP ≥200 pg/mL or NT-proBNP ≥600 pg/mL (BNP ≥400 pg/mL or 
NT-proBNP ≥1200 pg/mL, respectively, if associated with atrial fibrillation) measured 
by local laboratory at screening (Visit 1).
5
Participants with unstable HF requiring hospitalisation for optimisation of HF treatment 
and/or who have not been stable on HF therapy within 6 months prior to screening.
6
Heart failure due to cardiomyopathies that would primarily require other specific 
treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative 
diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic 
cardiomyopathy, cardiomyopathy related to toxic or infective conditions (ie,
chemotherapy, infective myocarditis, septic cardiomyopathy).
7
High output HF (eg, due to hyperthyroidism or Paget’s disease).
8
Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral 
or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
9
Participants with uncontrolled diabetes mellitus (HbA1c > 12%).
10 Participants with T1DM.
11 Hyponatremia, defined as serum Na+ < 135 mmol/L at the time of screening (Visit 1).
12 Intermittent or persistent second or third degree atrioventricular (AV) block after sinus 
node dysfunction, with clinically significant bradycardia or sinus pause when not treated 
with pacemaker.
13 Prolonged QT interval (QTcF > 470 ms) on ECG at screening (Visit 1) or randomisation 
visit (Visit 2), known congenital long QT syndrome or history of QT prolongation 
associated with other medications.
14 History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or 
uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter).


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15 Cardiac surgery or non-elective percutaneous coronary interventions (PCI/TAVI) (within 
3 months) or open chest coronary artery bypass grafting or valvular repair/replacement 
(within 3 months) prior to screening or is planned to undergo any of these procedures 
after randomisation.
16 Heart transplantation or left ventricular assist device at any time.
17 Kidney or any organ transplantation.
18 History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, 
dapagliflozin, canagliflozin, empagliflozin) or drugs with a similar chemical structure to 
zibotentan.
19 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 participant at risk because 
of participation in the study, or probable alternative primary reason for participant’s 
symptoms in judgment 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 (Hb) level < 100 g/L or 10 g/dL at screening
(Visit 1).
(c) Severe chronic obstructive pulmonary disease (COPD) or other lung disease 
including but not limited to pulmonary fibrosis requiring chronic O2 therapy, regular 
nebuliser use, or oral steroid therapy.
20 Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 
3 months prior to screening.
21 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas 
of the skin) and malignancies 5 years prior to screening.
22 Severe hepatic impairment (Child-Pugh class C Hepatic impairment), aspartate 
transaminase [AST] or alanine transaminase [ALT] > 2x the upper limit of normal 
[ULN]; or total bilirubin > 2x ULN at time of screening. An isolated increase in bilirubin 
in participants with known Gilbert’s syndrome is not a reason for exclusion.
23 Participants 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 Drug or alcohol abuse, either current or within 12 months before screening.
25 Positive hepatitis C antibody or hepatitis B virus surface antigen at screening.
26 Positive human immunodeficiency virus (HIV) test.
27 Participants treated with strong or moderate CYP3A4 inhibitor or inducer.


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28 Any condition outside the renal and CV disease area, such as but not limited to 
malignancy, with a life expectancy of less than 2 years based on investigator’s clinical 
judgment.
29 Confirmation of COVID-19 infection:
(a) Participant has a positive test result for SARS-CoV-2 during screening. Participants 
who are not hospitalised for COVID-19 infections can be re-screened 4 weeks after 
they have recovered.
(b) Participant has been previously hospitalised with COVID-19 infection.
30 Ejection fraction < 50% measured by ECHO at screening.
Prior/Concurrent Clinical Study Experience
31 Participation in another clinical study with an investigational product administered in the 
last 3 months prior to screening.
Other Exclusions
32 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
33 Judgment 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.
34 Previous randomisation into the present study.
35 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.
36 Male participant in a sexually active relation with pregnant or breastfeeding partner.
Genetic Sampling (Optional)
Participants can decline to participate in the genetic research and may still participate in the 
study. Exclusion from this optional genetic research may be for any of the exclusion criteria 
specified for the main study or any of the following:
37 Previous allogeneic bone marrow transplant.
38 Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
1
Participants will be advised to adhere to diet as per clinical recommendations by dietician.


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2
Investigational products should be taken at approximately the same time each morning
(no later than 12:00), and the time recorded by the participant in the diary (can be digital 
recording).
3
On certain days when participants will attend the study site for a study visit and 
assessments, they will be asked to not take their investigational products prior to 
attending the study visit (see Table 1). The participant will take the investigational 
product at the site, provided they are permitted to continue in the study following 
assessments.
4
On the day of the short PK profile assessments (sub-study), participants will be asked to 
come to the study site fasted and will be given a light standardised breakfast after taking 
the dose. This light meal should be approximately 350 kilocalories and should be sourced 
locally to meet cultural requirements.
5
Participants should fast prior to the collection of blood samples for HbA1c, cholesterol,
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. Still or sparkling, unflavoured water is 
allowed during this period.
5.3.2
Tobacco
Participants who use tobacco products will be instructed that use of such products may be 
restricted while they are in the clinical unit.
5.3.3
Activity
Participants should try to maintain their normal activity, including medically prescribed levels
of exercise activities during the study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
fully re-screened once. However, a second re-screening is allowed if the participant was 
excluded due to a criterion that is not applicable any more in the current protocol version or if 
the participant was a screen failure due to the recruitment halt based on recommendation of 
the AstraZeneca URC. No more than two re-screenings are allowed for any participant. 
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number as for the initial screening.
Where the values for the following investigations are outside the usual range for a participant 
during screening, based on their medical history, re-testing may be undertaken on 
one occasion without requiring a re-screen: blood pressure, eGFR, spot urine for ACR, ALT, 
AST, bilirubin, and serum sodium.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to, or medical device(s) utilised by, a study participant 
according to the study protocol.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Participants who meet the eligibility criteria will be randomised to either of the following 
treatments, in addition to receiving background local SoC therapy:
!
Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily.
!
Zibotentan 1.5 mg + Dapagliflozin 10 mg once daily.
!
Dapagliflozin 10 mg once daily.
To ensure blinding to treatment and zibotentan dose, daily dosing will consist of one
dapagliflozin tablet, containing dapagliflozin 10 mg and one zibotentan capsule containing 
zibotentan 1.5 mg, zibotentan 0.25 mg or placebo.
Table 4
Investigational Products
Intervention Name
Zibotentan
1.5 mg/placebo
Zibotentan
0.25 mg/placebo
Dapagliflozin
10 mg
Type
Drug/placebo
Drug/placebo
Drug
Dose Formulation
Capsule
Capsule
 tablet
Excipients
Contains gelatin with ingredients coming from pigs 
and cows in quantities that adhere to regulatory 
requirements.
Contains lactose, in 
quantities not likely to 
cause discomfort in 
lactose-intolerant 
individuals.
Unit Dose Strength(s)
1.5 mg/NA
0.25 mg/NA
10 mg
Dosage Level(s)
1.5 mg:
1 zibotentan capsule
0.25 mg: 
1 zibotentan capsule
10 mg: 1 dapagliflozin 
tablet
Placebo: 
1 placebo capsule
CCI


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Intervention Name
Zibotentan
1.5 mg/placebo
Zibotentan
0.25 mg/placebo
Dapagliflozin
10 mg
Route of 
Administration
Oral
Oral
Oral
Use
Experimental
Experimental
Experimental
IMP and NIMP
IMP
IMP
IMP
Sourcing
Zibotentan, dapagliflozin, and matching placebo treatments will be supplied 
centrally through AstraZeneca.
Packaging and 
Labelling
For each strength, zibotentan and matching placebo 
will be provided in bottles containing 28 capsules.
Dapagliflozin will be 
supplied in HDPE bottles 
containing 28 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; NA = not applicable; NIMP = non investigational medicinal product.
6.1.2
Medical Devices
1)
No AstraZeneca manufactured medical devices (or medical devices manufactured for 
AstraZeneca by a third party) are provided for use in this study.
2)
Other medical devices (not manufactured by or for AstraZeneca) provided for use in this 
study are:
(a) Home-based body weight digital scales.
(b) Bioimpedance spectroscopy (BIS).
(c) Hand-held electronic diary (eTablet).
3)
Instructions for medical device used by the participants are provided to each participant.
All devices provided for the study will be returned by the participant on or before the 
final safety follow-up visit.
4)
All medical device deficiencies (including malfunction, use error and inadequate 
labelling) shall be documented and reported by the investigator throughout the clinical 
investigation and appropriately managed by the sponsor.
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 manufacturers medical device complaint 
report will be used to collect the deficiency.


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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 having signed the ICF for 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 Intervention Handling Instructions.
6.3
Measures to Minimise Bias: Randomisation and Blinding
All participants will be centrally assigned to randomised, blinded study intervention using an 
Interactive Response Technology/Randomisation and Trial Supply Management (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.
Participants will be stratified by diabetes (DKD versus non-DM CKD) and baseline eGFR 
(below or equal versus above 45 mL/min/1.73m2) at the time of randomisation to ensure an 
approximate balance between treatment arms within each sub-population.
!
Stratum 1: DKD participants with eGFR ≤45 mL/min/1.73m2.
!
Stratum 2: DKD participants with eGFR > 45 mL/min/1.73m2.
!
Stratum 3: non-DM CKD participants with eGFR ≤ 45 mL/min/1.73m2.
!
Stratum 4: non-DM CKD participants with eGFR > 45 mL/min/1.73m2.
The number of randomised participants in each stratum will be monitored to ensure that the 
non-DM CKD sub-population is approximately 30 to 50% of the total number of participants 
randomised in the study.
Study intervention will be dispensed at the study visits summarised in the SoA (Table 1).
Returned study intervention should not be re-dispensed to the participants.
The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number 
to be allocated to the participant at the dispensing visit.


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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.
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 following personnel will be unblinded as to the exact content of investigational treatments
(ie, the randomisation code):
!
Personnel carrying out the packaging and labelling of investigational treatment.
!
Personnel generating the randomisation list.
!
Personnel analysing the pharmacokinetic samples.
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention 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.
Unblinded Study Data
Unblinded study data will be reported to the AstraZeneca internal URC for assessment at each 
of the interim analyses. These data will be clearly defined in the URC charter for individual 
analysis parameters but will include unblinded PK data on each occasion.
Unblinded study data may also be reported to the URC for emergent safety issues. The 
information provided will be pertinent to the safety concern being reviewed (eg, change in 
fluid-related measures for fluid retention events).
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screened. Access to unblinded study data by individual roles will be defined in the URC 
charter and these roles will not take part in blinded data decisions.
6.4
Study Intervention Compliance
Participants will take treatment at the clinic on indicated visit days and at home on all other 
occasions.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time of dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
When participants self-administer study interventions at home, compliance with study 
intervention will be assessed at each visit. Diaries will be given to the participants at the 
randomisation visit and the participants will be asked to fill in the dose intake information 
(date and time) at home (can be digital recording). The diaries 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 zibotentan/placebo
capsules and dapagliflozin tablets 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.
A record of the number of zibotentan/placebo capsules and dapagliflozin tablets 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 
and/or dose reductions will also 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 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.
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.


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6.5.1
Prohibited Concomitant Medications
The medications and supplements listed below are prohibited from the time of consent and for 
the duration of the study. Participants taking any of these medications at the time of 
randomisation cannot be included into the study:
!
SGLT2i.
!
Direct renin inhibitor (eg, Aliskiren).
!
Cyclosporin or tacrolimus.
!
Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for 
primary or secondary renal disease within 6 months prior to screening.
In addition to the above, the following medications cannot be initiated or any changes to dose 
made after the participant has consented, and until the participant has completed the study (or 
discontinued / withdrawn participation):
!
ACEi.
!
ARB.
!
ARNi.
!
MRA.
6.5.2
Medications Inducing Hypoglycaemia
Participants using medications that can cause hypoglycaemia in T2DM patients, including 
insulin or sulfonylurea (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.
6.5.3
Background Standard of Care Therapy
Prescribed SoC treatment for CKD (eg, ACEi and/or ARB) should be stable for at least 
4 weeks prior to screening (see inclusion criterion #4) and remain stable during the study.
It is preferable that any background medical therapy (eg, antidiabetic or antihypertensive 
therapy [including diuretics] or therapy with statins) does not change during study 
intervention; ie, between the screening visit and the last dose of investigational product. 
However, if this is necessary, the participant does not need to be withdrawn from study 
intervention.
6.5.4 Rescue Medicine
If a participant’s medical condition requires rescue therapy, the participant should be treated,


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and withdrawn from investigational product administration at the investigator’s discretion. 
Rescue therapy should be recorded in the eCRF.
Diabetic participants may require adjustment of their other glucose-lowering treatments on 
commencing blinded investigational product (due to the potential of dapagliflozin treatment) 
to avoid hypoglycaemia as described in Section 6.5.2.
6.6
Dose Modification
No dose modifications are permitted during the study due to its short duration. However, 
investigational product dose(s) may be withheld if clinically necessary. In the case of a 
delayed or missed dose for any reason, subsequent doses should be administered according to 
the original schedule (ie, at the planned time point relative to the first dose of investigational 
product).
6.7
Intervention After the End of the Study
After the end of the study (safety follow-up visit), participants will no longer receive 
zibotentan and/or dapagliflozin.
Participants should maintain their other prescribed treatments at the discretion of the 
investigator.
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.
An individual participant 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.


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An individual participant will be discontinued from study intervention in the following 
situations:
!
If BNP is increased > 100% from baseline AND is greater than 200 pg/mL; or if BNP is 
increased > 100% from baseline AND is greater than 400 pg/mL in a participant with 
atrial fibrillation.
!
If the participant or male participant’s partner becomes pregnant during the course of the 
study, investigational products should be discontinued immediately, and an AZ 
representative notified.
!
Diabetic ketoacidosis: DKA including euglycemic DKA have been reported with use of 
dapagliflozin. Consider temporary interrupting study treatment if DKA is suspected. The 
participant should be promptly evaluated. If diabetic ketoacidosis is confirmed, 
investigational product(s) should be discontinued permanently. If diabetic ketoacidosis is 
not confirmed, restart of study intervention should be considered (see Section 7.1.1 for 
details).
!
Symptomatic hypotension (defined as systolic BP < 90 mmHg OR diastolic 
BP < 60 mmHg with symptoms).
!
eGFR reduction: investigational study products must be discontinued in case of 
confirmed eGFR reduction from baseline >50% and/or any confirmed decrease below 
15 mL/min/1.73m2.
If an unexpected, acute decline in kidney function is observed, the participant should be 
promptly evaluated. Volume depletion, hypotension, intercurrent medical problems 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 non-steroidal anti-inflammatory drugs and certain antibiotics such as 
trimethoprim. If any drug is suspected of causing or contributing to worsening kidney 
function, their use should be reconsidered.
!
More than 3% increase in weight (at least 2.5% must be from total body water as 
measured by bioimpedance) from start of treatment (Day 1).
!
Heart failure.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
If study interventions are permanently discontinued, the participant will continue with the 
study visits and complete further evaluations as per the SoA (Table 1).
7.1.1
Ketoacidosis in Participants with T2DM
Pre-disposing factors to ketoacidosis include a low beta-cell function reserve resulting from 


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pancreatic disorders (eg, type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin 
dose reduction, reduced caloric intake or increased insulin requirements due to infections, 
illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in these 
participants.
Participants treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath 
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L 
(250 mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of study 
treatment should be considered, and the participant should be promptly evaluated.
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 Early Discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study withdrawal and follow-up and for any further evaluations that need to be 
completed.
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
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 
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:


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!
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.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timings are summarised in the SoA. Protocol waivers or 
exemptions are not allowed.
!
Emerging 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, blood 
count) and obtained before signing of the ICF may be utilised for screening 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 an individual participant over the duration 
of the study, including any PK assessments that may be required, will not exceed 500 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.


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8.1
Efficacy Assessments
8.1.1
Primary/Secondary Variable: Urinary Albumin to Creatinine Ratio 
(UACR)
The UACR is a key marker for assessing kidney function. The UACR is a ratio between 
2 measured substances (urine albumin and creatinine), which estimates 24-hour urine albumin 
excretion.
The UACR is calculated as follows:
!
UACR (mg/g) = urine albumin (mg/dL) / urine creatinine (g/dL)
Urine samples for the determination of albumin and creatinine levels and calculation of 
UACR will be collected at the time points described in the SoA (Table 1):
!
At screening, containers to collect the urine samples will be dispensed to the participants. 
A spot urine from first morning void will be collected the next day and analysed centrally.
!
For subsequent visits, containers to collect the urine samples will be dispensed to the 
participants. Participants will collect first morning void urine samples at home on 
3 consecutive days (ideally day of visit and preceding 2 days [refrigerated overnight] 
which will be returned on the day of visit). Samples will be analysed centrally.
Note: The samples collected on visit days will also be used for the determination of 
exploratory urinary parameters (see Section 8.5.3.1).
!
At each visit (except for screening), the geometric mean of the triplicate UACRs will be 
computed and used for all analysis of UACR.
8.1.2
Other Secondary Variables
8.1.2.1
Office/Clinic Blood Pressure Measurement
Blood pressure measurements for participants who receive dapagliflozin monotherapy or 
different doses of zibotentan combined with dapagliflozin 10 mg will be done during clinic 
visits at the time points for vital signs indicated in the SoA (Table 1 and Section 8.2.2).
8.1.2.2
Serum Analysis of Creatinine and Cystatin C (eGFR)
Estimated GFR is another measure that is considered as a standard for assessment of kidney 
function. Estimated GFR is calculated based on serum creatinine values using the widely 
validated and accepted CKD-EPI equation. Blood samples for estimation of serum creatinine 
(clinical chemistry) are collected at various time points during the course of the study as 
shown in the SoA (Table 1).


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Estimated GFR, using serum creatinine, is calculated as follows:
!
eGFR (mL/min/1.73 m²) = 141 × min (SCr/κ,1) α × max (SCr/κ,1)-0.209 × 0.993 Age × 
(1.018 if female) × (1.159 if Black)
Where SCr = serum creatinine (in mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 
for females and -0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates 
the maximum of SCr/κ or 1.
Alternatively, serum cystatin C provides GFR estimates that are nearly as accurate as serum 
creatinine adjusted for age, sex, and race thus providing an alternative GFR estimate that is 
not linked to muscle mass (Scholtes et al, 2020, Stevens et al, 2008). Blood samples will be 
collected for measurement of cystatin C, at specified time points in the SoA (Table 1).
Estimated GFR, using cystatin C, is calculated as follows:
!
eGFR = 133 x min(Scys/0.8, 1)-0.499 x max (Scys/0.8, 1)-1.328 x 0.996Age x 0.932 [if female]
Where Scys is standardised serum cystatin C (in mg/L), min indicates the minimum of Scys/0.8 
or 1, max indicates the maximum of Scys/0.8 or 1, and age = years.
Estimated GFR calculations using the CKD-EPI formulae (in both ways, based on cystatin C 
and based on creatinine) will be performed by the central laboratory.
8.1.3
Exploratory Variables
8.1.3.1
Electronic Scale Measurement of Body Weight
Home-based body weight monitoring will be performed each morning using the provided
digital scales from 2 days before randomisation to end of follow-up (Visit 8) (Table 1 and 
Section 6.1.2) (also refer to Section 8.2.1).
8.1.3.2
Bioimpedance Spectroscopy
Bioimpedance spectroscopy (BIS) will be performed at the site at the time points specified in 
the SoA to monitor body fluid volumes (Table 1).
This non-invasive procedure uses skin electrodes to pass a low-level alternating current 
through the body and measures the impedance to the flow of this current. Tissues such as fat 
and bone act as insulators; whereas, electrolyte body fluids conduct electrical current and as 
the fluid increases, impedance to current flow decreases (ie, changes in impedance are 
inversely proportional to the volume of the extracellular fluid in the body). At low 
frequencies, cell membranes are non-conductive and current passes only through the 
extracellular fluid, while at high frequencies, the current passes through cell membranes in 
addition to the extra-and intracellular fluids.


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8.1.3.3
Echocardiography Assessment of Cardiac Structure and Function
An assessment of cardiac structure and function using echocardiography will be performed 
during the Screening period and at Week 12. The examination is non-invasive and prior 
preparation is not required.
The following parameters will be assessed:
!
The LVEF threshold for inclusion ≥50% with no evidence of significant ventricular wall 
motion abnormality or severe cardiac valve abnormalities.
The echocardiography data will be analysed by a blinded central reader.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Physical Examinations
Physical examination, and measurement of weight and height will be conducted at the time 
points 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 include: assessments of general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) and 
neurological systems and an assessment of the presence and extent of peripheral 
(ankle/leg) oedema.
!
A brief physical examination will include: assessment of skin (colour, turgor), lungs 
(breathing rate and breath sounds), cardiovascular system (HR, JVP, sounds), and 
abdomen (liver and spleen to detect any increase) in addition to vital signs, 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.
Body weight will be monitored at home using an electronic scale measurement throughout the 
interventional period as detailed in Section 8.1.3 at the times outlined in the SoA.
8.2.2
Vital Signs
Vital signs will include resting BP, pulse, and respiratory rate measurements.


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Routine BP, pulse, and respiratory rate will be assessed at the study site, as outlined in the 
SoA, prior to blood collection for laboratory tests with the participant resting in a supine 
position using a completely automated device. Manual techniques will be used only if an 
automated device is not available.
Vital sign measurements should be preceded by at least 5 minutes of rest for the participant in 
a quiet setting without distractions (eg, television, cell phones) and will consist of 1 pulse, 
1 respiratory rate, 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.
There will be real-time safety monitoring of body weight online data from home monitoring 
devices by the study physician. The study physician will alert the respective investigator if any 
significant weight gain is seen. The investigator will also have direct access to the online data 
for their participants.
The investigator will contact the participant immediately and arrange a clinic visit to assess 
health status.
Participants will also be advised to self-monitor and contact the investigator with any 
concerns.
8.2.3
Electrocardiograms
Triplicate 12-lead ECGs will be performed after the participant has been resting in a supine 
position for at least 10 minutes, at the visits outlined in the SoA (Table 1). Three individual 
ECGs will be recorded per time point, 1 minute apart or maximum within 2 minutes from the 
previous measurement. The mean value of the 3 measurements will be used will be used (eg, 
QTcF interval requirement will be the mean of the three ECGs).
Digital ECGs performed at site will be transferred to, centrally read, and stored by ERT. A 
digital ECG machine that automatically calculates the heart rate and measures PR, RR, QRS, 
QT, and QTcF intervals will be used. Interpretation of the clinical safety digital ECG findings 
will be reviewed and confirmed by the investigator and recorded in the eCRF.
Investigators will assess participants’ eligibility according to the Screening ECG report 
(Visit 1) but also be vigilant for any abnormal findings at the randomisation clinic visit 
(Visit 2), prior to the centrally read report being available. Abnormal ECG findings will be 
evaluated by the investigator and the participant screen failed if required.
Throughout the study, clinically relevant new findings or worsening of a pre-existing finding 


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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 (Table 1).
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 central laboratory. 
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site.
In addition, samples will also be collected for analysis of the following parameters:
!
Screening samples for parameters needed to confirm eligibility:
∀
For women only: FSH, LH, and serum pregnancy test.
∀
Local test for SARS-CoV-2.
∀
Serology test for HIV I and II, Hepatitis B surface antigen, Hepatitis C virus 
antibody.
∀
Local laboratory BNP or NT-proBNP.
!
Samples for the determination of cystatin C by a central laboratory at the visits indicated 
in the SoA.
Laboratory variables will be measured as indicated in Table 5.
Table 5
Laboratory Safety Variables
Haematology/Haemostasis (whole blood) a
Clinical Chemistry (serum or plasma) a
White blood cell (WBC) count
Serum sodium (Na+)
Red blood cell (RBC) count
Serum potassium (K+)
Haemoglobin (Hb)
Serum urea
Haematocrit
Blood urea nitrogen (BUN)
Neutrophils absolute count
Serum creatinine
Lymphocytes absolute count
Estimated glomerular filtration rate (eGFR), 
calculated by CKD-EPI formula b


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Monocytes absolute count
Uric acid
Eosinophils absolute count
Albumin
Basophils absolute count
Calcium
Platelets
Phosphate
International normalised ratio (INR)
Alkaline phosphatase (ALP)
Urinalysis
Alanine aminotransferase (ALT)
Glucose
Aspartate aminotransferase (AST)
Erythrocytes
Total bilirubin (TBL)
Protein
Creatine kinase (CK)
Albumin
Chloride (Cl-)
Creatinine
Magnesium (Mg+)
Glucose (fasting, see Section 5.3.1)
HbA1c (fasting, see Section 5.3.1)
Cholesterol and lipids (fasting, see Section 5.3.1)
Serology (serum or plasma), at screening a
Other assessments a
Hepatitis B virus surface antigen
Cystatin C (serum)
Hepatitis C antibodies
Test for SARS-CoV-2 (at screening) c
Human immunodeficiency virus (HIV)
Follicle stimulating hormone (FSH) and luteinising 
hormone (LH) (women only, at screening)
Serum pregnancy test (women only, at screening)
NB. In case a participant shows an AST or ALT ≥3 × ULN together with total bilirubin 
≥2 × ULN please refer to Appendix E - Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law - for further instructions.
a
Central laboratory for all visits.
b
eGFR will be calculated by the central laboratory analysing the sample, using the CKD-EPI formulae in 
both ways, based on cystatin C and based on creatinine.
c
Any SARS-CoV-2 test except for antibody tests will be acceptable.
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 principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative).


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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 after the participant has received the first dose of study 
intervention throughout the interventional period and including the follow-up period (Visit 8).
SAEs will be recorded from the time of signing of the informed consent form.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product 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 
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).
!
The 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 SAE.
!
Date investigator became aware of SAE.
!
AE is serious due to.
!
Date of hospitalisation.


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!
Date of discharge.
!
Probable cause of death.
!
Date of death.
!
Autopsy performed.
!
Causality assessment in relation to study procedure(s).
!
Causality assessment to other medication.
8.3.3 Causality Collection
The investigator should assess causal relationship between investigational product 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 products?’
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’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
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 CSP-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 intervention, eg,
dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 


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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 unless 
unequivocally related to the disease under study.
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.
If any SAE occurs in the course of the study, investigators or other site personnel will 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 will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one 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 will be undertaken immediately. Investigators or other site personnel will 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.


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For further guidance on the definition of a SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for both 
AstraZeneca investigational products.
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 intervention.
8.3.8.1
Maternal Exposure
Zibotentan, in common with other ET antagonists, has been demonstrated to induce 
teratogenic effects in animals. Pregnant or breastfeeding women must not receive the 
compound. To prevent potential exposure via semen, men receiving zibotentan who are 
sexually active with a woman of childbearing potential should employ the use of condoms 
together with other highly effective methods of contraception.
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.
Women of childbearing potential will not be included in this study (for definition see inclusion 
criteria, Section 5.1). Should a pregnancy still occur, the investigational product 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 abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in 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 (Initial Fatal/Life-Threatening or follow up Fatal/Life-Threatening) or 5 (other serious 
initial and follow up) calendar days for SAEs (see Section 8.3.7) and within 30 days for all 


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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 paper-based
PREGOUT module 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 investigational product.
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 investigational product administration until 3 months after 
the last dose of investigational product. In addition, male participants should use a condom for 
the duration of the study and for 3 months after the last dose of study intervention.
See Section 5.1 for methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly, and are considered highly effective birth control methods:
Male participants should not donate or bank sperm for the duration of the study and for at least 
3 months after the study follow-up visit.
Male participants will be instructed that if they father a pregnancy during the study, this 
should be reported to the investigator and the study intervention should be discontinued. If the 
male participant fathers a pregnancy within 3 months after last dose of the study intervention, 
it should also be reported to the investigator. 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.
A pregnancy notification form and follow-up will be completed.
8.3.9
Medication Error
If a medication error occurs in 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 


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SAE associated with the medication error (see Section 8.3.7) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 4.
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 zibotentan in humans. For the 
purposes of this study, an overdose will be defined as the use of investigational product in 
doses in excess of that specified in the protocol.
!
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 intervention occurs in 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 (Initial Fatal/Life-Threatening or follow up Fatal/Life-Threatening) or 5 (other serious 
initial and follow up) 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 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples 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.


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!
Pharmacokinetic 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 PK 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
Plasma samples will be collected for measurement of plasma concentrations of zibotentan and 
dapagliflozin, and exploratory zibotentan metabolite evaluation, as specified in the SoA
(Table 1; also Section 8.5.1.2).
Samples may be collected at additional time points 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 (eg, to obtain data closer to the time of peak or 
trough matrix concentrations) to ensure appropriate monitoring.
Backup PK samples may be used to evaluate safety or efficacy aspects during or after the 
study.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.1.1
PK Sub-Study
A sub-group of at least 20% of the overall study population will have 4 PK samples taken in 
addition to the pre-dose sample, spread over 4 different time points (0.5-1.0 h, 1.5-2.0 h, 
2.5-3.0 h and 3.5-4.5 h post-dose). Zibotentan and dapagliflozin concentrations will be 
measured separately. As indicated in the SoA (Table 1), the additional samples will be taken at 
Visit 4. Participants will be asked to come to the site in the morning and fasted. They will be
given a light standardised breakfast after taking the dose. Participants need to stay in the clinic 
until the last PK post-dose sample has been taken for measurement of zibotentan and 
dapagliflozin plasma concentrations.
The sub-study will be performed in all participants that agree to it, if the site investigators 
deem it feasible. When the target of evaluable PK profiles in at least 20% of the study 
population has been reached, or if recruitment is deemed too slow, the sites may be notified 
that further inclusions are not necessary. While participants are encouraged to take part in the 
PK sub-study, hesitation to take part should never be a hindrance to recruiting of the overall 
study. If participants or investigators choose not to take part in the PK sub-study or when the 
target number of samples has been reached, a single pre-dose PK sample will be taken instead 
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8.5.1.2
Determination of Drug Concentration
Samples for determination of zibotentan and dapagliflozin concentrations in plasma will be 
assayed by Labcorp Bioanalytical Services LLC on behalf of AstraZeneca, using appropriately 
validated bioanalytical methods. Zibotentan and dapagliflozin plasma concentrations will be 
measured separately. Full details of the analytical methods used will be described in a separate 
Bioanalytical Report.
Samples for zibotentan metabolite evaluation will be analysed by AstraZeneca. Results from 
this analysis may not be reported in the CSR.
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, if any, will be performed alongside the bioanalysis 
of the test samples. The results from this evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Immunogenicity analysis will not be done in this study.
8.5.3
Pharmacodynamics
Urinary and serum/plasma parameters will be measured during the study for the evaluation of 
the exploratory endpoints.
The following parameters will be measured from the blood samples collected for safety (from 
Visit 2 to 8) (analysed at a central laboratory) (see Section 8.2.4):
!
Plasma/serum K+, Na+, uric acid, BUN, and fasting plasma glucose as part of clinical 
chemistry.
!
Haematocrit and haemoglobin, as part of haematology.
8.5.3.1
Collection of Samples
Urine Samples
Urine samples will be collected and analysed by a central laboratory for the determination of 
the exploratory urinary parameters at the time points 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 they can also be used for the determination of Na+, K+, uric acid, urea, glucose, 
creatinine, osmolality and cortisol levels.
Results for urine cortisol will not be reported in the CSR.


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Blood Samples
Blood samples will be collected at the time points specified in the SoA and analysed by a 
central or local laboratory for the determination of the following parameters:
Central laboratory:
!
Cystatin C, ET-1, ELDP, CT-proET-1, copeptin, NT-proBNP, and BNP.
!
Fasting plasma glucose (for fasting conditions, see Section 5.3.1).
Local laboratory:
!
BNP or NT-proBNP.
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.
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. However, biomarker samples collected for future analyses are seen 
as optional; participants are able to participate in the study even if they do not consent to the 
purpose of collection for the below samples:
!
Plasma or serum sample collection for future analysis to assess the effect of zibotentan 
and dapagliflozin in combination versus dapagliflozin monotherapy on cardiovascular 
biomarkers in blood by a central laboratory.
!
Plasma, serum, and urine samples for future analysis aimed at exploring biomarkers 
involved in PK, PD, safety, and tolerability related to zibotentan and dapagliflozin in 
combination versus dapagliflozin monotherapy or related to cardiorenal diseases by a 
central laboratory.
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 agreement in the participant’s Informed Consent Form.
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 


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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
Health Economics OR Medical Resource Utilisation and Health 
Economics (Not Applicable)
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary hypothesis for this study is that zibotentan 1.5 mg and dapagliflozin 10 mg in 
combination will reduce UACR compared with dapagliflozin 10 mg monotherapy.
The secondary hypothesis for this study is that zibotentan 0.25 mg combined with 
dapagliflozin 10 mg will reduce UACR compared with dapagliflozin 10 mg monotherapy.
Dose-response for the reduction in UACR, as a function of the zibotentan dose, as combined 
with dapagliflozin, will be evaluated.
9.2
Sample Size Determination
With a 1-sided type I error rate of 5%, 150 evaluable participants in the zibotentan 1.5 mg and 
dapagliflozin 10 mg arm and dapagliflozin 10 mg monotherapy arm will have approximately 
% power to detect a dapagliflozin-corrected UACR reduction of 
% or more assuming a 
SD of 
 on the natural log-scale. In the DKD sub-population (which will be about 70% of 
the total population), the power to detect the same reduction is estimated to be 
%.
For the dose-response models, the sample size below will have at least 
% power across 
multiple dose-response models to detect dose-response significance. This assumes a 1-sided 
type I error of 5% and a maximum UACR reduction of 
% for the zibotentan 1.5 mg and 
dapagliflozin 10 mg combination arm relative to dapagliflozin 10 mg.
!
Zibotentan/Dapagliflozin dose = 0/10 mg: n = 150.
!
Zibotentan/Dapagliflozin dose = 0.25/10 mg: n = 77.
!
Zibotentan/Dapagliflozin dose = 1.5 mg/10 mg: n = 150.
A total of 495 participants will be randomised into this study, including participants 
randomised under the earlier design. Four hundred and fifteen (415) participants will be 
randomised to have 166 participants in the zibotentan 1.5 mg/dapagliflozin 10 mg 
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combination arm and dapagliflozin 10 mg monotherapy arm, and 83 participants in the 
zibotentan 0.25 mg/dapagliflozin 10 mg combination arm. 
A participant is considered to be evaluable if the participant received at least one dose of study 
intervention, has baseline UACR, and at least one post-treatment UACR result available.
9.3
Populations for Analyses
The following populations are defined:
Table 6
Populations for Analysis
Population/Analysis set
Description
Screened
All participants who signed the ICF.
Full Analysis Set (FAS)
All participants who are randomised and 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 Analysis Set
(PPS)
A subset of the FAS consisting of all participants who completed at least 
6 weeks of treatment and 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 Analysis Set (SAS)
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 the treated dose, not 
the randomisation dose. If a participant received investigational product
from the wrong kit for only part of the treatment duration, they will be 
analysed according to their randomisation dose.
The SAS will be used for all safety analyses.
Ambulatory Blood Pressure 
Monitoring population
All participants in the FAS who have valid ambulatory BP data for change 
from baseline analyses.
Pharmacokinetic Analysis Set
All participants in the FAS who have at least one detectable zibotentan or 
dapagliflozin plasma concentration measurement post-treatment.
The Pharmacokinetic Analysis Set will be used for all PK analyses.
Additional analysis sets may be defined in the Statistical Analysis Plan (SAP) for exploratory 
analyses. Participants or sites identified prior to database lock with major GCP violations and 
where the integrity of the data is strongly questioned through thorough independent 
investigations will be excluded from all analyses and all analysis sets.
9.4
Statistical Analyses
The SAP will be finalised prior to first participant in, and it will include a more technical and 


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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 arm 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 
summaries will be provided by time point of assessment, as appropriate.
When change from baseline is described, the baseline value will be, in general, the last 
non-missing value prior to or on the same date as administration of the first dose. Further 
details will be described in the SAP.
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 with a hypothetical
estimand. In addition, the primary efficacy endpoint will also be analysed using the PPS, and a 
treatment policy estimand as sensitivity analyses.
9.4.2.1
Primary Endpoint
The primary efficacy endpoint for this study is the change in log-transformed UACR from 
baseline to Week 12 for zibotentan 1.5 mg combined with dapagliflozin 10 mg versus 


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dapagliflozin 10 mg.
For the intercurrent events, if a participant is lost to follow-up, prematurely discontinues study 
treatment, or uses prohibited medication, the UACR data are treated as missing after the event 
and no imputation is performed.
UACR will be log-transformed and analysed using a mixed model repeated measures
(MMRM) method. The values will be back transformed onto the original scale to give the 
geometric mean relative change from baseline to Week 12. The analysis model will include 
the fixed categorical effects of stratification factor, CSP version (Amendment 2 versus pre-
Amendment 2), treatment, visit, and treatment-by-visit interaction, plus the continuous 
covariates of baseline log (UACR) and baseline log(UACR)-by-visit interaction. An 
unstructured covariance structure will be used for the within-participant errors.
9.4.2.2
Secondary Endpoints
The change in UACR for zibotentan 0.25 mg combined with dapagliflozin 10 mg versus 
dapagliflozin 10 mg monotherapy from baseline (Visit 2) to Week 12 (Visit 7) will be 
assessed. A MMRM model similar to that described for the primary endpoint will be fitted.
The dose-response relationship between different doses of zibotentan/a fixed dose of 
dapagliflozin and UACR reduction will be characterised by assessing the UACR reduction 
analysed in primary and first secondary objective.
The change from baseline (Visit 2) to Week 12 (Visit 7) in office systolic and diastolic BP will 
be assessed for doses of zibotentan combined with dapagliflozin 10 mg compared to
dapagliflozin 10 mg monotherapy.
The effect of different doses of zibotentan and dapagliflozin in combination on eGFR will be 
determined from the change in eGFR from baseline to Week 1, Week 12, and Week 14, and 
from Week 1 to Week 12.
These secondary variables of BP and eGFR will be analysed using ANCOVA, adjusting for 
stratification factors, treatment arm, and baseline. The FAS will be used for these analyses. 
More details will be provided in the SAP.


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9.4.2.3
Exploratory Endpoints
The following exploratory endpoints will be summarised by treatment arm based on the FAS:
!
Body weight changes in response to different doses of zibotentan and dapagliflozin in 
combination versus dapagliflozin 10 mg monotherapy, throughout the interventional
period.
!
Evaluation of changes in body fluid volume and distribution over time during the study. 
Change in total body water, extracellular water, and intracellular water volumes will be 
analysed.
9.4.3
Safety
Safety analyses will be performed using the SAS. 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 or on 
the same date as administration of the first dose of investigational products. Details are 
described in the SAP.
9.4.3.1
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.
Adverse events will be presented for each treatment arm by system organ class (SOC) and/or 
PT covering number and percentage of participants reporting at least 1 event and number of 
events, where appropriate.
Adverse events will be presented in summary tables. Serious AEs occurring prior to start of 
study intervention will be included in data listings.
An overview of AEs will be presented for each treatment arm; the number and percentage of 
participants with any AE, AEs with outcome of death, SAEs, AEs leading to discontinuation 
of investigational product, AEs leading to investigational product 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 taking into consideration relationship as assessed by the 
investigator, maximum intensity, seriousness, death, and AEs leading to discontinuation of 
investigational product as well as action taken with respect to the investigational product, 
other significant AEs, and timing of events.
An additional table will present number and percentage of participants with most common 


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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 participants in any treatment arm.
Key participant information will be presented for participants with AEs with outcome of 
death, SAEs, and AEs leading to discontinuation of investigational product.
An AE listing for the SAS will cover details for each individual AE; an AE listing for 
participants who were not exposed to investigational product is presented separately.
Full details of AE analyses will be provided in the SAP.
9.4.3.2
Vital Signs
Vital sign parameters (office/clinic BP, pulse, and respiratory rate) will be presented for each 
treatment arm. Summary statistics for continuous variables will 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.
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.
9.4.3.3
Laboratory Assessments
Laboratory parameters will be presented for each treatment arm. Summary statistics for 
continuous variables will cover n, mean, SD, minimum, Q1, median, Q3, and maximum. 
Frequency tables will cover number and percentage of participants 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.
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 participant information will be presented for participants with treatment-emergent 
changes in laboratory parameters outside of predefined criteria.
For urinalysis, a frequency table will present number of participants reporting at least 


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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 will cover observed values and changes from baseline for each 
individual participant 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.
9.4.3.4
Electrocardiograms
Descriptive statistics will be produced at each scheduled assessment time point 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 for QT, QTcF, QRS, and PR 
interval, and heart rate will be performed. The number and percentage of participants with 
potentially clinically significant ECG values will be tabulated across time and treatment arm. 
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.
!
Increase from baseline > 30 ms.
!
Increase from baseline > 60 ms.
9.4.4
Other Analyses
9.4.4.1
Exploratory PK Endpoints
The following exploratory PK endpoints will be summarised by treatment arm based on the 
Pharmacokinetic Analysis Set:
!
Plasma concentration of zibotentan and dapagliflozin.
!
Plasma concentration of zibotentan metabolites (results from this analysis may not be 
reported in the CSR).
!
Dose/exposure of zibotentan relative to safety and PD variables (BNP, creatinine, and 
cystatin C, and urine albumin and creatinine).


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The following analysis will not be part of the CSR:
!
Dose/exposure of zibotentan relative to blood NT-proBNP.
Additional PK analyses may be conducted as appropriate but will not be reported in the CSR.
Further details of this will be provided in the SAP.
9.4.4.2
Exploratory PD and Biomarker Endpoints
The following exploratory PD and biomarker endpoints will be summarised by treatment arm
based on the FAS:
!
Change in plasma/serum concentrations of K+, Na+, uric acid, BUN, fasting plasma 
glucose, haematocrit and haemoglobin over time during the study.
!
Evaluation of changes in cardiovascular biomarkers in blood over time during the study.
The following analyses will not be part of the CSR:
!
Change in plasma/serum concentrations of ET-1, ELDP, CT-proET-1, and copeptin levels 
over time during the study.
!
Change in cardiovascular biomarker NT-proBNP over time during the study.
9.4.4.3
Potential Future Exploratory Research and Optional Genetic Research
The following analyses will not be part of the CSR:
!
Evaluation of changes in blood and urine biomarkers relevant to cardiorenal mechanisms, 
inflammation, and fibrosis over the time course of the study.
!
Optional exploratory research into genes/genetic variation that may influence response to 
treatment.
Analyses for these exploratory objectives will be described in a separate analysis plan and 
results will be presented separately from the main CSR.
9.5
Interim Analyses
Up to 2 administrative interim analyses may be performed. The first interim analysis may
occur after 50% of participants have completed 6 weeks of treatment, and a second interim 
analysis may be performed after 100% of participants have completed 6 weeks of treatment or 
at a time selected by sponsor / percentage of participants with a planned week 6 visit before 
data cut selected by sponsor. The objective of the administrative interim analyses will be to 


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decide if an 
 zibotentan/dapagliflozin project activities is 
 
 on the interim data.
An internal URC of AstraZeneca representatives is set up for this study for ongoing safety 
monitoring and reviewing the unblinded interim results.
The SAP will describe the planned interim analyses in greater detail.
9.6
Data Monitoring Committee
An internal URC of AstraZeneca representatives is set up for this study for ongoing safety 
monitoring and reviewing the unblinded interim results. In addition to general 
safety/tolerability, the URC will focus on potential risks related to hypotension and 
hospitalisations due to HF. Changes in fluid-related measures (weight gain or BNP) that meet 
the defined threshold (Section 7.1) will be reported as an event of special interest.
For details on the review committee, refer to Appendix A.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines
∀
Applicable ICH GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigator’s Brochures, and other relevant 
documents (eg, advertisements) must be submitted to an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
!
Any revised 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.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations.
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.


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!
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
∀
Adherence to European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g, summary or listing of SAEs) from the sponsor will 
review and then file it along with the [Investigator’s Brochures or state other documents] 
and will notify the IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
!
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
∀
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.
!
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.
!
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
∀
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS.
!
The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach
∀
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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A 3
Informed Consent Process
!
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.
!
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 underwent any study-specific procedures, the study identifier, 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 re-screened 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 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 in accordance with local data protection law. 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.


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A 5
Committees Structure
An internal URC is set up for this study in accordance with the AstraZeneca charter for data 
review committees.
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 electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
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 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The sponsor or designee is 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.


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!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data 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 participant screened and included into the study (ie, who 
signed consent) at any study site 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.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines.
!
Inadequate recruitment of participants by the investigator.
!
Discontinuation of further study intervention development.


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(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 multicentre 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 adverse event is the development of any untoward medical occurrence in a patient 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 intervention has been administered.
B 2
Definition of Serious Adverse Events
A serious adverse event is an AE occurring during any study phase (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 abnormality 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 judgment 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 screened 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 judgment 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 
judgment must be used. Below are some examples of events that may be considered medically 
important based on the investigator’s judgment:
!
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) 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).


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 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.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.


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The causality assessment is performed based on the available data including enough 
information to make an informed judgment. 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, Drug Abuse, and Drug Misuse
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention 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.


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!
Accidental overdose (will be captured as an overdose).
!
Participant failed to return unused medication or empty packaging.
!
Errors related to background and rescue medication, or SoC 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.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:
!
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:
!
The drug is used with the intention to cause an effect in another person
!
The drug is sold to other people for recreational purposes 
!
The drug is used to facilitate assault in another person


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!
The drug is deliberately administered by the wrong route
!
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole
!
Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose
!
Someone who is not enrolled in the study intentionally takes the drug


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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 whilst 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 is documented, and study site is notified.


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C 3
International Airline Transportation Association 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 zibotentan and dapagliflozin or other 
AstraZeneca investigational products 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 must 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 within 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 main CSP.
Collection of Samples for Genetic Research
!
The blood sample for this genetic research will be obtained from the participants at 
Visit 2, 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 2, 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 inclusion/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 principal investigators are
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 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 Adverse Event 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 Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (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
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in Alkaline 
Phosphatase (ALP).
Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × 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.


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe 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 × ULN.
!
AST ≥3 × ULN.
!
TBL ≥2 × 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 the tests available 
in the Hy’s law laboratory kit should be used.
∀
Complete the three 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 total bilirubin) 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 Laboratory 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 and IgG anti-CMV
IgM and IgG anti-HSV
IgM and 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-glutamyltransferase; HAV = hepatitis A virus; 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-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix F
COVID-19 Specifics
F 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 World Health Organization 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 Food and Drug Administration (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 participants in the study and site staff involved in the 
investigations against infection with SARS-CoV-2 as requested by the newly issued EMA 
guideline.
F 2
Risk Assessment for COVID-19 Pandemic
The mechanism of action of either zibotentan and/or dapagliflozin are unlikely to impact the 
course of infection with SARS-CoV-2. Dapagliflozin is an anti-glycaemic agent and 
zibotentan is an ETA receptor antagonist; neither is expected to cause immune suppression.
Therefore, risk for the participants to be exposed 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 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 including participants 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.
!
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.


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!
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 investigational 
products 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.
F 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 1), 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 


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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.
F 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.
F 5
References
Guidance on the Management of Clinical Trials during the COVID 19 (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 July 02, 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 G
Abbreviations
Abbreviation or special 
term
Explanation
ABPM
ambulatory blood pressure monitoring
ABV
alcohol by volume
ACEi
angiotensin-converting enzyme inhibitor
ACS
acute coronary syndrome
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCA
anti-neutrophil cytoplasm antibody
ANCOVA
analysis of covariance
ARB
angiotensin receptor blocker
ARNi
angiotensin receptor neprilysin inhibitor
AST
aspartate aminotransferase/transaminase
AV
atrioventricular
BIS
bioimpedance spectroscopy
BMI
body mass index
BNP
B-type natriuretic peptide
BP
blood pressure
BUN
blood urea nitrogen
CKD
chronic kidney disease
CKD-EPI
chronic kidney disease epidemiology collaboration
COPD
chronic obstructive pulmonary disease
COVID-19
corona virus disease-2019
CRF
case report form (electronic/paper)
CRO
contract research organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT-proET-1
C-terminal pro-endothelin-1
CV
cardiovascular
CYP
cytochrome P450
DILI
Drug Induced Liver Injury
DKA
diabetic ketoacidosis
DKD
diabetic kidney disease
DM
diabetes mellitus


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Abbreviation or special 
term
Explanation
DNA
deoxyribonucleic acid 
DUS
Disease Under Study
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
eGFR
estimated glomerular filtration rate
ELDP
endothelin-like domain peptide
EMA
European Medicines Agency
ERT
eResearch Technology
ESKD
end-stage kidney disease
ET-1
endothelin-1
ETA
endothelin A
ETB
endothelin B
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
haemoglobin
Hb1Ac
glycated haemoglobin
HDPE
high density polyethylene
HF
heart failure
HL
Hy’s Law
IA
Interim analysis
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
IC50
concentration required to inhibit 50% of the activity
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology


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Abbreviation or special 
term
Explanation
LH
luteinising hormone
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
MoA
mechanism of action
MRA
mineralocorticoid receptor agonist
NICE
National Institute for Health and Care Excellence
NT-proBNP
N-terminal pro-B-type natriuretic peptide
NYHA
New York Heart Association classification
PD
Pharmacodynamic(s)
PHL
Potential Hy’s Law
PK
pharmacokinetic(s)
PPS
Per Protocol Analysis Set
QT
QT interval
QTcF
QT interval corrected using Fridericia’s formula
RTSM
Randomisation and Trial Supply Management
SAE
serious adverse event
SAF
Safety Analysis Set
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SD
standard deviation
SGLT2
sodium-glucose co-transporter 2
SGLT2i
sodium-glucose co-transporter 2 inhibitor
SoA
Schedule of Activities
SoC
standard of care
SOC
system organ class
SU
sulfonylurea
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
UACR
urinary albumin to creatinine ratio
ULN
upper limit of normal
URC
Unblinded Review Committee


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Appendix H
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 2 (05 Apr 2022)
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 amended CSP (Amendment 1, dated 03 December 2021) was updated to implement 
recommendations of an AstraZeneca URC following an ad hoc safety interim analysis on 
11 February 2022. The recommendation was to close further randomisation of participants to 
both the zibotentan 5 mg monotherapy arm and the zibotentan 5 mg/dapagliflozin 10 mg arm
due to the rate of fluid retention events in these two treatment arms. Fluid retention is a known 
risk with zibotentan. The study had to be temporarily halted for recruitment until the IXRS 
system was updated for this change. Participants that were already randomised at the time of 
discontinuation were allowed to continue with their randomised treatment allocation based on 
the assessment schedule provided in CSP Amendment 1. The dapagliflozin 10 mg arm and 
placebo arm were not affected by the halt. Principal investigators, regulatory authorities and 
IRBs were informed about the recruitment halt in the high dose zibotentan arms and 
temporary halt in the other treatment arms due to IXRS update.
Additionally, new clinical guidelines on the management of CKD have established SGLT2 
inhibitors as a SoC which has led to the need to reconsider the inclusion of a placebo 
treatment arm in the study. As a result, dapagliflozin 10 mg will be used in the new design as 
primary active comparator instead of placebo, thus further randomisation of participants to the 
placebo arm was closed. Following this change, participant numbers in the remaining
treatment arms were redistributed to ensure the study would achieve the desired level of 
statistical power. At the time of discontinuation of the zibotentan high dose monotherapy arm, 
high dose zibotentan/dapagliflozin combination arm and placebo comparator arm, 
54 participants were randomised into Part A and 52 participants had already been randomised 
into Part B. Approximately 26 out of the 52 participants were randomised to the treatment 
arms that have been closed to further randomisation. Data from Part A will be reported 
descriptively and separately from Part B within the CSR, unless specified otherwise.


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page
Changed 
“Placebo-Controlled” to 
“Active-Controlled”.
Dapagliflozin 10 mg will be 
used as primary active
comparator instead of 
placebo in the new design.
Substantial
Replaced Bergur 
Stefansson with Glenn 
Carlson as AstraZeneca 
Study Physician.
Change within study team.
Non-substantial
Section 1.1
Synopsis
The synopsis was revised 
to align with revisions in 
the CSP sections.
Revisions were made for 
consistency.
Non-substantial
Section 1.2 Schema
Updated study schema 
and footnote with the 
remaining treatment 
arms, and number and 
timing of IAs.
To reflect new study design.
Substantial
Section 1.3
Schedule of 
Activities
Deleted SoA for Part A.
To reflect new study design 
as dapagliflozin 10 mg will 
be used as primary active
comparator instead of 
placebo.
Substantial
Removed End of 
Treatment visit.
To collect 12 weeks’ data in 
all participants irrespective of 
premature study intervention
discontinuation.
Substantial
Updated text to refer to 
“diaries” instead of 
“diary cards”.
To allow for either paper 
diary cards or electronic 
diaries to be used.
Non-substantial
Deleted that home body 
weight measurement will 
be used to establish 
baseline body weight.
Body weight measurements 
at the study site will be used 
for baseline body weight.
Non-substantial
Section 2.2
Background
Added information on 
the SoC for patients with 
T2DM and CKD.
New clinical guidelines on 
the management of CKD 
have established SGLT2 
inhibitors as a SoC.
Non-substantial
Section 2.3
Benefit/Risk 
Assessment
Updated the mitigation 
strategy for potential 
fluid retention risk from 
zibotentan.
Updated due to safety issues 
related to fluid retention in 
participants receiving high 
dose of zibotentan.
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
The planned URC is now 
set up to monitor 
ongoing safety in the 
study.
To clarify.
Non-substantial
Section 2.3.1 Risk 
Assessment, Table 2
Updated risk assessment 
data and mitigation 
strategy for dapagliflozin 
and zibotentan.
To align CSP with new 
information which became 
available.
Non-substantial
Section 2.3.2 Benefit 
Assessment
Updated text to state that 
new clinical guidelines 
on the management of 
CKD have established 
SGLT2 inhibitors as a 
SoC.
To align CSP with new 
information which became 
available.
Non-substantial
Section 3 Objective 
and Endpoints, 
Table 3
Updated objectives and 
endpoints.
To reflect new study design 
as dapagliflozin 10 mg will 
be used as primary active
comparator instead of 
placebo.
Substantial
Section 4.1
Overall Design
Updated number of study 
sites to be used and 
overall study design: 
further randomisation of 
participants to the 
placebo arm was closed
and dapagliflozin 10 mg 
became the primary
active comparator, 
redistributed participant
numbers in the 
remaining treatment 
arms and updated the 
number and timing of 
IAs.
To reflect new study design.
Substantial
Section 4.2
Scientific Rationale 
for Study Design
Updated doses for 
remaining treatment 
arms. Removed placebo 
as control and added 
dapagliflozin as primary 
active comparator.
To reflect new study design.
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.3
Justification for 
Dose
Updated the initially 
selected dose range.
Updated based on 
observations in ad hoc safety 
interim analysis.
Substantial
Section 5.1
Inclusion Criteria
Added that participants 
on a stable dose of MRA 
may be included in the 
study.
To clarify.
Substantial
Section 5.2
Exclusion Criteria
Updated exclusion 
criteria regarding BNP 
and NT-proBNP.
To clarify.
Non-substantial
Section 5.3.1 Meals 
and Dietary 
Restrictions
Removed time range 
during which 
investigational products 
should be taken and 
stated that it should be 
taken approximately at 
the same time each 
morning, but no later 
than 12:00.
To allow flexibility.
Non-substantial
Removed reference to 
study Part A and Part B.
Not applicable for new study 
design.
Non-substantial
Section 5.4 Screen 
Failures
Added that a participant
who was a screen failure 
due to the recruitment 
halt based on 
recommendation of the 
AstraZeneca URC, can 
be re-screened.
To facilitate recruitment.
Non-substantial
Section 6.1.1
Investigational 
Products, Table 4
Updated doses for 
remaining treatment 
arms and investigational 
product information.
To reflect new study design.
Substantial
Section 6.3
Measures to 
Minimise Bias: 
Randomisation and 
Blinding
Removed information 
regarding sub-population 
for Part A.
Not applicable for new study 
design.
Non-substantial
Added list of personnel 
who will be unblinded as 
to the exact content of 
To clarify.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
investigational 
treatments.
Section 6.4 Study 
Intervention 
Compliance
Updated text to refer to 
“diaries” instead of 
“diary cards”.
To allow for either paper 
diary cards or electronic 
diaries to be used.
Non-substantial
Removed information 
regarding placebo 
tablets.
Not applicable for new study 
design.
Non-substantial
Section 6.5.1
Prohibited 
Concomitant 
Medications
Added MRA to the 
medications allowed in 
the study on stable doses.
To clarify.
Substantial
Section 7.1
Discontinuation of 
Study Intervention
Updated discontinuation 
criteria regarding BNP 
and NT-proBNP, 
diabetic ketoacidosis, 
and hypotension.
To clarify.
Substantial
Described procedure to 
be followed when study 
interventions are 
permanently 
discontinued.
To clarify.
Non-substantial
Section 7.1.1
Ketoacidosis in 
Participants with 
T2DM
Updated information 
regarding ketoacidosis in 
participants with T2DM.
To clarify.
Non-substantial
Section 7.2
Participant 
Withdrawal from the 
Study
Updated study visit 
name.
To clarify and for 
consistency within the CSP.
Non-substantial
Section 8.1.2.1
Office/Clinic Blood 
Pressure 
Measurement
Updated description of 
different treatment arms.
To reflect new study design.
Non-substantial
Section 8.2.3
Electrocardiograms
Added that QTcF 
interval requirement will 
be the mean of the three 
ECGs.
To clarify.
Non-substantial
Section 8.3.8.2
Paternal Exposure
Removed list of 
contraception methods
and added reference to 
Section 5.1.
Already included in 
Section 5.1.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Added that if a male 
participant fathers a 
pregnancy within 
3 months after last dose 
of study intervention, it
should be reported to the 
investigator.
To clarify paternal exposure.
Non-substantial
Section 8.5.1
Pharmacokinetics
Removed reference to 
study Part A and Part B.
Not applicable for new study 
design.
Non-substantial
Removed that analysis of 
PK samples is planned 
only for actively treated 
participants and may be 
analysed for placebo 
participants, if necessary.
Not applicable for new study 
design.
Non-substantial
Section 8.5.1.1 PK 
Sub-study
Removed reference to 
study Part B.
Not applicable for new study 
design.
Non-substantial
Section 8.5.1.2
Determination of 
Drug Concentration
Removed reference to 
study Part B.
Not applicable for new study 
design.
Non-substantial
Section 8.6.1
Collection of 
Mandatory Samples 
for Biomarker 
Analysis
Clarified that biomarker 
samples collected for 
future analyses will be
optional and participants 
will be able to participate 
in the study even if they 
do not consent to the 
purpose of collection for 
these samples.
To clarify.
Non-substantial
Removed placebo as 
control and added 
dapagliflozin as primary 
active comparator.
Dapagliflozin 10 mg will be 
used as primary active
comparator instead of 
placebo in the new design.
Substantial
Section 9.1
Statistical 
Hypotheses
Updated doses for 
remaining treatment 
arms. Removed placebo 
as control and added 
dapagliflozin as primary 
active comparator.
To reflect new study design.
Substantial
Section 9.2 Sample 
Size Determination
Updated sample size 
determination based on 
new study design.
To reflect new study design.
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Sample 9.3
Populations for 
Analyses
Added that participants 
or sites identified prior to 
database lock with major 
GCP violations and 
where the integrity of the 
data is strongly 
questioned will be 
excluded from all 
analyses and all analysis 
sets.
To reflect handling of data 
with questionable quality.
Substantial
Section 9.4.1
General 
Considerations
Added that the baseline 
value for statistical 
analysis can also be the 
last non-missing value 
on the same date as 
administration of the first 
dose of investigational 
products.
To clarify.
Non-substantial
Section 9.4.2
Updated description of 
efficacy analyses.
To clarify.
Non-substantial
Section 9.4.2.1
Primary Endpoint
Updated primary 
endpoint based on new 
study design.
To reflect new study design.
Substantial
Section 9.4.2.2
Secondary 
Endpoints
Updated secondary 
endpoints based on new 
study design.
To reflect new study design.
Substantial
Section 9.4.2.3
Exploratory 
Endpoints
Updated exploratory 
endpoints based on new 
study design.
To reflect new study design.
Substantial
Section 9.4.3 Safety
Added that the baseline 
value for statistical 
analysis can also be the 
last non-missing value 
on the same date as 
administration of the first 
dose of investigational 
products.
To clarify.
Non-substantial
Section 9.4.4.1
Exploratory PK 
Endpoints
Removed reference to 
study Part B.
Not applicable for new study 
design.
Non-substantial
Added that possible 
additional PK analyses 
will not be reported in 
the CSR.
To clarify.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.5 Interim 
Analyses
Updated number and 
timing of IAs.
To reflect new study design.
Substantial
The planned URC is now 
set up.
To clarify.
Non-substantial
Section 9.6 Data 
Monitoring 
Committee
The planned URC is now 
set up.
To clarify.
Non-substantial
Section 10
Supporting 
Documentation and 
Operational 
Considerations 
Appendix A: A 5
The planned URC is now 
set up.
To clarify.
Non-substantial
Section 10
Supporting 
Documentation and 
Operational 
Considerations 
Appendix H
Moved Protocol 
Amendment Summary of 
Changes Table for 
previous amendment to 
appendix section.
Template requirement.
Non-substantial
Section 11
References
Added reference to 
websites referring to in 
Section 2.2.
To provide source for newly 
added information.
Non-substantial
Throughout
Minor editorial and 
document formatting 
revisions.
Minor, therefore, have not 
been summarised.
Non-substantial
BNP = B-type natriuretic peptide; CKD = chronic kidney disease; CSP = Clinical Study Protocol; 
CSR = Clinical Study Report; GCP = Good Clinical Practice; IA = interim analysis; MRA = mineralocorticoid 
receptor agonist; NT-proBNP = N-terminal pro-B-type natriuretic peptide; PK = pharmacokinetic; QTcF = QT 
interval corrected using Fridericia’s formula; SGLT2 = sodium-glucose co-transporter 2; SoA = Schedule of 
Activities; SoC = standard of care; T2DM = type 2 diabetes mellitus; URC = Unblinded Review Committee.
Amendment 1 (03 Dec 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 original CSP was updated to provide overall clarification on study procedures based on 
investigator feedback. To align the study population with the target population in Phase 3, the 
lower eGFR limit was decreased to eGFR ≥20 mL/min/1.73 m2, the upper limit of 
≤60 mL/min/1.73 m2 was removed, and the lower UACR limit was decreased to ≥150 mg/g. 
Local BNP testing after screening was removed from the CSP as the existing testing at the 
central laboratory will ensure more homogeneous results and some countries are unable to 
perform local BNP testing. Accordingly, local NT-proBNP was added as an option at the 


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screening visit. Home-based ABPM and heart rate monitoring was removed as only 
clinic-based monitoring is contributing to the database and participants were finding the 
home-based device too burdensome to wear during daily activities.
The start of Part A of the study was delayed due to the COVID-19 pandemic causing a greater 
overlap of Part A and Part B recruitment timelines globally than was originally planned. 
Therefore, the data contributing to the interim analyses (1.0 and 1.1) and the data to be 
reviewed was combined from Part A and Part B to reduce unnecessary exposure of 
participants to the study intervention.
The COVID-19 testing regimen was updated to facilitate enrolment and because testing as 
screening only is sufficient.


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page
Lower the eGFR limit to 
eGFR 
≥20 mL/min/1.73 m2, 
remove the upper eGFR 
limit of eGFR ≤60 
mL/min/1.73 m2.
To align the study population 
to the target population in 
Phase 3. 
Substantial
Section 1.1
Synopsis
The synopsis was revised 
to align with revisions in 
the CSP sections.
Revisions were made for 
consistency.
Non-substantial
Section 1.2
Schema
Clarified that for Part A, 
all participants in IA1 are 
to be included in IA1.1.
Updated number of 
participants for Part B in 
the schema and footnote 
and clarified that an 
administrative analysis 
will be done for IA2 with 
details provided in the 
SAP.
To reduce the number of 
participants randomised in 
Part B while maintaining 
more than 90% statistical 
power for the primary 
endpoint.
Substantial
Section 1.3
Schedule of 
Activities 
(Table 1)
Shortened visit window 
for screening.
To give more flexibility to 
shorten screening period if all 
test results are available.
Non-substantial
Removed SARS-CoV-2 
testing on Day 1.
Testing during screening is 
sufficient.
Non-substantial
Clarified that 
echocardiography results
must be available before 
randomisation.
To discontinue participant 
from the study prior to 
randomisation, if necessary.
Non-substantial
Removed home-based 
monitoring of ABPM.
To decrease home-based 
digital monitoring burden.
Non-substantial
Removed home-based 
heart rate monitoring.
To decrease home-based 
digital monitoring burden.
Non-substantial
Added testing of 
exploratory PD samples 
to screening assessments.
To discontinue participant 
from study drug, if necessary.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Clarified that central 
BNP results must be 
reviewed by the 
investigator within 
24 hours from receipt.
Optional local laboratory 
NT-proBNP testing 
added at the screening 
visit.
NT-proBNP is used to check 
Exclusion Criterion #4 if local 
BNP testing is not possible.
Non-substantial
Clarified that vital signs 
must be performed, and 
results reviewed before 
randomisation.
To discontinue participant 
from the study prior to 
randomisation, if necessary.
Non-substantial
Clarified that clinical 
chemistry and 
haematology results must 
be reviewed by the 
investigator within 
48 hours from receipt of 
the result.
To discontinue participant 
from study drug, if necessary.
Non-substantial
Clarified that participants 
will take their study 
intervention at home 
between clinic visits and 
as directed for visits with 
PK sampling.
To align with Section 6.4.
Non-substantial
Section 2.2
Background
Updated data from 
published study that 
investigated dapagliflozin 
in patients with CKD.
Study completed and 
published.
Non-substantial
Section 2.3
Benefit/Risk 
Assessment
Realigned text to reflect 
data contribution to 
interim analysis to 
include ALL data at a 
certain time point, not 
just Part A data.
To clarify what data will be 
reviewed by the sponsor 
during the interim analyses 
1.0 and 1.1.
Non-substantial
Section 4.1
Overall Design
Lower the eGFR limit to 
eGFR 
≥20 mL/min/1.73 m2, 
remove the upper eGFR 
limit of eGFR ≤60 
mL/min/1.73 m2, and 
lower UACR limits to 
To align the study population 
to the target population in 
Phase 3. 
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
≥150 mg/g and 
≤5000 mg/g.
Realigned text to reflect 
that interim analyses 1.0 
and 1.1 will include ALL 
data at a certain time 
point, not just Part A data 
and clarified what data 
will be reviewed by the 
sponsor.
To capture safety signal of 
fluid retention with zibotentan 
treatment sooner to be able to 
stop randomising participants 
to that treatment.
Non-substantial
Updated number of 
participants to be 
included in Part B of the 
study.
To reduce the number of 
participants randomised in 
Part B while maintaining 
more than 90% statistical 
power for the primary 
endpoint.
Substantial
Section 4.3
Justification for 
Dose
Added CKD as indication 
for which dapagliflozin 
10 mg is approved.
To align CSP with new 
information which became 
available.
Non-substantial
Section 5.1
Inclusion Criteria
Lower the eGFR limit for 
inclusion to eGFR 
≥20 mL/min/1.73 m2 and 
remove the upper eGFR 
limit of eGFR 
≤60 mL/min/1.73 m2.
Lower UACR limit was 
decreased to ≥150 mg/g.
To align the study population 
to the target population in 
Phase 3. 
Substantial
Clarified that participants 
who have been deemed 
unable to tolerate ACEi 
or ARB therapy due to 
allergy or complications 
may be enrolled in the 
study.
To clarify that participants 
with medical contraindication 
for ACEi/ARB use can 
participate in the study.
Non-substantial
Updated the period from 
which participants should 
refrain from using 
cytotoxic therapy, 
immunosuppressive 
To align with Section 6.5.1
and to only exclude 
participants needing these 
therapies for inflammation in 
the kidneys.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
therapy or other 
immunotherapy prior to 
screening and clarified 
what participants treated 
with immune/cytotoxic 
therapy are excluded.
Clarified criteria 
regarding highly effective 
methods of contraception.
To clarify and define highly 
effective methods of 
contraception.
Non-substantial
Section 5.2
Exclusion Criteria
Deleted “anatomical 
causes of CKD”.
To not exclude patients that 
are expected to benefit from 
the treatment. The definition 
of “anatomical causes” is 
unclear and leads to 
unnecessary exclusion.
Non-substantial
Deleted history of 
epilepsy syndrome as 
exclusion criterion.
Participants with epilepsy 
syndrome will be allowed to 
participate in the study.
Substantial
NT-proBNP added as an 
optional test that can be 
used instead of BNP to 
check eligibility.
Local BNP testing not 
possible in all countries.
Non-substantial
Updated criteria 
regarding participants 
with hyponatremia.
Participants with Na+ levels 
< 135 mmol should be 
excluded from the study at 
screening.
Non-substantial
Updated criteria 
regarding participants 
with prolonged QT 
interval.
Participants with a prolonged 
QT interval at screening 
should not proceed to 
randomisation.
Non-substantial
Updated criteria 
regarding open chest 
coronary artery bypass 
grafting or valvular 
repair/replacement.
Corrected typing error 
regarding the period within 
which participants should not 
had cardiac surgery prior to 
screening.
Non-substantial
Updated criteria 
regarding participants 
with anaemia.
Participants with 
haemoglobin levels < 100 g/L 
or 10 g/dL should be 
excluded from the study at 
screening.
Non-substantial
Removed chronic cystitis 
and/or recurrent urinary 
tract infections (3 or 
Not a safety risk as per the 
Investigator’s Brochure and 
can be justified by data from 
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
more in the previous 
year) as exclusion 
criterion.
the DAPA-CKD study 
(NCT03036150).
Removed positive 
hepatitis B virus core 
antibody as exclusion 
criterion.
Remove a test which is 
inappropriate to exclude 
patients with active hepatitis.
Non-substantial
Updated criteria 
regarding COVID-19 
testing.
To reflect the sponsor 
position on accepting 
COVID-19 participants in 
clinical studies.
Non-substantial
Added ejection fraction 
< 50% at screening as 
exclusion criterion.
To align with Section 8.1.3.3.
Substantial
Added that a male 
participant in a sexually
active relation with 
pregnant or breastfeeding 
partner should not be 
included in the study.
To give more clarity on this 
reproduction exclusion.
Substantial
Section 5.3.1
Meals and Dietary 
Restrictions
Added details regarding 
the light breakfast to be 
taken on the day of the 
short PK profile 
assessments.
To specify the source and 
content of the breakfast.
Non-substantial
Section 5.4 Screen 
Failures
Added that re-screened 
participants should 
re-sign informed consent.
To align with 
Appendix A A 3.
Non-substantial
Clarified that one re-test 
for certain assessments 
will be allowed, if in the 
opinion of the 
investigator, values are 
close to the inclusion 
criteria.
Re-test is allowed due to high 
day-to-day variability of 
creatinine (eGFR) and 
UACR.
Non-substantial
Section 6.1.1
Investigational 
Products (Table 4)
Added details about 
zibotentan and 
dapagliflozin excipients.
To align with ICF.
Non-substantial
Section 6.1.2
Medical Devices
Updated description of 
devices to be used in the 
study.
To specify what devices will 
be used.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 6.4 Study 
Intervention 
Compliance
Clarified that participants 
will take their study 
intervention at the clinic 
on indicated visit days 
and at home on all other 
occasions.
To clarify and avoid 
confusion.
Non-substantial
Section 7.1
Discontinuation of 
Study Intervention
Updated the BNP study 
intervention 
discontinuation criteria to 
two separate bullet 
points.
To clarify and avoid 
confusion.
Non-substantial
Added that at least 2.5% 
of increase in weight 
must be from total body 
water as measured by 
bioimpedance.
To clarify the site-specific 
instructions to be followed 
with the bioimpedance 
machine.
Non-substantial
Section 7.1.1
Ketoacidosis in 
Participants with 
T2DM
Added additional 
information on signs and 
symptoms regarding 
ketoacidosis in 
participants with T2DM.
To give the investigator a 
clinical guidance for 
identification of this rare 
condition.
Non-substantial
Section 8.1.3.1
Electronic Scale 
Measurement of 
Body Weight
Added that the provided 
digital scales will be used 
to monitor home-based 
body weight.
To specify what devices will 
be used.
Non-substantial
Section 8.1.3.3
Ambulatory Blood 
Pressure 
Monitoring
Removed home-based
monitoring of ABPM.
To decrease home-based
digital monitoring burden.
Non-substantial
Section 8.2.2 Vital 
Signs
Removed home-based 
ABPM and heart rate 
monitoring from CSP.
To decrease home-based 
digital monitoring burden.
Non-substantial
Section 8.2.3
Electrocardiograms
Added that 
3 measurements will be 
taken per time point and 
that the average of the 
readings will be recorded 
in the eCRF.
To align with triplicate ECGs 
declared in ICF. Triplicate 
ECGs give a more robust 
result.
Non-substantial
Section 8.2.4
Clinical Safety 
Laboratory 
Assessments
Added local BNP or 
NT-proBNP testing to 
screening samples for 
parameters needed to 
confirm eligibility.
Local BNP testing not 
possible in all countries.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Removed blood gas and 
pH testing from central 
laboratory clinical 
chemistry panel.
Testing needs to be done on 
an arterial sample to be 
meaningful, therefore is not 
applicable.
Non-substantial
Removed hepatitis B 
virus core antibodies 
testing from central 
laboratory clinical 
chemistry panel.
Remove a test which is 
inappropriate to exclude 
patients with active hepatitis.
Non-substantial
Added footnote to 
Table 5.
To specify which 
SARS-CoV-2 tests are 
allowed.
Non-substantial
Section 8.3.8.1
Maternal Exposure
Removed text regarding 
the potential inclusion of 
women of childbearing 
potential in future studies
with zibotentan.
The removed text is not 
relevant for the study 
protocol, women of 
childbearing potential are 
excluded from this study.
Non-substantial
Section 8.3.8.2
Paternal Exposure
Updated text regarding 
paternal exposure.
To align with the exclusion 
criterion and to avoid a 
potential risk due to paternal 
exposure.
Non-substantial
Section 8.5.1.2
Determination of 
Drug 
Concentration
Replaced Covance with 
Labcorp Bioanalytical 
Services LLC.
Updated Covance to Labcorp 
information to reflect 
organisational name change
of vendor.
Non-substantial
Section 8.5.3.1
Collection of 
Samples
NT-proBNP added as an 
optional test that can be 
used instead of BNP to 
check eligibility.
Local BNP testing not 
possible in all countries.
Non-substantial
Section 9.2
Sample Size 
Determination
Updated sample size 
determination to state that 
a 1-sided type I error rate 
of 5% will have at least 
91% power to detect a 
placebo-corrected UACR 
reduction of 40% or 
more.
Updated sample size for 
Part B of the study.
To reduce the number of 
participants randomised in 
Part B while maintaining 
more than 90% statistical 
power for the primary 
endpoint.
Substantial
Section 9.4.3.1
Adverse Events
Clarified which AEs will 
be presented in summary 
tables.
To clarify how AEs will be 
presented.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.5 Interim 
Analyses
Updated text to reflect 
the number of interim 
analyses planned and data 
contribution to the 
interim analyses.
To clarify the number and 
timing of planned interim 
analyses.
Non-substantial
Section 10
Supporting 
Documentation 
and Operational 
Considerations 
Appendix F: F 4
Deleted the example of 
“home nursing” as this 
was never applicable to 
this CSP.
Only on-site visits will be 
allowed.
Non-substantial
Section 11
References
Added reference to 
publication referring to in 
Section 2.2.
To provide source for newly 
added information.
Non-substantial
Throughout
Minor editorial and 
document formatting 
revisions.
Minor, therefore have not 
been summarised.
Non-substantial
ABPM = Ambulatory Blood Pressure Monitoring; ACEi = angiotensin-converting enzyme inhibitor; 
ARB = angiotensin receptor blockers; BNP = B-type natriuretic peptide; CKD = chronic kidney disease; 
COVID-19 = coronavirus disease 2019; CSP = Clinical Study Protocol; ECG = electrocardiogram; 
eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; ICF = informed consent form; 
Na+ = sodium; NT-proBNP = N-terminal pro-B-type natriuretic peptide; PK = pharmacokinetic; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; UACR = urinary albumin to creatinine ratio.


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11
REFERENCES
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Agarwal R. Resistant hypertension and the neglected antihypertensive: sodium restriction. 
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Bakris et al, 2000
Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, et al. Preserving renal 
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De Zeeuw R, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. The Endothelin 
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Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, Grams ME. Change in 
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Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of 
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Munter et al, 2002
Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and subsequent death 
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Perkovic et al, 2019
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. 
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 
2019;380:2295-306.
Pollock et al, 2019
Pollock C, Stefansson B, Reyner D, Rossing P, Sjostrom CD, Wheeler DC, et al. Albuminuria-
lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of 
dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic 
kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial. Lancet 
Diabetes Endocrinol 2019;7:429-41.


Clinical Study Protocol - Amendment 3
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CONFIDENTIAL AND PROPRIETARY
126 of 126
Scholtes et al, 2020
Scholtes R, Muskiet MHA, Van Baar MJB, Greasley PJ, Karlsson C, Hammarsterdt A, et al. 
Natriuretic effect of 2 weeks of dapagliflozin treatment in patients with type 2 diabetes and 
preserved kidney function: results of the DAPASALT trial. Abstract. ESC Congress 2020.
Stevens et al, 2008
Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J et al. Estimating GFR 
using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 
3,418 individuals with CKD. Am J Kidney Dis. 2008;51:395-406.
Tanner et al, 2013
Tanner RM, Calhoun DA, Bell EK, Bowling CB, Gutierrez OM, Irvin MR, et al. Prevalence 
of apparent treatment-resistant hypertension among individuals with CKD. Clin J Am Soc 
Nephrol 2013;8(9):1583-90.
Wanner et al, 2016
Wanner C, Inzucchi SE, Zinman B. Empagliflozin and Progression of Kidney Disease in Type 
2 Diabetes. N Engl J Med 2016;375:1801-2.
Webster et al, 2017
Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet 
2017;389(10075):1238-52.
Xie et al, 2018
Xie Y, Bowe B, Mokdad AH, Xian H, Yan Y, Li T, et al. Analysis of the Global Burden of 
Disease study highlights the global, regional, and national trends of chronic kidney disease 
epidemiology from 1990 to 2016. Kidney Int 2018;94(3):567-81.
Zelniker et al, 2019
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for 
primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a 
systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d4325c00001-csp-v3
Document Title:
D4325C00001 Clinical Study Protocol version 3
Document ID:
Doc ID-004335116
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
28-Mar-2023 19:06 UTC
Content Approval
28-Mar-2023 09:14 UTC
Content Approval
28-Mar-2023 09:08 UTC
Content Approval
28-Mar-2023 14:15 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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SAP_003.pdf: 
Parexel International
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D4325C00001
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 3.0
Effective Date:  26 Nov 19
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Page 1 of 59
Parexel International
AstraZeneca
D4325C00001
A Phase 2b Multicentre, Randomised, Double-Blind, Active-Controlled, Parallel Group Dose-
Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin in 
Patients with Chronic Kidney Disease with Estimated Glomerular Filtration Rate (eGFR) ≥20 
mL/min/1.73 m2
Statistical Analysis Plan
Version: 3.0
Parexel Project Number: 252886


Parexel International
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Statistical Analysis Plan
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Page 2 of 59
TABLE OF CONTENTS
1
INTRODUCTION ................................................................................................................. 10
2
STUDY OBJECTIVES.......................................................................................................... 11
2.1
Primary Objective.............................................................................................................. 11
2.2
Secondary Objectives ........................................................................................................ 11
2.3
Safety Objective ................................................................................................................ 12
2.4
Exploratory Objectives ...................................................................................................... 13
3
INVESTIGATIONAL PLAN ................................................................................................ 14
3.1
Overall Study Design and Plan .......................................................................................... 14
3.2
Endpoints .......................................................................................................................... 16
3.2.1
Efficacy Variables........................................................................................................... 16
3.2.1.1
Urinary Albumin to Creatinine Ratio (UACR) .............................................................. 16
3.2.1.2
Office/Clinic Blood Pressure Measurement................................................................... 17
3.2.1.3
Serum Analysis of Creatinine and Cystatin C (eGFR) ................................................... 17
3.2.2
Safety Variables .............................................................................................................. 17
3.2.2.1
Adverse Events and Serious Adverse Events................................................................. 17
3.2.2.2
Physical Examinations .................................................................................................. 18
3.2.2.3
Vital Signs .................................................................................................................... 18
3.2.2.4
Electrocardiograms ....................................................................................................... 18
3.2.2.5
Clinical Safety Laboratory Assessments........................................................................ 19
3.2.2.6
Echocardiography Assessment of Cardiac Structure and Function................................. 20
3.2.2.7
Events of special interest............................................................................................... 21
3.2.3
Exploratory Variables...................................................................................................... 21
3.2.3.1
Bioimpedance Spectroscopy.......................................................................................... 21
3.2.3.2
Pharmacokinetics .......................................................................................................... 21
3.2.3.3
Pharmacodynamics ....................................................................................................... 22
4
STATISTICAL METHODS .................................................................................................. 22
4.1
Data Quality Assurance ..................................................................................................... 22
4.2
General Presentation Considerations.................................................................................. 22
4.2.1
Study Period.................................................................................................................... 22
4.2.2
Data Presentation............................................................................................................. 22
4.2.3
Analysis Visit Windows .................................................................................................. 24
4.2.4
Global/Country Situation Summaries............................................................................... 25
4.2.5
Japan-Specific Analysis................................................................................................... 25
4.3
Software............................................................................................................................ 25
4.4
Handling of Dropouts or Missing Data............................................................................... 25
4.5
Study Subjects................................................................................................................... 26
4.5.1
Disposition of Subjects.................................................................................................... 26
4.5.2
Protocol Deviations ......................................................................................................... 26
4.6
Analysis Sets ..................................................................................................................... 28
4.7
Demographic and Other Baseline Characteristics............................................................... 30
4.8
Concomitant Medication.................................................................................................... 31
4.9
Treatment Compliance....................................................................................................... 32
4.10
Efficacy Evaluation ........................................................................................................... 33
4.10.1
Analysis and Data Conventions ....................................................................................... 33
4.10.1.1
Null Hypothesis for Primary Objective and Related Secondary Objective ..................... 33


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4.10.1.2
Multi-centre Studies...................................................................................................... 33
4.10.1.3
Examination of Subgroups ............................................................................................ 34
4.10.2
Analyses of UACR Objectives ........................................................................................ 34
4.10.2.1
Primary Estimand for Primary Objective....................................................................... 34
4.10.2.2
Primary Analysis of Primary Objective ......................................................................... 34
4.10.2.3
Multiple Imputation ...................................................................................................... 36
4.10.2.4
Tipping Point Analysis.................................................................................................. 36
4.10.2.5
Jump to Reference Analysis .......................................................................................... 37
4.10.2.6
Supplementary Analysis of Primary Objective .............................................................. 37
4.10.2.7
Analysis of Secondary UACR Objectives...................................................................... 37
4.10.3
Analysis of Secondary Objectives Other Than UACR ..................................................... 38
4.10.4
Exploratory Evaluations .................................................................................................. 39
4.11
Safety Evaluation............................................................................................................... 39
4.11.1
Extent of Exposure.......................................................................................................... 39
4.11.2
Adverse Events................................................................................................................ 40
4.11.3
Deaths, Serious Adverse Events, and Adverse Events Leading to the Discontinuation of 
Study Intervention........................................................................................................... 41
4.11.4
Clinical Laboratory Evaluation........................................................................................ 41
4.11.5
Vital Signs, Electrocardiograms, Echocardiography and Other Observations Related to 
Safety.............................................................................................................................. 42
4.11.5.1
Fluid-Related Measures................................................................................................. 43
4.12
Other Analyses .................................................................................................................. 44
4.12.1
Pharmacokinetics ............................................................................................................ 44
4.12.2
Pharmacodynamics.......................................................................................................... 44
4.12.3
Potential Future Exploratory Research and Optional Genetic Research............................ 44
4.13
Interim Analysis ................................................................................................................ 45
4.14
Determination of Sample Size............................................................................................ 45
4.15
Changes in the Conduct of the Study or Planned Analysis ................................................. 46
5
REFERENCES...................................................................................................................... 46
6
APPENDICES....................................................................................................................... 48
Appendix A: Schedule of Activities .............................................................................................. 49
Appendix B: Interim Analysis Plan ............................................................................................... 55
Appendix C: Treatment-Emergent Changes in Relevant Laboratory Parameters............................ 59


Parexel International
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Page 4 of 59
REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
22 Jan 21
New document
1.1
25 May 22
Updates for alignment with Protocol Amendment 2
Updates to Appendix B to ensure alignment with the November 
2021 version of the URC charter
1.2
15 Jul 22
Updates throughout document to ensure alignment with 
Protocol Amendment 2
Addition 
of 
multiple 
imputation, 
tipping 
point 
and 
supplementary analyses
Updates to Appendix B to clarify 
1.3
15 Aug 22
Updates to the Data Presentation and Analysis Sets sections
Updates to Appendix B to clarify the interim analysis sets
1.4
04 Oct 22
Updates to the Data Presentation and Analysis Sets sections
Updates to the Efficacy Evaluation section
Updates to Appendix B to clarify the interim analysis plan
1.5
14 Nov 22
Updates to the Data Presentation section
Updates to the sensitivity analyses part of the Primary Analysis 
of Primary Objective section and related sections added within 
the Analyses of UACR Objectives section
Updates to the eGFR part of the Analysis of Secondary 
Objectives Other Than UACR section
Updates to the Fluid-Related Measures section
Updates to the Interim Analysis section
Updates to Appendix B to clarify the interim analysis plan
CCI


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Version No.
Effective Date
Summary of Change(s)
1.6
27 Nov 22
Updates throughout SAP to make clear results for ELDP and 
CT-proET-1 will not be reported in the CSR
Updates to the eGFR part of the Analysis of Secondary 
Objectives Other Than UACR section
Updates to the Extent of Exposure section
Updates to the Fluid-Related Measures section
Updates to the Interim Analysis section
Updates to the Analysis Sets part of Appendix B to clarify the 
interim analysis plan
1.7
07 Dec 22
Update to the baseline disease characteristics part of the 
Demographic and Other Baseline Characteristics section
Updates to the Copy Reference Analysis section and the Jump 
to Reference Analysis section
2.0
07 Dec 22
Finalised version
2.1
05 Feb 23
Updates to the Echocardiography Assessment of Cardiac 
Structure and Function section
Creation of new Global/Country Situation Summaries section 
from the previous COVID-19 Analysis and Ukraine/Russia 
Crisis Analysis sections
Updates to the Protocol Deviations section
Updates to the Primary Estimand for Primary Objective section
Updates to the Primary Analysis of Primary Objective section, 
including the sensitivity analyses part and the subgroup 
analyses part
Updates to the Tipping Point Analysis section
Updates to the Jump to Reference Analysis section; removal of 
the Copy Reference Anaysis section and the BOCF-like 
Analysis section
Updates to the Supplementary Analysis of Primary Objective 
section
Updates to Extent of Exposure section


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Version No.
Effective Date
Summary of Change(s)
2.2
21 Feb 23
Updates throughout SAP to make clear results for ET-1, 
copeptin and cortisol will not be reported in the CSR
Updates throughout SAP to remove loss to follow up as an ICE 
and to include death as an ICE
Updates to the Pharmacodynamics section within the 
Exploratory Variables section
Updates to the Study Period section
Updates to the Treatment Compliance section
Updates to the Null Hypothesis for Primary Objective and 
Related Secondary Objective section
Updates to the Primary Estimand for Primary Objective section
Updates to the subgroup analyses part of the Primary Analysis 
of Primary Objective section
Updates to the Tipping Point Analysis section
Updates to the Jump to Reference Analysis section
Updates to the Supplementary Analysis of Primary Objective 
section
Updates to the eGFR part of the Analysis of Secondary 
Objectives Other Than UACR section
Updates to Extent of Exposure section
Updates to Adverse Events section
Updates to Changes in the Conduct of the Study or Planned 
Analysis section


Parexel International
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D4325C00001
Statistical Analysis Plan
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Project Document Version No. 3.0
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Related to:  SOP-GDO-WW-019
Page 7 of 59
Version No.
Effective Date
Summary of Change(s)
2.3
16 Mar 23
Updates throughout SAP to make clear results for NT-proBNP 
will not be reported in the CSR
Updates throughout SAP for how the second administrative 
interim analysis will be triggered
Updates to the dose-response relationship secondary objective 
endpoints text in the Secondary Objectives section
Updates to the Clinical Safety Laboratory Assessments section
Updates to the Software section
Updates to the Null Hypothesis for Primary Objective and 
Related Secondary Objective section
Dose-response Testing for the Dose-response Relationship 
Secondary Objective removed
Updates to reformulate the dose-response relationship 
secondary objective part of the Analysis of Secondary UACR 
Objectives section
Updates to the Extent of Exposure section
Updates to the Clinical Laboratory Evaluation section
Updates to the Pharmacokinetics section
Updates to the Analysis Sets section of Appendix B
2.4
30 Mar 23
Updated section 4.2.2 to specify the list of variables that are 
expected to be skewed. 
Updated section 4.6 to change “plasma concentration 
measurement post-randomisation” to “plasma concentration 
measurement post-treatment” to be in line with CSP. 
Updated sections 4.10.2.2 and 4.10.3 to replace continuous 
covariates of baseline eGFR (serum creatinine) by baseline 
eGFR strata (<= 45 versus > 45 mL/min/1.73 m2).
Updated section 4.6 to remove the statement “all measurements
for an included participant will be considered” from the last 
paragraph of the definition of the Pharmacokinetic Analysis Set.
Updated section 4.15 to add deviations with CSP v3.0 
3.0
05 May 2023
Updated section 4.10.3 to consider continuous covariates of
baseline eGFR (serum creatinine) instead of baseline eGFR 
strata (<= 45 versus > 45 mL/min/1.73 m2).


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LIST OF ABBREVIATIONS
Abbreviation / Acronym
Definition / Expansion
ABPM
ambulatory blood pressure monitoring
ACEi
angiotensin-converting enzyme inhibitor
AE
adverse event
AIC
Akaike’s Information Criterion
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase/transaminase
BIS
bioimpedance spectroscopy
BMI
body mass index
BNP
B-type natriuretic peptide
BOCF
baseline observation carried forward
BP
blood pressure
BUN
blood urea nitrogen
CI
confidence interval
CKD
chronic kidney disease
COVID-19
Coronavirus Disease 2019
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT-proET-1
C-terminal pro-endothelin-1
DAE
adverse event leading to the discontinuation of study intervention
DBL
database lock
DKD
diabetic kidney disease
DM
diabetes mellitus
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELDP
endothelin-like domain peptide
ET-1
endothelin-1
FAS
Full Analysis Set
HF
heart failure
ICE
intercurrent event
IPD
important protocol deviation
LLOQ
lower limit of quantification
LVEF
left ventricular ejection fraction
MAR
missing at random
MCT
multiple contrast test
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
mixed model for repeated measures
MNAR
missing not at random
MRA
mineralocorticoid receptor agonist
NT-proBNP
N-terminal pro-B-type natriuretic peptide
PD
pharmacodynamic(s)
PEY
participant exposure year


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Abbreviation / Acronym
Definition / Expansion
PK
pharmacokinetic(s)
PPS
per protocol analysis set
PT
preferred term
QT
QT interval
QTcF
QT interval corrected using Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SGLT2
Sodium-glucose co-transporter 2
SoA
Schedule of Activities
SoC
standard of care
SOC
system organ class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TLF
tables, listings and figures
UACR
urinary albumin to creatinine ratio
ULN
upper limit of normal
URC
Unblinded Review Committee
WHO-DD
World Health Organization - Drug Dictionary


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1
INTRODUCTION
Patients with chronic kidney disease (CKD) have limited treatment options with current standard of 
care (SoC). The mechanisms of action of zibotentan and dapagliflozin are different and the outcome 
of combined treatment is expected to be synergistic, since the main biological effects of zibotentan 
are to block endothelin-1-dependent vasoconstriction and hypertension, to increase renal blood flow, 
and to reduce podocyte loss, vascular stiffness, endothelial dysfunction, fibrosis and inflammation; 
and of dapagliflozin are to inhibit sodium-glucose co-transporter 2 (SGLT2) to increase urinary 
excretion of glucose, sodium and water, to improve metabolic health, decrease vascular stiffness, 
improve endothelial function, and decrease oxidative stress and inflammation. Both mechanisms 
show efficacy in reducing albuminuria in CKD. However, unlocking the renal benefit of endothelin 
antagonists requires mitigation of their potential to cause fluid retention and to increase the risk of
developing heart failure (HF) in some patients.
The primary objective of this study is to evaluate the effect of zibotentan 1.5 mg and dapagliflozin
10 mg in combination, compared to dapagliflozin 10 mg monotherapy, on urinary albumin to 
creatinine ratio (UACR). The secondary objectives are to determine the change in UACR for 
zibotentan 0.25 mg combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy, 
and the change in office systolic and diastolic blood pressure (BP) for doses of zibotentan combined 
with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy, to characterise the dose-response 
relationship of the different zibotentan/dapagliflozin doses and the UACR reduction, and to determine 
the effect of zibotentan and dapagliflozin in combination versus dapagliflozin 10 mg on eGFR.
This Statistical Analysis Plan (SAP) documents the variables to be analysed and the methods of 
analyses planned. The analyses of the following variables will be reported outside the clinical study 
report (CSR) and are therefore outside the scope of this SAP:
!
Plasma concentration of zibotentan metabolites
!
Blood and urine biomarkers relevant to cardiorenal mechanisms, inflammation, and fibrosis
!
Genes/genetic variation that may influence response to treatment
An electronic case report form (eCRF) will be used to capture participant data into a secure,
validated database. The following data are captured outside the eCRF and will be transferred
electronically into the database periodically during the study:
!
Safety laboratory data
!
Electrocardiogram (ECG) data
!
Plasma concentration of zibotentan and dapagliflozin
!
Pharmacodynamic (PD) urine and blood samples
!
Bioimpedance spectroscopy (BIS)
!
Ambulatory blood pressure monitoring (ABPM)
!
Hand-held electronic diary (eTablet) or paper diary (information may be entered in the eCRF 
based on the paper diary)
!
Protocol deviations


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The analyses described in this SAP are based upon the following study documents:
!
Study Protocol, Amendment 2 (05 APR 2022)
!
electronic Case Report Form, Version 8.0 (09 AUG 2022)
2
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective
Estimand Description/Endpoint
!
To evaluate the effect of zibotentan 1.5 
mg/dapagliflozin
10 
mg
versus
dapagliflozin 10 mg monotherapy on 
UACR.
!
Change in log-transformed UACR from
baseline to Week 12.
The primary estimand is a hypothetical estimand 
such that the treatment effect is quantified in the 
optimal
situation 
where 
any 
potential 
confounder is avoided. The population of 
interest is the Full Analysis
population. 
Participants will be included in the analysis if 
they have a non-missing baseline and at least 
one post-treatment visit UACR measurement.
For the intercurrent events, if a participant dies, 
prematurely discontinues study treatment, or 
uses prohibited medication, the UACR data are 
treated as missing after the event and no
imputation is performed. The summary measure
being evaluated is the geometric mean reduction 
difference of UACR from baseline to Week 12.
Abbreviations: AE = adverse event; UACR = urinary albumin to creatinine ratio.
2.2
Secondary Objectives
Secondary Objectivesa
Endpoints
!
To evaluate the effect of zibotentan 0.25
mg/dapagliflozin 10 mg versus dapagliflozin
10 mg monotherapy on UACR.
! Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the change in office systolic 
and diastolic BP for doses of zibotentan 
combined with dapagliflozin 10 mg versus 
dapagliflozin 10 mg monotherapy.
! Change in BP from baseline (Visit 2) to
Week 12.
!
To 
characterise 
the 
dose-response 
relationship (relationship between different 
doses of zibotentan/a 
fixed dose of 
dapagliflozin and UACR reduction).
! Change in log-transformed UACR from 
baseline to Week 12.
!
To determine the effect of different doses of
zibotentan and dapagliflozin 10 mg in 
combination versus dapagliflozin 10 mg 
monotherapy on eGFR.
! Change in eGFR from baseline to Week 1.
! Change in eGFR from baseline to Week 12.
! Change in eGFR from baseline to Week 14.
! Change in eGFR from Week 1 to Week 12.
Abbreviations: BP = blood pressure; eGFR = estimated glomerular filtration rate; UACR = urinary albumin to creatinine ratio
a The estimand for the secondary objectives is defined with the same approach as for the primary objective.


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2.3
Safety Objective
Safety Objective
Measurements
!
To assess the safety and tolerability of all
doses 
of 
zibotentan 
combined 
with 
dapagliflozin 10 mg and dapagliflozin 10 mg 
monotherapy.
! AEs/SAEs/DAEs.
! Vital signs.
! Clinical laboratory tests.
! 12-lead ECG assessment.
! Echocardiography assessment.
! Event of special interest (changes in fluid-
related measures).
Abbreviations: AE = adverse event; DAE = adverse event leading to the discontinuation of study intervention; ECG = 
electrocardiogram; SAE = serious adverse event.


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2.4
Exploratory Objectives
Exploratory Objectives
Endpoints
!
To assess the pharmacokinetics of different
doses of zibotentan and of dapagliflozin 10 
mg in plasma.
!
Plasma concentrations of zibotentan and 
dapagliflozin.
!
Exploratory 
analysis 
of 
zibotentan 
metabolites.
!
Plasma 
concentration 
of 
zibotentan 
metabolites.
Results from this analysis will not be reported in 
the CSR.
!
To assess body weight changes in response 
to different
doses of zibotentan and 
dapagliflozin 10 mg in combination versus 
dapagliflozin 10 mg monotherapy.
!
Change in body weight, as measured at the 
study site, throughout the interventional 
period.
!
To explore the relationships between 
zibotentan dose/exposure and safety/PD 
variables.
!
Dose/exposure of zibotentan relative to 
safety and PD variables.
Safety/PD variables include blood assessment 
for NT-proBNP, BNP, creatinine, and cystatin 
C, and urine assessment of albumin and 
creatinine.
Results for NT-proBNP will not be reported in 
the CSR.
!
To assess the effect of zibotentan and 
dapagliflozin 
in 
combination 
versus
dapagliflozin 10 mg monotherapy
on 
plasma/serum K+, Na+, uric acid, BUN, 
fasting 
plasma 
glucose, 
haematocrit, 
haemoglobin, ET-1, ELDP, CT-proET-1,
and copeptin levels.
!
Change in plasma/serum concentrations of 
K+, Na+, uric acid, BUN, fasting plasma 
glucose, haematocrit, haemoglobin, ET-1, 
ELDP, CT-proET-1, and copeptin levels 
over time during the study.
Results for ET-1, ELDP, CT-proET-1 and 
copeptin levels will not be reported in the CSR.
!
To assess the effect of zibotentan and 
dapagliflozin 
in 
combination 
versus 
dapagliflozin 10 mg monotherapy
on 
cardiovascular biomarkers in blood.
!
Evaluation of changes in cardiovascular 
biomarkers in blood (NT-proBNP and BNP)
over time during the study.
Results for NT-proBNP will not be reported in 
the CSR.
!
To assess the effect of zibotentan and 
dapagliflozin 
in 
combination 
versus 
dapagliflozin 10 mg monotherapy on body 
fluid volume and distribution status.
!
Evaluation of changes in body fluid volume 
and distribution over the time course of the 
study. 
Change 
in 
total 
body 
water, 
extracellular water and intracellular water 
volumes.
Results 
will 
be 
obtained 
from 
using 
bioimpedance spectroscopy.


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Exploratory Objectives
Endpoints
!
Optional: collect and store plasma, serum, 
and urine
samples for potential future 
exploratory research aimed at exploring 
biomarkers involved in PK, PD, safety and 
tolerability 
related 
to 
zibotentan
and 
dapagliflozin 
in 
combination 
versus 
dapagliflozin monotherapy or related to 
cardiorenal diseases.
!
Evaluation of changes in blood and urine 
biomarkers 
relevant 
to 
cardiorenal 
mechanisms, inflammation, and fibrosis over 
the time course of the study.
Results from this future analysis will not be 
reported in the CSR.
!
Optional: 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.
Results from this optional genetic research will 
not be reported in the CSR.
Abbreviations: BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CSR = clinical study report; CT-proET-1 = C-terminal 
pro-endothelin-1; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; K+ = potassium; Na+ = sodium; NT-proBNP = 
N-terminal pro-B-type natriuretic peptide; PD = pharmacodynamics; PK = pharmacokinetics.
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a Phase 2b, multicentre, randomised, double-blind, active-controlled, parallel group dose-
ranging study to assess the efficacy, safety and tolerability of zibotentan and dapagliflozin in 
participants with CKD with eGFR ≥20 mL/min/1.73 m2, and UACR ≥ 150 mg/g and ≤ 5000 mg/g.
The study will be conducted in approximately 220 sites in North America, South America, Africa, 
Asia/Pacific, and European countries.
Participants will be randomised to 12 weeks of treatment plus 2 weeks follow-up, as shown in Figure 
1. All the variables will be collected (eCRF and third party vendor data) to verify the inclusion and 
exclusion criteria and additional demographic data such as race/ethnicity, serum creatinine, and 
height.
Participants who meet the eligibility criteria will be randomised to study treatments in addition to 
receiving background local SoC therapy. To ensure blinding to treatment and zibotentan dose, daily 
dosing will consist of one dapagliflozin tablet, containing dapagliflozin 10 mg and one zibotentan 
capsule containing zibotentan 1.5 mg, zibotentan 0.25 mg or placebo.
A total of 495 participants will be randomised into this study, including participants randomised under 
the earlier study design. Four hundred and fifteen (415) participants will be randomised to have the 
following number of participants in the main analysis (marked as M in Table 4):
!
Zibotentan 0.25 mg + Dapagliflozin 10 mg once daily, 83 participants
!
Zibotentan 1.5 mg + Dapagliflozin 10 mg once daily, 166 participants
!
Dapagliflozin 10 mg once daily, 166 participants
Participants who were previously randomised cannot be re-randomised.
Participants will be stratified by diabetes (diabetic kidney disease [DKD] versus non-diabetes mellitus 
[non-DM] CKD) and baseline eGFR (below or equal versus above 45 mL/min/1.73m2) at the time of 


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randomisation to ensure an approximate balance between treatment arms within each sub-population. 
The strata are:
!
Stratum 1: DKD participants with eGFR ≤ 45 mL/min/1.73m2.
!
Stratum 2: DKD participants with eGFR > 45 mL/min/1.73m2.
!
Stratum 3: non-DM CKD participants with eGFR ≤ 45 mL/min/1.73m2.
!
Stratum 4: non-DM CKD participants with eGFR > 45 mL/min/1.73m2.
The number of randomised participants in each stratum will be monitored to ensure the non-DM CKD 
subpopulation is approximately a minimum of 30% and a maximum of 50% of the total number of 
participants randomised.
A first administrative interim analysis may be performed when 50% of participants have completed 
6 weeks of treatment or at a time selected by the sponsor. A second administrative interim analysis 
may be performed after 100% of participants have completed the 6 weeks of treatment or at a time
selected by sponsor / percentage of participants with a planned week 6 visit before data cut selected 
by sponsor. For further details on the interim analysis, see Section 4.13.
For each participant, the total duration of participation will be approximately 17 to 19 weeks. The 
screening period can be up to approximately 4 weeks in duration prior to randomisation. The first 
dose will be taken after randomisation at the baseline visit on Day 1. In addition to the baseline visit, 
the participant will visit the clinic 5 times during the following 12 weeks of treatment. Approximately 
2 weeks after the last dose, the participant will visit the clinic again for a follow-up assessment.
The primary objective is to evaluate the effect of zibotentan 1.5 mg/dapagliflozin 10 mg as assessed 
by change from baseline in (log-transformed) UACR at Week 12, when compared to dapagliflozin 
10 mg monotherapy as defined in Section 4.10.2.
The study schedule of assessments (SoA) can be found in Appendix A: Schedule of Activities.


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Figure 1 Study Schema
DAPA = dapagliflozin; N = numbers of participants; QD = once daily; R = randomisation; SAP = Statistical Analysis 
Plan; W = week; ZIBO = zibotentan.
3.2
Endpoints
For a full list of all study assessments and the timings of the assessments, see the SoA in Appendix 
A: Schedule of Activities.
3.2.1
Efficacy Variables
3.2.1.1
Urinary Albumin to Creatinine Ratio (UACR)
The UACR is a key marker for assessing kidney function. The UACR is a ratio between 2 measured 
substances (urine albumin and creatinine), which estimates 24-hour urine albumin excretion.
The UACR is calculated as follows:
!
UACR (mg/g) = urine albumin (mg/dL) / urine creatinine (g/dL)
Urine samples for the determination of albumin and creatinine levels and calculation of UACR will 
be collected at the time points described in the SoA in Appendix A: Schedule of Activities.
Spot urine from first morning void will be collected the day after screening and analysed centrally.
For subsequent visits, participants will collect first morning void samples at home on 3 consecutive 
days. Samples will be analysed centrally.
At each visit (except for screening), the geometric mean of the triplicate UACRs will be computed 
and used for all analysis of UACR. If any of the samples for a triplicate UACR is missing, then the 
geometric mean will be calculated based on the available samples for the triplicate.


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3.2.1.2
Office/Clinic Blood Pressure Measurement
Blood pressure measurements for participants who receive dapagliflozin monotherapy or different 
doses of zibotentan combined with dapagliflozin 10 mg will be done during clinic visits at the time 
points for vital signs indicated in the SoA in Appendix A: Schedule of Activities.
3.2.1.3
Serum Analysis of Creatinine and Cystatin C (eGFR)
Estimated GFR is another measure that is considered as a standard for assessment of kidney function. 
Estimated GFR is calculated based on serum creatinine values using the widely validated and 
accepted CKD-EPI equation (Levey et al, 2009). Blood samples for estimation of serum creatinine 
(clinical chemistry) are collected at various time points during the course of the study as shown in the 
SoA in Appendix A: Schedule of Activities.
Estimated GFR, using serum creatinine, is calculated as follows:
!
eGFR (mL/min/1.73 m2) = 141 × min (SCr/κ, 1)α × max (SCr/κ, 1)-1.209 × 0.993Age × (1.018 if 
female) × (1.159 if Black)
Where SCr = serum creatinine (in mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the 
maximum of SCr/κ or 1.
Alternatively, serum cystatin C provides GFR estimates that are nearly as accurate as serum creatinine 
adjusted for age, sex, and race thus providing an alternative GFR estimate that is not linked to muscle 
mass (Scholtes et al, 2020, Stevens et al, 2008). Blood samples will be collected for measurement of 
cystatin C, at specified time points as shown in the SoA in Appendix A: Schedule of Activities.
Estimated GFR, using cystatin C, is calculated as follows:
!
eGFR = 133 × min (Scys/0.8, 1)-0.499 × max (Scys/0.8, 1)-1.328 × 0.996Age × 0.932 [if female]
Where Scys is standardized serum cystatin C (in mg/L), min indicates the minimum of Scys/0.8 or 1, 
max indicates the maximum of Scys/0.8 or 1, and age = years.
Estimated GFR calculations using the CKD-EPI formulae (in both ways, based on cystatin C and 
based on creatinine) will be performed by the central laboratory.
3.2.2
Safety Variables
Safety will be assessed by descriptive analysis of AEs (including serious adverse events [SAEs] and 
adverse events leading to the discontinuation of study intervention [DAEs]), vital signs, ECGs,
laboratory assessments, echocardiography assessments and events of special interest.
Treatment-emergent throughout this document has the meaning of an event such as an AE or 
laboratory/ECG/vital sign value outside of predefined ranges occurring during on-treatment as 
defined in Section 4.2.1 and Section 4.11.2.
3.2.2.1
Adverse Events and Serious Adverse Events
Adverse events will be collected after the participant has received the first dose of study intervention
throughout the interventional period and including the follow-up period (Visit 8).
SAEs will be recorded from the time of signing of the informed consent form.


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3.2.2.2
Physical Examinations
Physical examination, and measurement of weight (analyses will be based on weight measured at the 
study site, not the home-based monitoring using the digital scales) and height will be conducted at 
the time points outlined in the SoA in Appendix A: Schedule of Activities. For further information 
on the physical examinations refer to Section 8.2.1 in the clinical study protocol (CSP).
The only information relating to physical examinations that will be included in the CSR are any 
associated AEs, the recording and reporting of which are specified in Section 8.3.5 of the clinical 
study protocol (CSP).
Body weight must be taken and reviewed before continuing treatment at each visit as indicated in the 
SoA in Appendix A: Schedule of Activities. Weight will be analysed as indicated in one of the
exploratory objectives (the third bullet point in the table from Section 2.4). 
3.2.2.3
Vital Signs
Vital signs will include resting BP, pulse, and respiratory rate measurements. For further information 
on vital signs refer to Section 8.2.2 in the CSP.
For information on how AEs based on vital sign results should be recorded and reported, refer to 
Section 8.3.5 in the CSP.
Notable changes from pre-dose at each post-dose time point for vital sign parameters will be 
identified. The predefined criteria for notable changes in vital signs values are displayed in Table 1
Table 1 Vital sign notable change predefined criteria
Vital sign
Observed
value
Notable change from
baseline
Systolic BP (mmHg)
High
≥ 140
Increase of ≥ 20
Low
< 90
Decrease of ≥ 20
Diastolic BP (mmHg)
High
≥ 90
Increase of ≥ 10
Low
< 60
Decrease of ≥ 10
Pulse Rate (bpm)
High
≥ 100
Increase of ≥ 20
Low
< 50
Decrease of ≥ 20
Respiratory Rate (breaths/min)
High
> 20
Low
< 12
BP = Blood pressure.
3.2.2.4
Electrocardiograms
Triplicate 12-lead ECGs will be performed after the participant has been resting in a supine position 
for at least 10 minutes, at the visits outlined in the SoA in Appendix A: Schedule of Activities. For
further information on ECGs refer to Section 8.2.3 in the CSP.
Digital ECGs performed at site will be transferred to Clario (ERT), where they will be centrally read 
and stored. A digital ECG machine that automatically calculates the heart rate and measures PR, RR, 
QRS, QT, and QTcF intervals will be used. Interpretation of the clinical safety digital ECG findings 
will be reviewed and confirmed by the investigator, classified as normal/abnormal and whether 
clinically significant, and recorded in the eCRF.
For information on how AEs based on ECG results should be recorded and reported, refer to Section 
8.3.5 in the CSP.


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Potentially clinically significant (PCS) ECG values will be identified from third party vendor data. 
The predefined criteria (based on severity) for PCS ECG values are displayed in Table 2.
Table 2 PCS ECG predefined criteria
Variable
Unit
Outside 
lower
limit if
Outside
upper 
limit if
AZ 
extended
reference
range -
low
AZ 
extended
reference
range -
high
Treatment 
emergent 
increase if
Extended treatment 
emergent increase if
Heart 
rate
bpm
<50
>100
<45
>120
NA
NA
<30
>150
RR 
interval
ms
<600 
>1200 
<500 
>1333 
NA
NA
<400
>2000 
PR 
interval 
ms
<110
>220
<100
>240
>40
>60
QRS
ms
<75
>115
<70
>120
>15
>30
QT 
ms
<320
>450
<300
>480
>30
>60
>500
QTcF 
ms
<320
>450*
<300
>480*
>30*
>60*
>500*
ms = milliseconds, bpm = beats per minute, NA= not applicable.
*Cut-off values for categorical analyses as recommended by ICH E14 (Note, more than one category for high range 
increases in QT/QTc values)
Note, no standard criteria are established for treatment emergent increases or decreases in RR intervals or heart rates, or 
for treatment emergent decreases in PR, QRS or QT/QTc intervals
Note, lower and upper RR interval limits and low and high RR interval reference ranges (all in ms), represent 
respectively the upper and lower heart rate limits and high and low heart rate reference ranges (all in bpm) 
3.2.2.5
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 in Appendix A: Schedule of Activities.
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 central laboratory. Sample 
tubes and sample sizes may vary depending on laboratory method used and routine practice at the 
site.
In addition, samples will also be collected for analysis of the following parameters:
!
Screening samples for parameters needed to confirm eligibility:
o
For women only: serum pregnancy test (only included in listings).
!
Samples for the determination of cystatin C by a central laboratory at the visits indicated in 
the SoA in Appendix A: Schedule of Activities.
Laboratory variables will be measured as indicated in Table 3.


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Table 3 Laboratory Safety Variables
Haematology/Haemostasis (whole blood) a
Clinical Chemistry (serum or plasma) a
White blood cell (WBC) count
Serum sodium (Na+)
Red blood cell (RBC) count
Serum potassium (K+)
Haemoglobin (Hb)
Serum urea
Haematocrit
Blood urea nitrogen (BUN)
Neutrophils absolute count
Serum creatinine
Lymphocytes absolute count
Estimated glomerular filtration rate (eGFR), 
calculated by CKD-EPI formula b
Monocytes absolute count
Uric acid
Eosinophils absolute count
Albumin
Basophils absolute count
Calcium
Platelets
Phosphate
International normalised ratio (INR) (including 
prothrombin time, required to calculate INR)
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Urinalysis
Aspartate aminotransferase (AST)
Glucose
Total bilirubin (TBL)
Erythrocytes
Creatinine kinase (CK)
Protein
Chloride (Cl-)
Albumin
Magnesium (Mg+)
Creatinine
Glucose (fasting, refer to Section 5.3.1 of the 
CSP)
HbA1c (fasting, refer to Section 5.3.1 of the 
CSP)
Other assessments a
Cholesterol and lipids (fasting, refer to Section 
5.3.1 of the CSP)
Cystatin C (serum)
Serum pregnancy test (women only, at 
screening)
NB. In case a participant shows an AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN, refer to Appendix E in the CSP.
a Central laboratory for all visits.
b eGFR will be calculated by the central laboratory analysing the sample, using the CKD-EPI formulae in both ways, based on cystatin C 
and based on creatinine.
At each visit (except for screening), the geometric mean of the triplicate urine albumin and urine 
creatinine samples will be computed and used for summarising the parameters. If any of the samples 
for triplicate urine albumin or urine creatinine are missing, then the geometric mean will be calculated 
based on the available samples for the triplicate.
3.2.2.6
Echocardiography Assessment of Cardiac Structure and Function
An assessment of cardiac structure and function using echocardiography will be performed during 
the Screening period and at Week 12. The examination is non-invasive and prior preparation is not 
required.
The following parameters will be assessed:
!
The left ventricular ejection fraction (LVEF) (%)
!
Overall echocardiography evaluation (normal/abnormal)


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!
Left ventricular wall motion
!
Method of left ventricular volume/ejection fraction calculation
!
Mitral valve evaluation
!
Aortic valve evaluation
!
Tricuspid valve evaluation
!
Pulmonic valve evaluation
!
Mitral valve closure to open time (s)
!
Tricuspid valve closure to open time (s).
3.2.2.7
Events of special interest
Changes in fluid-related measures (weight gain or BNP) meet the defined threshold to be considered 
as an event of special interest if they are as follows:
!
BNP is increased > 100% from baseline and is greater than 200 pg/mL in a participant without 
atrial fibrillation or
!
BNP is increased > 100% from baseline and is greater than 400 pg/mL in a participant with 
atrial fibrillation or
!
More than 3% increase in study site body weight (at least 2.5% of which must be from total 
body water [increase of at least 2.5% in total body water from baseline as a percentage of 
baseline study site body weight] as measured by bioimpedance) from start of treatment 
(Day 1)
3.2.3
Exploratory Variables
3.2.3.1
Bioimpedance Spectroscopy
BIS will be performed at the site at the time points specified in the SoA in Appendix A: Schedule of 
Activities to monitor body fluid volumes: total body water, extracellular fluid, and intracellular fluid.
3.2.3.2
Pharmacokinetics
Plasma samples will be collected for measurement of plasma concentrations of zibotentan and 
dapagliflozin, and exploratory zibotentan metabolite evaluation, as specified in the SoA in Appendix 
A: Schedule of Activities.
A sub-group of at least 20% of the overall study population will have 4 PK samples taken in addition 
to the pre-dose sample, spread over 4 different time points (0.5-1.0 h, 1.5-2.0 h, 2.5-3.0 h and 3.5-4.5 
h post-dose). Zibotentan and dapagliflozin concentrations will be measured separately. As indicated 
in the SoA in Appendix A: Schedule of Activities, the additional samples will be taken at Visit 4. For 
further information on the PK sub-study refer to Section 8.5.1.1 in the CSP.
Samples for determination of zibotentan and dapagliflozin concentrations in plasma will be assayed 
by Labcorp Bioanalytical Services LLC on behalf of AstraZeneca, using appropriately validated 
bioanalytical methods. Zibotentan and dapagliflozin plasma concentrations will be measured 
separately. Full details of the analytical methods used will be described in a separate Bioanalytical
Report.
Samples for zibotentan metabolite evaluation will be analysed by AstraZeneca. Results from this 
analysis may not be reported in the CSR.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.


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Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of the 
test samples. The results from this evaluation, if performed, will be reported in a separate 
Bioanalytical Report.
3.2.3.3
Pharmacodynamics
Urinary and serum/plasma parameters will be measured during the study for the evaluation of the 
exploratory endpoints.
The following parameters will be measured from the blood samples collected for safety (from Visit 
2 to 8, analysed at a central laboratory, see Section 3.2.2.5):
!
Plasma/serum K+, Na+, uric acid, BUN, and fasting plasma glucose as part of clinical 
chemistry.
!
Haematocrit and haemoglobin, as part of haematology.
Urine samples will be collected and analysed by a central laboratory for the determination of the 
exploratory urinary parameters at the time points specified in the SoA in Appendix A: Schedule of 
Activities.
The urine samples collected on visit days for the analysis of UACR (see Section 3.2.1.1) will be split, 
so that they can also be used for the determination of Na+, K+, uric acid, urea, glucose, creatinine, 
osmolality and cortisol levels. Cortisol levels will not be reported in the CSR.
Blood samples will be collected at the time points specified in the SoA in Appendix A: Schedule of 
Activities and analysed by a central or local laboratory for the determination of the following 
parameters:
!
Cystatin C, ET-1, ELDP, CT-proET-1, copeptin, NT-proBNP, and BNP. Results for ET-1, 
ELDP, CT-proET-1 and copeptin will not be reported in the CSR.
!
Fasting plasma glucose (for fasting conditions, refer to Section 5.3.1 of the CSP).
4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures.
4.2
General Presentation Considerations
4.2.1
Study Period
The following study periods are defined (if the specified visit did not take place, the date for planned 
visit should be used):
!
Overall study period – from date of Visit 1 to date of Visit 8
!
Screening period – from date of Visit 1 up to the day before Visit 2; this can be up to 
approximately 4 weeks in duration prior to randomisation
!
Treatment (Interventional) period – from date of Visit 2 to date of Visit 7
!
On-treatment period – from the same date as the first administration of study intervention until 
the earliest of: 28 days after last dose of zibotentan/placebo and/or dapagliflozin/placebo; end 
of study; lost to follow-up; and withdrawal of consent
!
Off-treatment period – from more than 28 days after the last dose of study intervention
!
Follow-up period – from day after Visit 7 to date of Visit 8


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4.2.2
Data Presentation
All efficacy and safety variables will be summarised by study treatment arm using descriptive 
statistics. The type of analysis that will be performed for a treatment arm – main (M) or only 
descriptive (D) – depends on the protocol version and study part as specified in Table 4. Note that 
descriptive analysis will also be performed for M as a way of presenting data as detailed in this SAP.
For treatment arms marked with D in Table 4, a selection of descriptive statistics will be presented. 
The outputs will be identified in the tables, listings and figures (TLF) mock shells. The following 
information will be part of these selected outputs:
!
Disposition
!
Demographics
!
Baseline characteristics
!
UACR descriptive summary
!
AEs/SAEs/DAEs
!
Vital signs
!
Clinical laboratory tests (including eGFR)
!
12-lead ECG assessment
!
Event of special interest (changes in fluid-related measures)
!
Study site body weight and total body water
!
Exposure
!
PK.
Table 4 Protocol version, study part, treatment arm and type of analysis
Protocol Version 1.0 and CSP
Amendment 1
CSP
Amendment 2
Study part
Treatment arm
A
B
-
Placebo once daily
X/D
X/D
Zibotentan 5 mg once daily
X/D
X/D
Dapagliflozin 10 mg once daily
X/D
X/M
X/M
Zibotentan
5 
mg 
+ 
Dapagliflozin 10 mg once daily
X/D
X/D
Zibotentan
1.5 
mg 
+ 
Dapagliflozin 10 mg once daily
X/M
X/M
Zibotentan
0.25 
mg 
+ 
Dapagliflozin 10 mg once daily
X/M
X/M
X marks whether the treatment arm is included under the corresponding protocol version and study part, M marks the treatment arms 
that are included in the main analysis and D marks the treatment arms that will only be presented with descriptive statistics.
For continuous variables, descriptive statistics will include the number of non-missing observations
(n), mean, standard deviation (SD), median, minimum and maximum. For log-normal variables, the 
geometric mean (GeoMean) and coefficient of variation (CV) will be presented in addition to those 
already specified for continuous variables. Continuous data that are expected to be skewed (e.g.
duration of exposure, time on study and laboratory variables) will be presented in terms of the 
maximum, upper quartile, median, lower quartile, minimum and number of observations. The 
minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean, median, lower quartile and upper quartile will be reported to one 
more decimal place than the raw data recorded in the database. The SD will be reported to two more 


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decimal places than the raw data recorded in the database. In general, the maximum number of 
decimal places reported shall be four for any summary statistic.
Categorical variables will be summarised using frequency counts and percentages. Percentages will 
be presented to one decimal place. Percentages will not be presented for zero counts. Percentages will 
be calculated using the number of non-missing observations as the denominator, unless otherwise 
specified in the TLF mock shells. If sample sizes are small, the data displays will show the 
percentages, but any textual report will describe frequencies only.
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. P-values 
less than 0.001 will be presented as “<0.001”.
Confidence intervals will be presented to one more decimal place than the raw data.
Data will be summarised by visit, as appropriate. For information on analysis visit windows, please 
refer to Section 4.2.3
‘Baseline’ is defined as the last non-missing value obtained prior to or on the same date as the 
administration of the first dose of study treatment, unless otherwise stated. For participants without a 
first dose, the last non-missing value obtained prior to or on the same date as the randomisation date 
will be used for ‘baseline’. ‘End of Study’ is defined as the last available post-treatment assessment. 
‘Study Day’ will be calculated relative to the date of first dose of study treatment i.e.:
if Assessment Date < Date of First Dose of Study Treatment, then
 	
 =  	
 −	
   	   

else if Assessment Date ≥ Date of First Dose of Study Treatment, then
 	
 =  	
 −	
   	   
 + 1
If the date of first dose of study treatment is not present, the randomisation date will be used in the 
above calculations.
4.2.3
Analysis Visit Windows
All visit-based summaries will use analysis visits. All post-randomisation scheduled and unscheduled 
visits (excluding Discontinuation visit), will be mapped to an appropriate analysis visit as shown in
Table 5.
Table 5 Analysis Visit Windows
CRF Visit
Target Day1
Protocol Visit 
Window1
Actual 
Assessment 
Day2
Analysis Visit
Visit 3 (Wk 1)
D8
D7 to D9
D2 to D15
Week 1
Visit 4 (Wk 3)
D22
D20 to D24
D16 to D32
Week 3
Visit 5 (Wk 6)
D43
D41 to D45
D33 to D53
Week 6
Visit 6 (Wk 9)
D64
D62 to D66
D54 to D74
Week 9
Visit 7 (Wk 12)
D84
D82 to D86
D75 to D91
Week 12
Visit 8 (Wk 14)
D98
D95 to D101
D92 to D129
Follow-up
1 Relative to the date of randomisation
2 Relative to the date of first dose of study treatment or randomisation date if no first dose
For visit-based summaries, if there is more than one value per participant within a time window, then 
the closest value will be summarised, or the earliest in the event the values are equidistant from the 


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nominal visit date. The listings will highlight the value for that participant that went into the summary 
table, wherever feasible.
4.2.4
Global/Country Situation Summaries
The Coronavirus Disease of 2019 (COVID-19) pandemic was declared by the World Health 
Organisation on 11th March 2020 and is considered a global/country situation. The Ukraine/Russia 
crisis started on 24th February 2022 and is considered a global/country situation. Global/country 
situation summaries will be presented (see Section 4.5.1).
4.2.5
Japan-Specific Analysis
A subset of the planned outputs will be repeated for participants from Japan, as required for 
interactions with the Japanese Regulatory Agency. The outputs will be identified in the TLF mock 
shells.
4.3
Software
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and validated 
environment.
4.4
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values. Information on how missing data will be 
handled for UACR is provided in Section 4.10.2. Missing safety data will generally not be imputed. 
However, safety assessment values (vital signs, laboratory assessments excluding urine albumin, 
urine creatinine and UACR) of the form “<x” (i.e. below the lower limit of quantification [LLOQ]) 
or “>x” (i.e. above the upper limit of quantification) will be imputed as “x” in the calculation of 
summary statistics but displayed as “<x” or “>x” in the listings. Measurements of urine creatinine, 
urine albumin and UACR which are displayed as “<x” will be imputed by using half of the “x” value, 
as this represents the LLOQ, justified by assuming that any value is equally likely between 0 and the 
LLOQ. These imputations are required in order to effectively calculate the geometric mean.
Partial or missing dates
If the start date of the concomitant medication or AE is missing, the following rules will be applied:
!
If the year is missing, the year should be imputed as the year that participant received the first 
dose of study treatment.
!
If the year is available and the month and day are missing, then impute the month as January
and the day as 01.
!
If the year and month are available and the day is missing, impute the day as 01 (the first day 
of the month).
!
If any of the above puts the date before the date of first dose of study treatment, a conservative 
approach is followed, and the date is imputed using the date of first dose if the year matches 
the year of the date of first dose of study treatment when only the year is available or if the 
year and month matches the year and month of the date of first dose of study treatment when
only the year and month are available.
If the stop date of the concomitant medication or AE is missing and there is an indication that there 
should be a stop date (ongoing flag marked as “N” for concomitant medication, outcome reported as 
resolved/fatal for AE), the following rules will be applied:
!
If the year is missing, the year should be imputed as the year that participant received the last 
dose of study treatment.


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!
If the year is available and the month and day are missing, then impute the month as December 
and the day as 31.
!
If the year and month are available and the day is missing, impute the day as the last day of 
the month (e.g. 28, 29, 30 or 31).
!
If any of the above puts the date after the date of end of study or date of death, the date is 
imputed using the earliest of the date of end of study and the date of death.
It is not expected to have missing dates for unscheduled laboratory or ECG data. However, if there 
are missing dates, for any derivations, the dates should be imputed following the rules for concomitant 
medications and AEs.
4.5
Study Subjects
4.5.1
Disposition of Subjects
A clear accounting of the disposition of all participants who enter the study (signed the informed 
consent form) will be provided, from screening to study completion.
The following summaries will be provided:
!
A summary of the number of participants screened, screen failures, randomised, treated, 
completed treatment (a participant who has not prematurely discontinued IP during the study), 
completed treatment period (a participant who has completed the last visit during the treatment 
period i.e. Visit 7, or a later visit) and completed study (a participant who has completed the 
follow-up visit at Week 14), by treatment arm and overall. In addition, reasons for not being 
treated, not completing the treatment period and not completing the study will be summarised 
by treatment arm and overall (Analysis set: Screened).
!
A summary of subject disposition related to the global/country situation (Analysis set: Full 
Analysis Set).
!
A summary of the number of participants randomised per region, country and centre, by 
treatment arm and overall (Analysis set: All randomised set).
!
A summary of Interactive Response Technology (IRT) stratification factors i.e. diabetes
(DKD participants
versus
non-DM CKD participants)
and baseline eGFR (≤ 
45 mL/min/1.73 m2 versus > 45 mL/min/1.73 m2) at randomisation by treatment arm and 
overall (Analysis set: All randomised set).
!
A summary of global/country situation study disruptions (Analysis set: Full Analysis Set).
By-participant listings of disposition details for discontinued participants, participants completing the 
study, participants affected by the global/country situation and participants with reported issues in the 
Clinical Trials Management System due to global/country situation will be provided. In addition, a 
by-participant listing of the randomisation scheme and codes will be provided.
4.5.2
Protocol Deviations
According to ICH E3 guidelines version dated 1995 (ICH 1995), 
“Protocol deviations consist of any change, divergence or departure from the study design or 
procedures defined in the protocol. Important protocol deviations (IPDs) are a subset of protocol 
deviations that may significantly affect the completeness, accuracy, and/or reliability of the study 
data or that may significantly affect a patient’s rights, safety or well-being.”


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The impact of important protocol deviations on the efficacy results will be investigated by assessing 
the robustness of the study results and conclusions to the choice of analysis set, both including and 
excluding data potentially affected by important protocol deviations.
Important protocol deviations and any action to be taken regarding the exclusion of participants or 
affected data from specific analyses are defined in the project-specific Protocol Deviation 
Specification.
For this study, the following general categories will be considered IPDs and will be summarised in 
the CSR:
!
Deviation 1: Participants who did not meet the inclusion criteria or met exclusion criteria and 
received study treatment.
!
Deviation 2: Participants assigned to treatment who received their assigned study treatment at 
an incorrect dose at one or more occasions or who received a study treatment to which they 
were not assigned.
!
Deviation 3: Participants who received prohibited medications during study treatment period
or as specified in Section 6.5.1 in the CSP.
!
Deviation 4: Participants who met study treatment discontinuation criteria but continued study 
treatment.
!
Deviation 5: Participants who persistently missed procedures related to key efficacy and 
safety objectives.
!
Deviation 6: Missed visits, assessments, or treatments that, in the Investigator’s opinion, were 
due to the COVID-19 pandemic and there was a significant effect on EITHER completeness, 
accuracy, and/or reliability of the participant’s data, OR the participant’s rights, safety or well-
being.
In addition to classifying protocol deviations (PDs) as important or non-important, PDs are also 
evaluated for whether they can be classified as resulting from COVID-19 or the Ukraine/Russia crisis.
The number and percentage of participants with any IPD will be summarised for each IPD category 
based on the full analysis set (FAS). There will be additional sections of the summary for IPDs related 
to COVID-19 and the Ukraine/Russia crisis. Participants with more than one deviation in the same 
IPD category will be counted once for that IPD category. Any participants who have deviations in 
more than one IPD category will be counted once in the overall summary.
A list of all PDs, including those reported by monitors, will be reviewed and decisions regarding how 
to handle these deviations will be documented by the study team physician, clinical pharmacology 
scientist and statistician prior to database lock (DBL). The final classification will be made prior to 
database lock.
Programmable PDs will be detected from the data recorded in the clinical database and will be 
reviewed at regular PD review meetings. At this meeting, the programmatically derived PDs will be 
checked to ensure that they have been correctly classified as important or not important PDs. 
On an ongoing basis throughout the study, monitoring notes or summaries will also be reviewed to 
determine any important post entry deviations that are not identifiable via programming. 
The final classification of IPDs will be made prior to DBL or data cut-off for final analysis. Any other 
deviations from monitoring notes or reports will be reported in an appendix to the CSR.


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A by-participant listing of important protocol deviations will be provided.
4.6
Analysis Sets
The following summaries will be provided:
!
A summary of the number of participants in each analysis set by treatment arm and overall. 
Exclusions from each analysis set will also be summarised by reason.
By-participant listings of participants excluded from each analysis set and the reasons for exclusion
from each analysis set will be provided.


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Table 6 Analysis Sets
Population/ 
Analysis set
Data selection as 
indicated in Table 4
Description
Screened
D+M
All participants who signed the informed consent 
form.
Descriptive 
Analysis Set
D
All participants randomised and who are to be
presented only descriptively as indicated with D in 
Table 4. Participants are evaluated according to the 
treatment assigned at randomisation.
All Randomised Set
M
All participants who are randomised. Participants are 
evaluated according to the treatment assigned at 
randomisation.
Full Analysis Set 
(FAS)
M
All participants who are randomised and receive any 
study treatment. Participants are evaluated according 
to the treatment assigned at randomisation.
Per 
Protocol 
Analysis Set (PPS)
M
A subset of the FAS consisting of all participants 
who completed at least 6 weeks of treatment and do 
not have any protocol deviations classified as 
important. All decisions to exclude participants from 
the PPS will be made and documented prior to the 
unblinding of the study.
Safety Analysis Set
M
All participants who are randomised and receive any 
study treatment. 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 
investigational product from the wrong kit for only 
part of the treatment duration but they received the 
correct kit at some point during treatment duration, 
they will be analysed according to their planned 
randomisation arm. If a participant receives multiple 
incorrect kits and never receives the correct kit 
during treatment duration, they will be analysed 
according to their first treated dose.
The Safety Analysis Set will be used for all safety 
analyses, unless otherwise specified.
Ambulatory Blood 
Pressure 
Monitoring Set
D
All participants in the Descriptive Analysis Set who 
have valid ambulatory BP data for change from 
baseline analyses.


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Population/ 
Analysis set
Data selection as 
indicated in Table 4
Description
Pharmacokinetic 
Analysis Set
M
All participants in the FAS who have at least one 
detectable zibotentan or dapagliflozin plasma 
concentration 
measurement 
post-treatment. 
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
investigational product from the wrong kit for only 
part of the treatment duration but they received the 
correct kit at some point during treatment duration, 
they will be analysed according to their planned 
randomisation arm. If a participant receives multiple 
incorrect kits and never receives the correct kit 
during treatment duration, they will be analysed 
according to their first treated dose.
The Pharmacokinetic Analysis Set will be used for 
all PK analyses.
Participants or sites identified prior to database lock with major Good Clinical Practice violations and 
where the integrity of the data is strongly questioned through thorough independent investigations 
will be excluded from all analyses and all analysis sets.
4.7
Demographic and Other Baseline Characteristics
Age will be taken from the demographics form in the eCRF.
Demographic and other baseline characteristics will be listed for all participants and summarised for 
the FAS as:
!
Demographics (age [years], age group [≥18-<50, ≥50-<65, ≥65-<85, and ≥85 years], sex, race 
(if collected), country and ethnicity)
!
Participant characteristics at baseline (height [cm], weight [kg], weight group [<40, ≥40-<75, 
≥75-<90, ≥90-<120, and ≥120 kg], body mass index [BMI], BMI group [Underweight (<18.5 
kg/m2), Normal weight (≥18.5 - <25.0 kg/m2), Overweight (≥25.0 - <30.0 kg/m2), Obese 
(≥30.0 kg/m2)], family history of premature cardiovascular disease [Y/N], and substance use 
[nicotine, alcohol, caffeine and drugs])
!
Baseline disease characteristics:
o
T2DM diagnosis [Y/N] and T2DM duration [years] from medical history form in the 
eCRF
o
Derived CKD stage (eGFR category) [Stage 2 (60-89 mL/min/1.73m2)/Stage 3a (45-
59 
mL/min/1.73m2)/Stage 
3b 
(30-44 
mL/min/1.73m2)/Stage 
4 
(15-29 
mL/min/1.73m2)/Stage 
5 
(<15 
mL/min/1.73m2)], 
eGFR 
(mL/min/1.73m2), 
albuminuria [defined as 150-5000 mg albumin/g creatinine, with a further 
categorisation of 'moderate albuminuria’ for 150-300 mg albumin/g creatinine and 


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‘severe albuminuria’ for >300-5000 mg albumin/g creatinine; count and percentage of 
participants meeting criteria], UACR (mg/g)
o
CKD diagnosis, including primary renal diagnosis [Cystic kidney disease, Diabetic 
nephropathy, Ischaemic/Hypertensive nephropathy, Chronic glomerulonephritis, 
Renal artery stenosis, Chronic pyelonephritis (infectious), Chronic interstitial 
nephritis, Obstructive nephropathy, Unknown, Other (Specify)]
and chronic 
glomerulonephritis type [IgA nephropathy, Focal segmental glomerulosclerosis 
(FSGS), Membranous nephropathy, Minimal change (which is part of exclusion 
criteria 1), Lupus nephritis, Other primary or secondary glomerulonephritis (Specify)]
from CKD diagnosis form in the eCRF
o
Angiotensin-converting enzyme inhibitor (ACEi) history [Y/N]
o
Angiotensin receptor blocker (ARB) history [Y/N]
o
Mineralocorticoid receptor agonist (MRA) history [Y/N]
Medical history and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 or later. The frequency and percentage of participants with each condition 
will be summarised by system organ class (SOC) and preferred term (PT). Participants with multiple 
unique terms will be counted once per each unique PT and unique SOC. A participant can have one 
or more PTs reported under a given SOC. Each summary will be sorted alphabetically by SOC and 
PT, unless otherwise stated.
By-participant listings of demographic data (including age, sex, race, baseline weight, baseline height 
and baseline BMI) and the baseline disease characteristics data detailed above will be provided.
4.8
Concomitant Medication
Any medication or vaccine (including over-the-counter or prescription medications, vitamins, and/or 
herbal supplements) that the participant is receiving on or after the date of first dose of randomised 
treatment (and could have started prior to or during treatment) will be recorded as concomitant. 
Medications starting after the date of discontinuation from study treatment/withdrawal from study 
will be listed but will not be classified or summarised. Medications completed prior to the date of 
first dose of randomised treatment will be listed but will not be classified or summarised.
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first dose of randomised treatment. Medications will be assumed to be 
concomitant unless there is clear evidence (through comparison of partial dates) to suggest that the 
medication stopped prior to first dose of randomised treatment.
The medications and supplements listed below are prohibited from the time of consent and for the 
duration of the study. Participants taking any of these medications at the time of randomisation cannot 
be included into the study:
!
SGLT2i.
!
Direct renin inhibitor (e.g. Aliskiren).
!
Cyclosporin or tacrolimus.
!
Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for 
primary or secondary renal disease within 6 months prior to screening.


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In addition to the above, the following medications cannot be initiated or any changes to dose made 
after the participant has consented, and until the participant has completed the study (or discontinued 
/ withdrawn participation):
!
ACEi.
!
ARB.
!
Angiotensin receptor neprilysin inhibitor (ARNi).
!
MRA.
A medical review will be performed to determine whether a medication is classified as prohibited and 
this medically reviewed classification of prohibited medications will be used for any outputs 
involving prohibited medications.
Concomitant medications will be summarised for the FAS by drug class and (generic) drug name. A 
summary table by drug class and generic drug name will be generated for each of the following:
!
all allowed concomitant medication taken during the study
!
prohibited concomitant medication taken during the study
A by-participant listing of concomitant medications at study entry and taken during treatment will be 
presented.
4.9
Treatment Compliance
Treatment compliance will be assessed by direct questioning and counting returned 
zibotentan/placebo capsules and dapagliflozin/placebo tablets 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.
A record of the number of zibotentan/placebo capsules and dapagliflozin/placebo tablets dispensed 
to and taken by each participant must be maintained and reconciled with study intervention and 
compliance records.
For all calculations of compliance below, dispensed and returned refers to capsules/tablets taken at 
clinic and at home.
The percentage treatment compliance for zibotentan/placebo will be calculated from the number of 
capsules returned as:

  −
 

    
 
× 100
The percentage treatment compliance for dapagliflozin/placebo will be calculated from the number 
of tablets returned as:

  −
 

    
 
× 100
The overall percentage compliance will be calculated from the number of capsules and tablets 
returned as:

  
  −
  
 

  
    
 
× 100


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A participant is expected to take one capsule and one tablet each day while on study treatment as 
indicated by the dosage regimen in the CSP, such that interruptions could mean compliance of less 
than 100%. The number of capsules and/or tablets expected to be taken is based on the number of 
study days between every set of clinic visits from Visit 2 to the end of treatment/early discontinuation 
visit. For any visits where a participant is required to take study treatment in clinic, the study treatment
would be included in the study treatment expected to be taken between the last visit and the current 
visit.
Participants taking ≥80% and ≤120% of planned study treatment are considered to be compliant.
Study compliance percentage for zibotentan/placebo, dapagliflozin/placebo and overall will be 
summarised for the FAS as follows:
!
Descriptive statistics will be summarised by treatment arms and overall. 
!
Percent compliance will be categorised according to the following categories:
o
<80% (drug non-compliance)
o
≥80% and ≤120% (drug compliance)
o
>120% (drug non-compliance)
A by-participant listing of treatment compliance data will be provided.
4.10 Efficacy Evaluation
4.10.1 Analysis and Data Conventions
4.10.1.1 Null Hypothesis for Primary Objective and Related Secondary Objective
This study is designed to test for superiority and assess the dose-response relationship. The null 
hypothesis for the primary treatment comparison will be that there is no difference between zibotentan
1.5 mg and dapagliflozin 10 mg in combination and dapagliflozin 10 mg monotherapy in UACR. The 
alternative hypothesis will be that there is a difference. Symbolically, this is expressed as follows:
H(0): ∀(zibotentan 1.5 mg and dapagliflozin 10 mg in combination) = ∀(dapagliflozin 10 mg 
monotherapy)
H(1): ∀(zibotentan 1.5 mg and dapagliflozin 10 mg in combination) < ∀(dapagliflozin 10 mg 
monotherapy)
Where ∀represents the least squares mean change in log-transformed UACR from baseline to 
Week 12. A one-sided test with #=0.05 will be used to test this hypothesis.
The null and alternative hypotheses for the secondary efficacy treatment comparison of the difference 
between zibotentan 0.25 mg and dapagliflozin 10 mg in combination and dapagliflozin 10 mg 
monotherapy in UACR will be the same as described above for the primary efficacy treatment 
comparison (with the treatment arms updated as required).
4.10.1.2 Multi-centre Studies
No per centre (where the term ‘centre’ defines each investigator site) summaries or analyses will be 
performed.


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4.10.1.3 Examination of Subgroups
When subgroup analyses are performed, it will be by diabetes (DKD versus non-DM CKD) and by 
stratification eGFR (≤ 45 mL/min/1.73m2 versus > 45 mL/min/1.73m2). No formal statistical testing 
will be performed within these subgroups.
4.10.2 Analyses of UACR Objectives
4.10.2.1 Primary Estimand for Primary Objective
The primary estimand is a hypothetical estimand such that the treatment effect is quantified in the 
optimal situation where any potential confounder is minimised. The analysis will be performed on
the FAS. The endpoint being assessed is the change in log-transformed UACR from baseline to Week 
12. Participants will be included in the analysis if they have a non-missing baseline and at least one 
non-missing post-treatment visit UACR measurement.
For the intercurrent events (ICEs), if a participant dies, prematurely discontinues study treatment, or 
uses prohibited medication, the UACR data are treated as missing after the event and no imputation 
will be performed. The summary measure being evaluated is the geometric mean reduction of UACR 
from baseline to Week 12.
The estimand is specified through the following definitions of population, variable, treatment 
condition, ICEs, and population-level summary:
Target population: 
Defined by the inclusion/exclusion criteria. 
Variable: 
Change in log-transformed UACR from baseline to Week 12.
Treatment condition: 
Zibotentan 1.5 mg combined with dapagliflozin 10 mg versus 
dapagliflozin 10 mg.
Intercurrent events: 
Death, premature discontinuation from study treatment, or use of 
prohibited medication (Handled by hypothetical strategy i.e. UACR 
data are treated as missing after the event. Deaths are expected to be 
relatively few and will be handled in the context of missing data).
Population-level summary: Difference in least squares mean change in log-transformed UACR from 
baseline to Week 12 between zibotentan 1.5 mg combined with 
dapagliflozin 10 mg and dapagliflozin 10 mg.
4.10.2.2 Primary Analysis of Primary Objective
The primary efficacy endpoint for this study is the change in log-transformed UACR from baseline 
to Week 12. As UACR is assumed to follow a log-normal distribution, it will be log-transformed for 
statistical analysis purposes. The mean log changes in UACR at Week 12 (#$%, #$') for zibotentan
1.5 mg combined with dapagliflozin 10 mg and dapagliflozin 10 mg alone will be estimated using a 
mixed model repeated measures [MMRM] method (Weeks 3, 6, 9, and 12). The least squares means
will be back transformed to give the geometric mean change from baseline to Week 12. The geometric 
means will be converted to percentage mean change for Week 12 from baseline on the original scale
using the following formula:
()*
(+,-../%'0123.456.) −1) × 100
The change in UACR from baseline to Week 12 for zibotentan 1.5 mg combined with dapagliflozin 
10 mg compared to the dapagliflozin 10 mg monotherapy arm will be presented as a geometric mean 
ratio. The analysis model will include the fixed categorical effects of CSP version (Amendment 2 


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versus pre-Amendment 2), diabetes (DKD versus non-DM CKD), treatment, visit, and treatment-by-
visit interaction, plus baseline eGFR strata (<= 45 versus > 45 mL/min/1.73 m2), log(UACR) and 
baseline log(UACR)-by-visit interaction. An unstructured covariance structure will be used for the 
within-participant errors. The denominator degrees of freedom will be estimated using the Kenward-
Roger approximation. If the MMRM model does not converge using an unstructured covariance 
structure, the Toeplitz, first-order autoregressive or compound symmetric covariance structure will 
be used. If that does not resolve the convergence issues, the analysis will be altered to use an analysis 
of covariance (ANCOVA) with a missing at random (MAR) multiple imputation (MI) method 
implemented (Section 4.10.2.3).
The geometric means, along with the conversion to percentage, for change from baseline to Week 12 
from the model, and the 90% confidence intervals will be presented. The geometric mean ratio, which 
is the back-transformed least squares mean difference in change from baseline to Week 12 between 
two treatment arms, will be converted to adjusted percentage mean change between treatment arms
as follows:
[() *
 ,
 −1) × 100]
The geometric mean ratio and the adjusted percentage mean change between treatment arms, as 
specified above, and the 90% confidence interval will be presented.
UACR will be summarised by treatment arm and visit in terms of absolute values and percentage 
change from baseline.
A plot showing the percentage mean change from baseline in UACR over time within each treatment 
arm will be provided.
A by-participant listing of the UACR data will be provided.
Sensitivity analyses
The following sensitivity analyses will be performed:
!
The mean log change from baseline in UACR at Week 12 for zibotentan 1.5 mg combined 
with dapagliflozin 10 mg and dapagliflozin monotherapy on the PPS, using a MMRM method 
as described above.
!
A multiple imputation analysis if not used as the primary analysis; see Section 4.10.2.3 for 
details.
!
A tipping point analysis, depending on the results of the multiple imputation analysis; see 
Section 4.10.2.4 for details.
!
A jump to reference analysis; see Section 4.10.2.5 for details.
Subgroup analyses
A forest plot will present the least squares mean and 90% CI overall and for each subgroup 
individually. The overall least square means will be taken from the primary analysis model and the 
subgroup least squares means will be taken from models including treatment arm by diabetes (DKD 
versus non-DM CKD) and treatment arm by stratification eGFR (below or equal versus above 
45 mL/min/1.73m2), respectively. Homogeneity assessments between the DKD and the non-DM 
CKD sub-populations, and between the stratification eGFR below or equal to 45 mL/min/1.73m2 and
the stratification eGFR above 45 mL/min/1.73m2 sub-populations, will be performed by visual 
inspection of the subgroups in the forest plot and by assessing the interaction p-values from the 
models.


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4.10.2.3 Multiple Imputation
The MI method specified in this section will either be a sensitivity analysis based on the primary 
estimand strategy or will be the primary efficacy analysis if no covariance structures for the MMRM 
converge. The MI will be performed on the FAS. It will involve the following steps:
Step 1 – Imputation Preparation
The dataset of participants with observed values, excluding any values after the ICEs specified in 
Section 4.10.2, and those needing estimation by multiple imputation will be created. The UACR 
values will be log-transformed.
Step 2 – Imputation
Imputation is the generation of multiple copies of the original dataset by replacing missing values by 
using an appropriate stochastic model. The missing data will be imputed using the Fully Conditional 
Specification (FCS) method. The FCS method is based on an iterative algorithm; at each iteration and 
for each variable of the prediction model, there is a prediction step and an imputation step. The models 
used for prediction and imputation will be linear regression models. A total of 200 imputations will 
be performed using a seed of 12345. 
The imputation model will include treatment arms, CSP version (Amendment 2, pre-Amendment 2),
diabetes (DKD, non-DM CKD), baseline eGFR strata (<= 45 versus > 45 mL/min/1.73 m2), baseline 
log(UACR), and the log(UACR) at each previous post-baseline visit. 
Step 3 – Analysis
The analysis step is performed for each of the imputed datasets. The statistical method for analysis of 
the change in log-transformed UACR from baseline to Week 12 will be ANCOVA and will include 
the same covariates as the MMRM that is specified in Section 4.10.2.2, except that the visit and by-
visit interaction variables – for treatment and baseline log(UACR) – will not be included.
Step 4 – Pooling
Pooling is the combination of the different parameter estimates across the multiple imputed datasets 
based on Rubin’s rules (Rubin, 2004
2004) to produce a unique point estimate and standard error taking into account the uncertainty of the 
imputation process.
4.10.2.4 Tipping Point Analysis
In order to check the assumption that the missing data is not MAR, a tipping point analysis will be 
conducted based on the multiple imputation analysis in Section 4.10.2.3. The objective of the tipping 
point analyses is to identify assumptions about the missing data under which the conclusions from
the main analysis change. These tipping point analyses will only be performed if the multiple 
imputation analysis results show a reduction in UACR for zibotentan 1.5 mg and dapagliflozin 10 mg 
in combination versus dapagliflozin 10 mg monotherapy.
If there is a reduction in UACR for zibotentan 1.5 mg and dapagliflozin 10 mg in combination versus 
dapagliflozin 10 mg monotherapy, additional tipping point analyses will be repeated after increasing 
the imputed log(UACR) values in the zibotentan 1.5 mg and dapagliflozin 10 mg in combination arm 
by ascending log(UACR) (1, 2, 3… etc.), with the goal to find the “tipping point” that will 
significantly reverse the analysis result. The smallest delta, for which a reduction in UACR cannot be 
shown anymore, will be the “tipping point”. The delta will only be applied to the Week 12 imputed 
values for all missing data regardless of the reason for imputation.


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For each value of delta, summary tables will include number of participants, the estimates described 
in Section 4.10.2.2 (such as geometric mean and geometric mean ratio) and their 90% CIs, and 
corresponding p-values.
This sensitivity analysis will be performed on the FAS.
4.10.2.5 Jump to Reference Analysis
The jump to reference analysis assumes that the participants who experience ICEs in the active 
zibotentan treatment arms immediately change to the mean of the dapagliflozin 10 mg arm at the 
relevant time point, where the participant’s residual relative to that of their treatment arm prior to the 
ICE is taken into account.
A sequential modelling approach will be used to implement the jump to reference analysis. Firstly, 
all missing values will be imputed under the MAR assumption as described in Section 4.10.2.3
(Steps I and II). Then data after an ICE in the active zibotentan treatment arms will be reset to missing. 
Missing data in the active zibotentan treatment arms will be imputed sequentially by visit using 
observed and imputed data from the reference arm. One imputation will be performed for each 
imputation already performed under the MAR assumption, thereby maintaining the overall number 
of imputations at 200, using a seed of 12345. The analysis and pooling steps will then be performed 
as described in Section 4.10.2.3.
4.10.2.6 Supplementary Analysis of Primary Objective
The treatment policy estimand is specified through the following definitions of population, variable, 
treatment condition, ICEs, and population-level summary:
Target population: 
Defined by the inclusion/exclusion criteria. 
Variable: 
Change in log-transformed UACR from baseline to Week 12.
Treatment condition: 
Zibotentan 1.5 mg combined with dapagliflozin 10 mg versus 
dapagliflozin 10 mg.
Intercurrent events: 
Death, premature discontinuation from study treatment, or use of 
prohibited medication (Handled by the treatment policy strategy i.e. 
UACR data after the event will be included if collected. Deaths are 
expected to be relatively few and will be handled in the context of 
missing data).
Population-level summary: Difference in least squares mean change in log-transformed UACR from 
baseline to Week 12 between zibotentan 1.5 mg combined with 
dapagliflozin 10 mg and dapagliflozin 10 mg.
The primary analysis in Section 4.10.2.2, excluding the sensitivity and subgroup analyses, will be 
replicated for the treatment policy estimand, with the exceptions that the analyses will be performed 
on the All Randomised Set and that step 1 in the MI (Section 4.10.2.3) will not exclude any UACR 
values from after an ICE.
4.10.2.7 Analysis of Secondary UACR Objectives
Comparison of zibotentan 0.25 mg and dapagliflozin 10 mg combined to dapagliflozin monotherapy
(Secondary Objective Related to Primary Objective)
The geometric mean ratio of UACR for the zibotentan 0.25 mg combined with 10 mg dapagliflozin 
versus 10 mg dapagliflozin alone from baseline to Week 12 will be assessed. The MMRM model as 
described in Section 4.10.2.2 will be used to extract the results.


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The results of the model parameters (estimates, p-values and 90% CIs) will be presented. Analyses 
and definitions described in Section 4.10.2.1, 4.10.2.2, 4.10.2.3, 4.10.2.4, 4.10.2.5 and 4.10.2.6 will 
be followed with the treatment arm adjusted as appropriate.
Dose-response Relationship Secondary Objective
The dose-response relationship between different doses of zibotentan/a fixed dose of dapagliflozin
and UACR reduction will be characterised by assessing the UACR reduction analysed in the primary 
objective and the secondary objective related to the primary objective.
In order to select the dose for future studies, a more comprehensive PK analysis, including additional 
dose and exposure response models and modelling of safety events, will be performed by the 
AstraZeneca PK team based on subject level data. This will only be done where there is sufficient 
data that allows the AstraZeneca PK team to perform the modelling.
4.10.3 Analysis of Secondary Objectives Other Than UACR
The secondary efficacy variables will be based on a similar estimand to the primary estimand for the 
primary objective in Section 4.10.2.1, with the variable and population-level summary updated to be 
relevant to the secondary efficacy variable specified.
Office systolic and diastolic BP
The change from baseline to Week 12 in office systolic and diastolic BP will be assessed for doses 
of zibotentan combined with dapagliflozin 10 mg compared to dapagliflozin 10 mg monotherapy. 
This will be analysed using the MMRM method specified in Section 4.10.2.2, adjusting for the same 
variables, though with baseline BP replacing baseline log(UACR). The FAS will be used for this 
analysis and BP will be evaluated on the original scale.
The results of each MMRM will be presented by treatment arm. A summary of change from baseline 
of office systolic and diastolic BP results will be presented by treatment arm and a by-participant
listing of office systolic and diastolic BP results at each visit will be provided. Plots of the mean office 
systolic and diastolic BP over time up to follow-up visit will be presented.
As a sensitivity analysis, a MMRM will be performed for office systolic and diastolic BP up to Week 
12, analysed on the PPS, similarly to that described above.
eGFR
The effect of different doses of zibotentan and dapagliflozin in combination compared to 
dapagliflozin 10 mg monotherapy on eGFR will be determined from the change in eGFR from 
baseline to Week 1, from baseline to Week 12, from baseline to Week 14 and from Week 1 to 
Week 12. Change from baseline to Week 1, baseline to Week 12, baseline to Week 14 and Week 1 
to Week 12 will be analysed using the MMRM methodology specified in Section 4.10.2.2. Change 
from baseline to Week 1, change from baseline to Week 3, change from baseline to Week 6, change 
from baseline to Week 9, change from baseline to Week 12 and change from baseline to Week 14
will be included in the model, adjusting for the fixed categorical effects of CSP version (Amendment 
2 versus pre-Amendment 2), diabetes (DKD versus non-DM CKD), treatment visit, and treatment-
by-visit interaction, plus the continuous covariates of baseline eGFR and baseline eGFR-by-visit 
interaction. The FAS will be used for these analyses and eGFR will be evaluated on the original scale.
The results of each MMRM will be presented by treatment arm. A summary of change from baseline 
of eGFR results will be presented by treatment arm and a by-participant listing of eGFR results at 
each visit will be provided. A plot of the least squares means by treatment arm over time will be 
presented.


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As a sensitivity analysis, a MMRM will be performed for eGFR from baseline to Week 1, from 
baseline to Week 12, from baseline to Week 14 and from Week 1 to Week 12, analysed on the PPS, 
similarly to that described above.
A visual inspection of the plot of the least squares means, mentioned above, will be used to examine 
the eGFR slope from baseline to Week 12.
4.10.4 Exploratory Evaluations
The exploratory efficacy variables will be based on a similar estimand to that described for the 
primary efficacy variable in Section 4.10.2.1, with the variable and population-level summary 
updated to be relevant to the exploratory efficacy variable specified.
The following exploratory endpoints will be summarised by treatment arm based on the FAS:
!
Body weight changes in response to different doses of zibotentan and dapagliflozin in 
combination versus dapagliflozin 10 mg monotherapy, throughout the interventional period.
!
Evaluation of changes in body fluid volume and distribution over time during the study. 
Change in total body water, extracellular fluid, and intracellular fluid volumes will be 
analysed.
Descriptive summary statistics, including change from screening, by treatment arm based on the 
ABPM set will be presented for:
!
Mean 24-hour systolic and diastolic BP in ABPM at screening, Week 6 and Week 12.
4.11 Safety Evaluation
All safety summaries and analyses will be based upon the Safety Analysis Set as defined in Section
4.6 and the on-treatment period as defined in Section 4.2.1, unless otherwise specified. Safety 
summaries will be presented by treatment arm.
Change from baseline will be calculated as the difference between the post-dose value at each time 
point and the last non-missing value prior to or on the same date as administration of the first dose of 
investigational products.
Individual safety and tolerability data will be provided in data listings and summarised as appropriate 
by treatment and overall. Continuous variables (laboratory parameters, ECG, and vital signs) will be 
summarised using descriptive statistics (n, mean, SD, minimum, median, and maximum) as 
appropriate by scheduled assessment time point. Where applicable, data will be summarised for the 
observed value, and for the corresponding change from baseline/screening. Categorical variables will 
be summarised in frequency tables (counts and percentage) as appropriate by scheduled assessment 
time point.
Changes from baseline in categorical data will be summarised using shift tables where appropriate.
4.11.1 Extent of Exposure
The extent of exposure (days) will be derived for zibotentan and dapagliflozin, combined, as follows:
	
   (
) = 	
  
  −	
    + 1
The following extent of exposure summaries will be provided for zibotentan and dapagliflozin
(combined):
!
Duration of exposure (days)


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!
A summary of the duration of exposure to treatment (days) and cumulative exposure over time 
(≥1 day, ≥8 days, ≥22 days, ≥43 days, ≥64 days, ≥85 days), by treatment arm.
!
Time on study (days) defined as:
   (
) = (	
  
  
  	
  :ℎ
:
) −
	
  

 + 1.
A listing for study drug administration according to protocol and the reason if the study drug 
administration is not according to protocol will be produced for the Safety Analysis Set.
A Kaplan-Meier figure for time to premature study drug discontinuation will be produced for the 
Safety Analysis Set. Time to premature study drug discontinuation (days) will be defined as:
!
	
  
 
   < −	
    + 1
for 
participants who prematurely discontinue study drug
!
	
  
 = 
  ℎ 
  −	
    + 1
for 
participants who do not prematurely discontinue study drug but are lost to follow-up during 
the treatment period
!
*(>ℎ
:
   
, 	
  
ℎ, 	
  ? 7,
	
   
 86) −	
    + 1 for any other participants who do not 
prematurely discontinue study drug.
4.11.2 Adverse Events
Adverse events will be coded using MedDRA version 25.0 or a later version, if available.
AEs (and also separately SAEs) will be summarised by study treatment arm in incidence summaries 
by MedDRA SOC and PT. AEs will be assigned to the period where they start and will be summarised 
for the Safety Analysis Set. SAE collection will begin after the participant signs the informed consent 
document, and all AE collection will begin after the participant has received the first dose of the study 
intervention. The SAE/AE collection will last until the end of the participant’s follow-up period.
All AEs will be listed and assigned to on/off treatment period as:
!
Prior treatment: The SAE occurred before the first administration of study intervention. 
Only applicable for SAEs.
!
On treatment: The AE occurred on the same date or after the first administration of study 
intervention until the earliest of: 28 days after last dose of zibotentan/placebo and/or 
dapagliflozin/placebo; end of study; lost to follow-up; and withdrawal of consent.
!
Off treatment: The AE occurred more than 28 days after the last dose of study intervention.
!
On + off treatment: The AE occurred on the same date or after the first administration of 
study intervention.
All AE summary tables will be presented for on treatment AEs and for on + off treatment AEs. Prior 
treatment and off treatment AEs will be listed but not summarised.
An overview of AEs will be presented for each treatment arm; the number and percentage of 
participants with any AE, any AE with outcome of death, any SAE, any DAE, any AE leading to 
study treatment dose interruptions, any AE leading to withdrawal from the study, and any AE possibly 
related to study treatment, as well as the number of individual occurrences in those categories.
The number and percentage of participants reporting AEs, SAEs and DAEs in each treatment arm
will be tabulated by SOC and PT. If more than one event occurs with the same preferred term for 


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the same participant, the participant will be counted only once for that preferred term using the most 
severe and most related occurrence for the summarisation by intensity and by relationship to the 
study treatment.
The distribution of AEs by intensity and relationship to study treatment will be summarised by 
treatment arm.
The incidence of common (≥5% of participants in any treatment arm) AEs will be summarised by PT
and treatment arm, sorted in decreasing overall (across treatments) frequency. For each participant 
and each AE, the worst intensity recorded will be attributed and used in the by-intensity summaries. 
Similarly, the worst causality will be attributed and used in the by-causality summaries. Multiple 
occurrences of an AE in the same participant will only be counted once overall. Non-serious AEs 
occurring in more than 5% of participants will be presented by treatment arm.
In addition, a tabulation of AEs, by PT, relevant for assessment of potential proarrhythmic effect will 
be provided based on the SMQ “Torsade de pointes/QT prolongation” (narrow and broad scope) and 
PT Seizure. A tabulation of AEs by PT will be provided for the SMQ “Haemodynamic oedema, 
effusions and fluid overload” (narrow scope).
Listings will be presented of participants with SAEs, AEs leading to discontinuation, and participants 
who died. A listing will be presented of participants with AEs, detailing whether these are SAEs, AEs 
leading to discontinuation, or result in death. Listings will include on- and off-treatment 
categorisation.
4.11.3 Deaths, Serious Adverse Events, and Adverse Events Leading to the Discontinuation of 
Study Intervention
The following summaries will be provided:
!
A summary of the number and percentage of participants reporting an AE with outcome of 
death by treatment arm, SOC and PT
!
A summary of key participant information for participants reporting an AE with outcome of 
death
!
A summary of the number of SAEs reported by treatment arm, SOC and PT
!
A summary of the number and percentage of participants reporting a SAE by treatment arm, 
SOC and PT
!
A summary of key participant information for participants reporting a SAE
!
A summary of the number and percentage of participants reporting a DAE by treatment arm, 
SOC and PT
!
A summary of key participant information for participants reporting a DAE.
4.11.4 Clinical Laboratory Evaluation
The following summaries will be provided:
!
A summary, which will cover n, mean, SD, minimum, Q1, median, Q3, and maximum, of the 
observed values and change from baseline for all clinical chemistry (including cystatin C),
haematology and quantitative urinalysis parameters by treatment arm and time point
!
A summary of baseline to maximum observation on treatment in each clinical chemistry 
(including cystatin C) and haematology laboratory parameter by treatment arm (shift table)


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!
A summary of baseline to minimum observation on treatment in each clinical chemistry 
(including cystatin C) and haematology laboratory parameter by treatment arm (shift table)
!
A plot of ALT versus total bilirubin, expressed as multiples of upper limit of normal (ULN)
!
A plot of AST versus total bilirubin, expressed as multiples of ULN
!
A summary of the number and percentage of participants reporting maximum on-treatment ALT 
and AST by maximum total bilirubin for assessing Hy’s Law criteria
!
A summary of individual participant data for participants with Potential Hy’s Law i.e. participants 
with combined ALT or AST, and bilirubin elevations
!
A summary of key participant information for participants with treatment-emergent changes in 
laboratory parameters (refers to clinical chemistry and haematology, other laboratory parameters 
are in supportive listings) outside of pre-defined criteria
!
A summary of treatment-emergent laboratory changes (see Appendix C: Treatment-Emergent 
Changes in Relevant Laboratory Parameters)
!
A summary of baseline versus maximum value on treatment for urinalysis by treatment arm (shift 
table)
!
A summary of treatment-emergent urinalysis changes
Treatment-emergent changes in relevant laboratory parameters outside pre-defined criteria for this 
study are provided in Appendix C: Treatment-Emergent Changes in Relevant Laboratory Parameters.
Treatment-emergent urinalysis changes are defined as: negative/trace at baseline to ++, +++, ++++ 
at any visit after baseline or an increase of at least ++, for example + to +++, ++ to ++++.
By-participant listings of all laboratory data will be provided including participant identifier, 
treatment, age, sex, race, visit, category, lab test name, result, change from baseline (where 
appropriate) and standard units. Laboratory reference ranges will also be listed and out of range values 
will be flagged.
BNP values from local laboratories will only be presented in listings; the central laboratory values 
will be used for summary tables and presented in listings. Results for central NT-proBNP will not be 
reported in the CSR.
4.11.5 Vital Signs, Electrocardiograms, Echocardiography and Other Observations Related 
to Safety
The number and percentage of participants with normal and abnormal ECG readings by visit will be 
presented by treatment arm. Abnormal ECG results and reasons entered into the eCRF will be listed 
by participant and by visit.
For by-visit summaries, the last non-missing assessment (including repeat assessments) recorded at 
each applicable scheduled visit will be summarised.
The following summaries will be provided:
!
A summary, which will cover n, mean, SD, minimum, Q1, median, Q3, and maximum, of the 
observed absolute values and change from baseline for all vital sign parameters by treatment 
arm and time point.
!
A summary of key participant information for participants reporting notable changes outside 
predefined criteria for all vital sign parameters.


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!
A summary of the number and percentage of participants experiencing notable changes from 
baseline outside predefined criteria, by vital sign parameter and treatment arm.
!
A summary of the observed absolute values and change from baseline in each ECG parameter
(excluding QTcB) by treatment arm and time point.
!
A summary of ECG assessment (normal/abnormal [clinically significant, not clinically 
significant]), baseline versus last observation on treatment.
!
A summary of key participant information for participants reporting PCS ECG values
(excluding QTcB) outside predefined criteria.
!
A summary of the number and percentage of participants reporting PCS ECG values
(excluding QTcB) outside predefined criteria, by ECG parameter and treatment arm.
!
A summary of the overall evaluation for echocardiography (normal/abnormal) and LVEF by 
treatment arm and time point.
By-participant listings of vital sign parameters, ECG parameters, ECG findings, echocardiography 
parameters, and weight, height and BMI will also be provided.
4.11.5.1 Fluid-Related Measures
Changes in fluid-related measures (weight gain or BNP) meet the defined threshold to be considered 
as an event of special interest if they meet the criteria defined in Section 3.2.2.7.
A summary of the number, percentage, incidence rate per participant exposure year (PEY) and 
incidence rate per participant year of participants reporting fluid-related events of special interest will 
be produced for the Safety Analysis Set, by treatment arm. The relative risk and one-sided 80% CI, 
where the standard error of the relative risk is based on the Katz-log method, for the composite of any 
fluid-related events of special interest compared to the dapagliflozin 10 mg arm will be presented.
The incidence rate per 100 PEY is defined as below for on-treatment:
C  D :ℎ=  
  -

 
  (
)  
 =  
 
F × 365.25 × 100
The time at risk, in days, for each participant for a fluid-related event of special interest is:
!
*(	
  
  + 28,   ,   :-,
:ℎ
:
  ) −	
    + 1 for participants who do not have an
on-treatment event
!
	
     =  
  -
 −
	
    + 1 for participants who have an on-treatment event.
The denominator is calculated per participant then summed.
The incidence rate per 100 participant years is defined as below for on+off treatment:
C  D :ℎ=  
  + 

   (
)   
 =  
 
F × 365.25 × 100


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The time in study, in days, for each participant for a fluid-related event of special interest is:
!
	
     −	
    + 1 for participants who do not have an 
on+off treatment event
!
	
     =  
  + 
 −
	
    + 1 for participants who have an on+off treatment event.
A by-participant listing of percentage weight gain from baseline, total body water change from 
baseline as a percentage of baseline weight, percentage change from baseline in BNP, BNP value and 
atrial fibrillation indicator will be provided.
4.12 Other Analyses
4.12.1 Pharmacokinetics
‘Baseline’ is defined as the last non-missing value obtained prior to the administration of the first 
dose of study treatment, taking into account both the date and time of the non-missing value and the 
first dose of study treatment.
The following exploratory PK endpoints will be summarised by treatment arm, visit and timepoint
based on the Pharmacokinetic Analysis Set:
!
Plasma concentration of zibotentan and dapagliflozin.
!
Dose of zibotentan relative to safety and PD variables (blood NT-proBNP, BNP, creatinine, 
and cystatin C, and urine albumin and creatinine).
Summary tables will be provided covering the results of the PK sub-study at Week 3.
All PK summary tables will include samples from visits for participants who had not previously 
permanently discontinued study treatment. PK listings will include samples from participants 
regardless of whether they were from visits after the participant had discontinued study treatment.
Additional PK analyses may be conducted as appropriate. Results for NT-proBNP will not be reported 
in the CSR.
The summary of plasma concentration of zibotentan metabolites are outside the scope of this SAP.
4.12.2 Pharmacodynamics
The following exploratory PD endpoints will be summarised by treatment arm based on the FAS:
!
Change in plasma/serum concentrations of K+, Na+, uric acid, BUN, fasting plasma glucose, 
haematocrit, and haemoglobin over time during the study. Results for ET-1, ELDP,
CT-proET-1 and copeptin will not be reported in the CSR.
!
Evaluation of changes in cardiovascular biomarkers in blood (NT-proBNP and BNP) over 
time during the study. Results for NT-proBNP will not be reported in the CSR.
4.12.3 Potential Future Exploratory Research and Optional Genetic Research
The following analyses will not be part of the CSR:
!
Evaluation of changes in blood and urine biomarkers relevant to cardiorenal mechanisms, 
inflammation, and fibrosis over the time course of the study.
!
Optional exploratory research into genes/genetic variation that may influence response to 
treatment.


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Analyses for these exploratory objectives are outside the scope of this SAP.
4.13 Interim Analysis
Up to 2 administrative interim analyses may be performed. The first interim analysis may occur after 
50% of participants (only considering the 415 participants randomised to the three treatment arms 
still in the CSP Amendment 2 study design and specified as part of the main analysis in Table 4) have 
completed 6 weeks of treatment or at a time selected by the sponsor, and a second interim analysis 
may be performed after 100% of participants have completed 6 weeks of treatment or at a time
selected by sponsor / percentage of participants with a planned week 6 visit before data cut selected 
by sponsor. The objective of the administrative interim analyses will be to decide if an 
 
zibotentan/dapagliflozin project activities 
 
 on the interim data.
An internal URC of AstraZeneca representatives is set up for this study for ongoing safety monitoring 
and reviewing the unblinded interim results. Changes in fluid-related measures (weight gain or BNP) 
that meet the defined threshold (see Section 4.11.5.14.11.5) will be reported as an event of special 
interest.
Full details of the URC are described in a separate URC charter.
The blinding maintenance plan and the study integrity plan document study roles which have access 
to and receive unblinding study data. A separate unblinded study team will be implemented at Parexel 
to run and deliver unblinded outputs to a separate independent unblinded team at AstraZeneca. 
Further details of the logistics of the interim within AstraZeneca are included in the URC charter, 
which will be stored in the AstraZeneca eTMF.
The interim analysis will be performed on data that is clean to the required level, such that the data 
for the participants included in the administrative interim analyses will be cleaned and fully coded, 
where appropriate. The outputs for the interim analysis will include a subset of the outputs for the 
primary analysis, as well as some unique outputs. These will be clearly marked in the mock shells.
See Appendix B for further details on the interim analysis.
4.14 Determination of Sample Size
With a 1-sided type I error rate of 5%, 150 evaluable participants in the zibotentan 1.5 mg and 
dapagliflozin 10 mg arm and dapagliflozin 10 mg monotherapy arm will have approximately
% 
power to detect a dapagliflozin-corrected UACR reduction of 
% or more assuming a SD of 
 on 
the natural log-scale. In the DKD sub-population (which will be about 70% of the total population), 
the power to detect the same reduction is estimated to be
%.
For the dose-response models (not part of CSR), the sample size below will have at least 
% power 
across multiple dose-response models to detect dose-response significance. This assumes a 1-sided
type I error of 5% and a maximum UACR reduction of 
% for the zibotentan 1.5 mg and 
dapagliflozin 10 mg combination arm relative to dapagliflozin 10 mg.
!
Zibotentan/Dapagliflozin dose = 0/10 mg: n = 150.
!
Zibotentan/Dapagliflozin dose = 0.25/10 mg: n = 75.
!
Zibotentan/Dapagliflozin dose = 1.5/10 mg: n = 150.
A total of 495 participants will be randomised into this study, including participants randomised under 
the earlier design. Four hundred and fifteen (415) participants will be randomised, accounting for 
10% drop-outs, to have the following number of participants in the main analysis (marked as M in 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table 4): 166 participants in the zibotentan 1.5 mg/dapagliflozin 10 mg combination arm and 
dapagliflozin 10 mg monotherapy arm, and 83 participants in the zibotentan 0.25 mg/dapagliflozin 
10 mg combination arm.
A participant is considered to be evaluable if the participant received at least one dose of study
intervention, has baseline UACR, and at least one post-treatment UACR result available.
The sample size was calculated using nQuery (version 8.2.0.0) for the pairwise comparisons. The 
sample size was calculated using the “DoseFinding” package (version 0.9-16) in R (version 3.5.3) for 
the dose-response models.
4.15 Changes in the Conduct of the Study or Planned Analysis
Echocardiography is included as an exploratory variable for efficacy assessments in the CSP but is 
included as a safety variable related to the safety objective in this SAP.
The CSP states that for the primary endpoint, no imputation is performed for UACR data that is 
treated as missing after the ICEs. If there are convergence issues with the MMRM proposed for the 
primary analysis, an ANCOVA with MI will be performed, meaning there is the possibility of 
imputation being performed. Regardless of the approach that will be taken for the primary analysis, 
sensitivity analyses will be performed that includes imputation for UACR data that is treated as 
missing after the ICEs.
The CSP states that the secondary variables of BP and eGFR will be analysed using ANCOVA but 
they will be analysed using a MMRM for consistency with the primary efficacy variable analysis, 
with an option for ANCOVA if none of the covariance structures converge.
The CSP does not include the phrase “or at a time selected by the sponsor” in relation to the first 
interim analysis for the planned timings of the interim analysis.
The CSP states that lost to follow-up is an ICE but it is not defined as an ICE in this SAP. It will be 
handled in the framework of missing data.
The CSP states that ABPM includes all participants in the FAS who have valid ambulatory BP data 
for change from baseline analysis, but as per SAP this analysis set will include all participants in the 
Descriptive Analysis Set who have valid ambulatory BP data for change from baseline analyses.
The CSP states that changes from baseline of ECG parameters will be listed, but as per SAP only the 
abnormalities (values outside the reference ranges) will be presented in the listings.
5
REFERENCES
Levey et al, 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to 
estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-12.
Scholtes et al, 2020
Scholtes R, Muskiet MHA, Van Baar MJB, Greasley PJ, Karlsson C, Hammarsterdt A, et al.
Natriuretic effect of 2 weeks of dapagliflozin treatment in patients with type 2 diabetes and
preserved kidney function: results of the DAPASALT trial. Abstract. ESC Congress 2020.
Stevens et al, 2008
Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, et al. Estimating GFR
using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of
3,418 individuals with CKD. Am J Kidney Dis. 2008;51(3):395-406.
Rubin, 2004


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Rubin DB. Multiple imputation for nonresponse in surveys. John Wiley & Sons; 2004.


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6
APPENDICES


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Appendix A: Schedule of Activities
Schedule of Activities (Part B)
Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Informed consent
X
Inclusion and exclusion criteria
X
X
Recheck clinical status before randomisation.
Screening in IRT/RTSM
X
Randomisation in IRT/RTSM
X
Diaries will be given to the participants and 
they will be asked to fill in the dose intake 
information (date and time) at home.
Routine clinical procedures
Demography and baseline 
characteristics (smoking history and 
alcohol consumption included)
X
Physical examination
X
X
X
X
X
X
X
X
A complete physical examination will be done 
at screening, randomisation and Week 12.
A brief physical examination will be done at 
Weeks 1, 3, 6, 9, 14.
Medical/surgical history, which 
includes substance usage and family 
history of premature cardiovascular 
disease
X
Substances: drugs, alcohol, tobacco, and 
caffeine


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Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Height
X
Serology (HIV I and II, Hepatitis B 
surface antigen, Hepatitis C virus 
antibody, central lab)
X
Results need to be available before 
randomisation.
FSH/LH and serum pregnancy test 
(females only, central lab)
X
Results need to be available before 
randomisation.
Local test for SARS-CoV-2
X
Testing is also required if participants show 
COVID-19 symptoms during the study.
Concomitant medication
X
X
X
X
X
X
X
X
Efficacy assessments
Spot urine from first morning void: 
albumin and creatinine (central lab)
X
Results need to be available before 
randomisation. A single sample for analysis is 
sufficient at screening.
Spot urine from first morning void over 
3 consecutive days: albumin, creatinine 
(central lab)
X
X
X
X
X
X
Spot urine from first morning void over 3 
consecutive days, ideally on day of clinic visit 
and preceding 2 days, collected at home in 
provided vials. Analysis will be done in all 3 
samples at central laboratory and averaged.
Spot urine from first morning void: 
Na+, K+, uric acid, urea, glucose, 
creatinine, osmolality, and cortisol 
(central lab)
X
X
X
X
X
X
Spot urine from first morning void, only from 
the third day sample (day of clinic visit), 
collected at home in provided vial. Analysis 
will be done at central laboratory.


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Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Body weight
X
X
X
X
X
X
X
X
Body weight must be taken and reviewed 
before treatment at each dosing visit.
Echocardiography
X
X
Screening and Week 12 only. ECHO will be 
performed locally and sent to central reader.
Bioimpedance spectroscopy
X
X
X
X
X
X
X
Home-based monitoring
Daily digital body weight measurement
Daily home measurement using a digital device from randomisation to end 
of follow up.
Home body weight measurements should start 
2 days before randomisation (same as for spot 
urine).
Pharmacodynamics
Plasma/serum K+, Na+, uric acid, BUN, 
fasting plasma glucose, cystatin C, 
haematocrit, haemoglobin, ET-1, 
ELDP, CT-proET-1, copeptin, NT-
proBNP, and BNP (central lab)
X
X
X
X
X
X
X
Results for central BNP testing must be 
reviewed within 24 hours of receipt by the 
investigator.
BNP or NT-proBNP (local laboratory)
X
Results need to be available before 
randomisation.
Safety assessments
Adverse event review
X
SAEs 
only
X
X
X
X
X
X
X
Vital signs (blood pressure, pulse, 
respiratory rate)
X
X
X
X
X
X
X
X
Vital signs at Visit 2 need to be performed 
and the results reviewed before randomisation 
in IWRS.


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Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Digital 12-lead safety
X
X
X
X
X
X
X
X
ECGs will be centrally read. ECG read out 
from Visit 2 to be reviewed by the 
investigator before randomisation as central 
report will not be available on the day. 
Unscheduled ECGs may be added if clinically 
indicated.
Clinical chemistry and haematology 
(central lab)
X
X
X
X
X
X
X
X
Central lab results must be reviewed by 
investigator within 48 hours from receipt of 
result, and eGFR and creatinine calculations 
made, and participant discontinued if 
required.
Clinical chemistry includes creatinine and 
eGFR calculation using the CKD-EPI formula 
in both ways: based on cystatin C and based 
on creatinine.
Urinalysis (central lab)
X
X
X
X
X
HbA1c, cholesterol and lipids (central 
lab)
X
X
X
X
Study intervention
Study intervention dispensed
X
X
X
X
Study intervention account
X
X
X
X


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Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Study intervention intake at the clinic
X
X
X
Between the clinic visits and at Visits 3, 5 and 
7, participants will take their study 
intervention at home. At Visits 4 and 6, study 
intervention will be taken in the clinic 
irrespective of participation in the PK 
sub-study.
Pharmacokinetics
4-hour PK blood sample profile
X
Total of 5 samples, spread over 5 time points: 
Pre-dose, 0.5-1.0 h, 1.5-2.0 h, 2.5-3.0 h, 3.5-
4.5 h post-dose.
Performed in the morning. Dose taken at 
clinic. Participants to arrive fasted at clinic 
(light breakfast provided). Participants to stay 
at clinic until last PK post-dose sample has 
been taken.
Zibotentan and dapagliflozin plasma 
concentrations will be measured separately.
If participants or investigators do not wish to 
participate in this sub-study, only one pre-
dose sample will be taken instead of the whole 
profile.
Post-dose PK plasma sample for all 
participants at a convenient day, time
X
X
X
Dose at home, sampling at clinic (any day, 
time). Zibotentan and dapagliflozin plasma 
concentrations will be measured separately. 
Document actual clock times of dosing at 
home and of sampling at clinic.


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Procedure
Scree-
ning
Interventional period
Follow-
up
Notes
Visit
1
2
3
4
5
6
7
(ED)
8
Week
-4
0
1
3
6
9
12
14
Day
-28
1
8
22
43
64
84
98
Day Visit Window
+7/
-14
±1
±2
±2
±2
±2
±3
Pre-dose PK plasma sample for all 
participants
X
Perform in the first half of the day. Dose taken 
at clinic, sampling before dose.
Zibotentan and dapagliflozin plasma 
concentrations will be measured separately.
Document actual clock times of dosing and 
sampling at clinic
Exploratory metabolite evaluation for 
all participants
X
Pre-dose plasma sample. Dose taken at clinic. 
Samples to be sent to AstraZeneca 
Gothenburg for exploratory zibotentan 
metabolite evaluation.
Exploratory biomarkers
Collect and store serum and plasma 
samples for future exploratory 
assessment of biomarkers
X
X
X
X
X
X
Collect and store urine samples for 
future exploratory assessment of 
biomarkers
X
X
X
X
X
X
Optional genetic sample
Optional genetic sampling (blood)
X
Abbreviations: BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CKD-EPI = chronic kidney disease epidemiology collaboration; COVID-19 = coronavirus disease 2019; 
CSP = Clinical Study Protocol; CT-proET-1 = C-terminal pro-endothelin-1; ECG = electrocardiogram; ECHO = echocardiogram; ED = Early Discontinuation; eGFR = estimated 
glomerular filtration rate; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; FSH = follicle stimulating hormone; HbA1c = glycated haemoglobin; HIV = human 
immunodeficiency virus; IRT = Interactive Response Technology; IWRS = interactive web response system; K+ = potassium; LH = luteinising hormone; Na+ = sodium; NT-proBNP 
= N-terminal pro–B-type natriuretic peptide; PK = pharmacokinetic; RTSM = Randomisation and Trial Supply Management, SAE = serious adverse event;
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.


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Appendix B: Interim Analysis Plan
This section describes definitions of analysis sets, key efficacy endpoints and statistical methods for 
the interim analyses (IAs). Further details of the interim analysis are included in the URC charter.
The first interim analysis may occur after 50% of participants have completed at least 6 weeks of 
treatment or at a time selected by the sponsor, and a second interim analysis may be performed after 
100% of participants have completed at least 6 weeks of treatment or at a time selected by sponsor /
percentage of participants with a planned week 6 visit before data cut selected by sponsor. The 
objective of the administrative interim analyses will be to decide if an 
 
zibotentan/dapagliflozin project activities 
 on the 
interim data.
The decision-making framework of the interim analyses is based on 
 
 
 
 
 
 
 
B.1.
Analysis Sets
The analysis sets are defined as follows.
Analysis Set
Data selection 
as indicated 
in Table 4
Description
Data Period
First 
Administrative 
Interim FAS
M
All participants who were randomised at 
least 44 days ago i.e. reached study day 45, 
and who have received any study treatment 
at the time of the first interim analysis data 
cut-off. Participants are evaluated according 
to the treatment assigned at randomisation.
Baseline to 
Week 6 
data
First 
Administrative 
Interim Safety
Analysis Set
M
All participants who have received any 
study treatment at the time of the first 
interim analysis data cut-off. Participants are 
evaluated according to the actual treatment 
they received.
All data
First 
Administrative 
Interim All 
Randomised Set
M
All participants who are randomised at least 
44 days ago i.e. reached study day 45 at the 
time of the first interim analysis data cut-off. 
Participants are evaluated according to the 
treatment assigned at randomisation.
Baseline to 
Week 6 
data
Second 
Administrative 
Interim FAS
M
All participants who were randomised at 
least 44 days ago i.e. reached study day 45, 
and who have received any study treatment 
at the time of the second interim analysis 
data cut-off. Participants are evaluated 
Baseline to 
Week 6 
data*
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Statistical Analysis Plan
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according to the treatment assigned at 
randomisation.
Second 
Administrative 
Interim Safety 
Analysis Set
M
All participants who have received any 
study treatment at the time of the second 
interim analysis data cut-off. Participants are 
evaluated according to the actual treatment 
they received.
All data
Second 
Administrative 
Interim All 
Randomised Set
M
All participants who are randomised at least 
44 days ago i.e. reached study day 45 at the 
time of the second interim analysis data cut-
off. Participants are evaluated according to 
the treatment assigned at randomisation.
Baseline to 
Week 6 
data*
*Some outputs will be based on longer data periods (not just baseline to Week 6)
B.2.
Fluid-related Analysis
Changes in fluid-related measures (weight gain or BNP) meet the defined threshold to be reported as 
an event of special interest if they meet the criteria defined in Section 3.2.2.7.
In the examination of the fluid-related safety 
 
 The examination depends on the actual number of participants with a fluid-related
event of special interest and the total number of participants in the zibotentan/dapagliflozin arm and 
in the dapagliflozin 10 mg monotherapy arm.
Assuming
participants in each arm for the first interim analysis, the scenario analysis is illustrated 
below where the 
 is used to estimate 
This will be performed for zibotentan/dapagliflozin 1.5/10 mg vs dapagliflozin 10 mg as well as for 
zibotentan/dapagliflozin 0.25/10 mg vs dapagliflozin 10 mg.
B.3.
Efficacy Analysis
In the administrative interim analyses, the primary efficacy endpoint is the UACR reduction
difference from baseline to Week 6, where the comparison will be made for each active zibotentan
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Parexel International
AstraZeneca
D4325C00001
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.3
Effective Date:  26 Nov 19
Project Document Effective Date: Date of last signature
Related to:  SOP-GDO-WW-019
Page 57 of 59
arm (1.5 mg and 0.25 mg) vs the dapagliflozin 10 mg monotherapy arm. The UACR reduction will 
be analysed by means of the MMRM approach as described in Section 4.10.2.2 using the 
Administrative Interim FAS. The least square estimate of the dapagliflozin-adjusted UACR reduction 
and its SE will be used
 UACR reduction difference.
The
in terms of the UACR reduction difference are calculated as
In total, 2
 will be created:
!
UACR reduction difference at Week 6
for zibotentan/dapagliflozin 1.5/10 mg
vs 
dapagliflozin 10 mg
!
UACR reduction difference at Week 6 for zibotentan/dapagliflozin 0.25/10 mg vs 
dapagliflozin 10 mg
 
 
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Parexel International
AstraZeneca
D4325C00001
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.3
Effective Date:  26 Nov 19
Project Document Effective Date: Date of last signature
Related to:  SOP-GDO-WW-019
Page 58 of 59
With reference to the 
, the URC will evaluate 
 
 
Note that the above will be done for each active treatment arm in the main analyses, 
zibotentan/dapagliflozin 1.5/10 mg and zibotentan/dapagliflozin 0.25/10 mg, 
 
 
B.4.
General Safety Analysis
General safety analysis will be based on the Administrative Interim Safety Analysis Set. Selected 
safety outputs will be presented by treatment arm and overall.
A summary of AEs in any category will be presented by treatment. The number and percentage of 
participants reporting AEs, SAEs and AEs leading to discontinuation of study treatment in each 
treatment arm will be tabulated by SOC and PT, sorted in decreasing overall (across treatments) 
frequency.
Listings may be presented of participants with SAEs, AEs leading to discontinuation of study 
treatment, and participants who died. A listing may be presented of participants with AEs, detailing 
whether these are SAEs, AEs leading to discontinuation of study treatment, or result in death.
Summary statistics of laboratory data (as described in Section 4.11.4) will be presented. Participants 
with laboratory values which are highlighted as abnormal will be listed. Summary statistics of vital 
signs and ECG data will be summarised (as described in Section 4.11.5).
Reference:
 
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AstraZeneca
D4325C00001
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.3
Effective Date:  26 Nov 19
Project Document Effective Date: Date of last signature
Related to:  SOP-GDO-WW-019
Page 59 of 59
Appendix C: Treatment-Emergent Changes in Relevant Laboratory Parameters
The treatment-emergent changes in relevant laboratory parameters for this study are as follows:
Laboratory Parameter
Range
Limits
Creatinine
≥1.5xBaseline Serum Creatinine
≥2xBaseline Serum Creatinine
Sodium
<120 mmol/L
<130 mmol/L
>150 mmol/L
Potassium
≤2.5 mmol/L
≥6.0 mmol/L
Creatine Kinase
>5xULN
>10xULN
Haemoglobin
<9 g/dL


SIGNATURE PAGE
This is a representation of an electronic record that was signed
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Document Name: d4325c00001-sap-ed-3
Document Title:
Statistical Analysis Plan Edition 3
Document ID:
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Version Label:
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