Clinical trial NCT04492722
Conditions: Chronic Kidney Disease
Keywords: Nephrology Chronic kidney disease Proteinuria Diabetic kidney disease Diabetes mellitus
Sponsor: AstraZeneca
Start date: 2020-10-01; Completion date: 2022-09-06
Enrollment: 613 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the dose-response efficacy, safety, and pharmacokinetics (PK) of AZD5718 in participants with proteinuric chronic kidney disease.

Detailed description:
The study will be conducted in approximately 118 study centers across 12 countries. The overall study period will be around 28 weeks. Approximately 632 participants comprising of 67% diabetic kidney disease (DKD) and 33% non-DKD participants will be enrolled. After a screening period of up to 4 weeks, the participants will be randomised in a 1:1:1:1 ratio to receive one of the doses of AZD5718 and/or placebo for the first 12 weeks (Day 85 \[treatment period 1\]), with an add-on therapy of 8 weeks of dapagliflozin for all participants from Week 12 to 20 (Day 85 to 141 \[treatment period 2\]). Only participants still taking their assigned treatment from treatment period 1 will progress to treatment period 2. Any participant with urine albumin to creatinine ratio (ACR) \< 30 mg/g at Week 12 will be excluded from treatment period 2. The eligibility check to enter treatment period 2 will be done at Visit 7 (Week 12) using the last available urine ACR result. The final analysis will be done after all participants have completed follow-up period of up to 4 weeks. The expected total study duration, including the Screening Period, for each participant will be at least 28 weeks.

Arms: arm 1: Participants will receive once daily oral dose 1 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks. arm 2: Participants will receive once daily oral dose 2 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks. arm 3: Participants will receive once daily oral dose 3 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks. arm 4: Participants will receive once daily oral dose of placebo matched to AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Interventions: intervention 1: AZD5718 intervention 2: Dapagliflozin 10 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20. intervention 2: Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy. intervention 3: Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Study Intervention
AZD5718
Study Code
D7551C00001
Version
3.0
Date
25 Jan 2021
A Phase 2b Randomised, Double-Blind, Placebo-Controlled, 
Multi-Centre, Dose-Ranging Study of AZD5718 in Participants
with Proteinuric Chronic Kidney Disease
Sponsor Name: 
Legal Registered Address: 
AstraZeneca AB, 151 85 Södertälje, Sweden
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s):
Investigational New Drug (IND) number: 148134
EudraCT number: 2020-002263-54
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number:
Amendment Number: 2
Study Intervention: AZD5718
Study Phase: 2b
Short Title: Dose Response Effect, Efficacy, and Safety of AZD5718 in Reducing 
Albuminuria in Participants with Proteinuric Chronic Kidney Disease
Study Physician Name and Contact Information will be provided separately
International Co-ordinating Investigator
Hiddo J. L. Heerspink
Department of Clinical Pharmacy and Pharmacology
University Medical Centre Groningen
PO BOX 30001
9700 AD Groningen
The Netherlands


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 3.0, Amendment 2
25-Jan-2021
Version 2.0, Amendment 1
05-Aug-2020
Version 1.0 
29-May-2020
The Protocol Amendment Summary of Changes Table for the current amendment
(Amendment 2) is provided below, and for previous amendment, is in Appendix H.
Amendment 2 (25-January-2021)
This protocol 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 Global Clinical Study Protocol (CSP), Final 2.0, dated 05 Aug 2020, is updated following 
a review by the several regulatory authorities and Ethics Committees (ECs). Updates have
been made in accordance with the requested clarifications.
Section # and 
Name
Description of Change
Brief Rationale
1.1 Synopsis, 
1.3 Schedule of 
Activities, and 
4.1 Overall Design 
Clarification that any participant with urine albumin to 
creatinine ratio (ACR) < 30 mg/g at Week 12 will be 
excluded from Treatment Period 2.
Process clarification
1.3 Schedule of 
Activities and 
Section 8.1.1.1
Urinary Albumin 
Creatinine Ratio
The following clarification was added regarding urine 
sampling in the event of delayed Visits 3 and 7: If 
scheduled Visit 3 (Week 1) or Visit 7 (Week 12) will 
need to be delayed due to the need to repeat ABPM 
recording there is no need to repeat collection of the 3 
urine samples.
Process clarification.
1.3 Schedule of 
Activities and 
Section 8.2.5 
Ambulatory Blood 
Pressure 
Monitoring
In Section 8.2.5, the following clarification was added 
regarding Ambulatory Blood Pressure Monitoring 
(ABPM): The participant may also visit the site for 
APBM cuff placement 1 day before their next 
assessment visit, as scheduled in the SoA (Table 1).
The site should check the validity of the ABPM 
session at the beginning of the scheduled visit prior to 
completion of any other study assessments. An ABPM 
session may be repeated once if the following validity 
criterion has not been met:
Process clarification.


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Section # and 
Name
Description of Change
Brief Rationale
•
A minimum 20 h recording with at least 70% of 
expected measurements being successful
If the validity criterion is not met, the associated study 
visit may be rescheduled to allow for a repeat ABPM 
recording only if the rescheduled visit can be 
completed within the specified tolerance period for 
study visits, as described in the SoA (Table 1).
If a repeat ABPM session is not possible, the study 
visit should proceed as indicated. In addition, the visit 
should also continue if ABPM session does not meet 
validity criterion after the repeat session.
A corresponding update was made to the footnotes in 
Table 1 in Section 1.3 Schedule of Activities: 
n
Participants will be provided an ABPM cuff at 
Screening Visit 2 and Visit 6 (Week 8) at the indicated 
visit and instructed to perform ABPM 24-hours before 
their next visit ie, Visit 3 (Week 1) and Visit 7 (Week 
12), respectively. Site will be asked to call the 
participant the day prior to next visit as a reminder to 
complete assessments. The participant may also visit 
the site for APBM cuff placement 1 day before their 
next visit of scheduled assessment (ie, Visit 3 [Week 
1] and Visit 7 [Week 12] respectively).
o
Sites should ensure that the validity criterion 
described in Section 8.2.5 is met prior to completing 
any other assessments at the visit. If the validity 
criterion is not met, the associated study visit may be 
rescheduled to allow for a repeat ABPM recording 
only if the rescheduled visit can be completed within 
the specified tolerance period for study visits:
•
Visit 3: up to 72 hours following the 
originally scheduled visit for Visit 3 but no more 
than 32 days from Screening Visit 1
•
Visit 7: ± 72 hours from Day 85
If a repeat ABPM session is not possible, the study 
visit should proceed as indicated. In addition, the visit 
should also continue if the ABPM session does not 
meet the validity criterion after the repeat session.


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Section # and 
Name
Description of Change
Brief Rationale
2.2 Background
The text in this section was updated as follows: 
Sodium glucose cotransporter 2 inhibitors have been 
shown to slow down CKD progression by lowering 
glomerular pressure in patients with CKD, with or 
without Type 2 Diabetes Mellitus (T2DM) (Wanner 
et al, 2016, Heerspink et al, 2020[b]). However, 
additional long term studies are required to assess 
whether SGLT2i should be added to the current 
standard of care for CKD patients, with or without 
Type 2 Diabetes Mellitus (T2DM) (Kelly et al, 2019).
……………………………………………
While it is anticipated that SGLT2i will be a key 
component of standard of care for proteinuric CKD in 
the future, based on data from DAPA-CKD 
(Heerspink et al, 2020[b]), this definitive evidence in 
non diabetic CKD is not yet available, and a licensed 
indication.
Updated with new 
information from a published 
article.
2.3.2 Dapagliflozin
The text in this section was updated as follows: 
Dapagliflozin is authorised for treatment of T2DM, and
T1DM, and heart failure with reduced ejection 
fraction, and is under development for treatment in 
patients with CKD and heart failure with preserved 
ejection fraction.
Clarification provided about 
the approved indications for 
dapagliflozin.
4.2.3 Rationale for 
Study Population
A correction was made to the range of values used to 
define albuminuria (text added in bold):
The study population with CKD (eGFR 20 –
75 mL/min/1.73m2) and albuminuria (200 – 5000 mg 
albumin/g creatinine) enables assessment of the 
clinical efficacy and safety as well as supporting dose 
selection in a population at risk for progression to 
renal failure (Go et al, 2018).
Correction made per the 
referenced article.
Section 5.1 
Inclusion Criteria
Inclusion criterion 1 was updated as: For participants 
who haven’t reached the age of maturity according 
to local regulations in their country aged 18 to < 20 
years and enrolled in Japan, a written informed consent 
should be obtained from the participant and his or her 
legally acceptable representative.
Inclusion criterion 1 was 
updated to accommodate 
local regulations in several 
countries.


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Section # and 
Name
Description of Change
Brief Rationale
Section 5.1 
Inclusion Criteria
Inclusion criterion 5 was updated as:
Female participants must be of non-childbearing 
potential and must have been surgically sterilised (ie, 
bilateral oophorectomy, and/or, complete 
hysterectomy, and/or bilateral tube ligation), 
salpingectomy; tubal ligation is not sufficient) or be 
postmenopausal (amenorrhoeic for 12 months or 
more following cessation of exogenous hormonal 
treatments and assessed by serum follicle stimulating 
hormone [FSH] and luteinising hormone [LH] levels 
at Screening Visit 1).
Inclusion criterion 5 was 
updated to provide more 
details on the eligibility of 
female study participants 
with regard to their child-
bearing potential.
Section 5.1 
Inclusion Criteria
The following text was added to inclusion criterion 6: 
Approved/Certified measurements in Japan are as 
below:
Vasectomy, tubal occlusion, intrauterine device 
(provided coils are copper banded), levonorgestrel 
intrauterine system (eg, Mirena®). These 
measurements are acceptable forms of highly 
effective birth control in Japan. Not 
Approved/Certified measurements in Japan are as 
below: Cerazette® (desogestrel) pills , 
medroxyprogesterone injections (eg, Depo-
Provera®), etonogestrel implants (eg, Implanon®, 
Norplan®), normal and low dose combined oral 
pills, norelgestromin/ethinylestradiol transdermal 
system (eg, Evra® Patch), intravaginal device (eg, 
NuvaRing®).
Inclusion criterion 6 was 
updated to accommodate 
Japanese Pharmaceuticals 
and Medical Devices Agency 
(PMDA) regulations.
Section 5.2 
Exclusion Criteria
Exclusion criterion 10 was edited to clarify the 
exclusion of participants who received treatment with
any concomitant medications known to be associated 
with Torsades de Pointes or potent inducers/inhibitors 
of cytochrome P450 3A4 within 4 weeks of Visit 3 
(Randomization).
Process clarification.
Section 5.2 
Exclusion Criteria
Exclusion criterion 15 was added to exclude 
participants who had a known hypersensitivity to 
dapagliflozin or any of the excipients of the product.
Since hypersensitivity to 
AZD5718 and its excipients 
is already part of the clinical 
study protocol, it was 
clarified that sensitivity to 
dapagliflozin should also be 
considered for study 
eligibility.


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Section # and 
Name
Description of Change
Brief Rationale
Section 5.2 
Exclusion Criteria
Exclusion criterion 23 was added to the study as 
follows: Participants working night shifts, and who 
cannot avoid strenuous manual labour during the 
study.
Added per FDA 
recommendation to ensure 
feasibility of a minimum 20 h 
ambulatory blood pressure 
monitoring.
Section 7.1 
Discontinuation of 
Study Drugs
Clarification was provided regarding participants who 
chose to discontinue either AZD5718 or dapagliflozin, 
or chose to discontinue both AZD5718 and 
dapagliflozin prior to the end of Treatment Period 2, as 
follows:
•
Participants who choose to discontinue either 
AZD5718 or dapagliflozin or both drugs together prior 
to the end of Treatment Period 2 are expected to 
continue in the study on the remaining study therapy
and are expected to complete the study assessments 
according to the schedule of study procedures for the 
remainder of the study.
•
Participants who choose to discontinue both 
AZD5718 and dapagliflozin prior to the end of 
Treatment Period 2 are expected to complete the study 
assessments according to the schedule of study 
procedures for the remainder of the study.
Process clarification for IMP 
discontinuation as indicated 
previously by an Ethics 
Committee.
Section 7.1, 
Discontinuation of 
Study Drugs
More specific language was added to qualify an 
unexpected acute decline in eGFR (ie, > 15% decrease 
in eGFR from the Screening Visit values) which would 
prompt participant evaluation. Instruction was added 
for the Investigator and the Study Physician to consider 
discontinuation of the IMP in participants with a > 30% 
decrease in eGFR from the Screening Visit values.
Process clarification for IMP 
discontinuation in the event 
of unexpected acute decline 
in kidney function, as 
indicated previously by a 
regulatory agency.
7.4 Study 
Termination
A new subsection (7.4 Study Termination) was created, 
and a statement was added under it regarding the 
criteria for study termination as follows “AstraZeneca 
may terminate the entire study prematurely if 
concerns for safety arise within this study or in any 
other study with AZD5718”. 
For clarity and continuity, the statement 
“Discontinuation of specific sites or of the study as a 
whole are handled as part of Appendix A.” was moved 
under the newly created Section 7.4 from its previous 
location in Section 7.3.
Added study termination 
criteria for clarity as 
indicated previously by an 
Ethics Committee.
Throughout
Minor editorial, typographical and document 
formatting revisions
Minor, therefore, have not 
been summarised.


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TABLE OF CONTENTS
1
PROTOCOL SUMMARY ................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 17
1.3
Schedule of Activities ....................................................................................... 18
2
INTRODUCTION............................................................................................ 23
2.1
Study Rationale ................................................................................................ 23
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 24
2.3.1
AZD5718.......................................................................................................... 24
2.3.2
Dapagliflozin.................................................................................................... 25
2.3.3
Other Risks....................................................................................................... 26
3
OBJECTIVES AND ENDPOINTS................................................................... 27
4
STUDY DESIGN ............................................................................................. 29
4.1
Overall Design.................................................................................................. 29
4.2
Scientific Rationale for Study Design ............................................................... 30
4.2.1
Rationale for Study Design ............................................................................... 30
4.2.2
Rationale for Study Endpoints .......................................................................... 30
4.2.3
Rationale for Study Population ......................................................................... 30
4.3
Justification for Dose........................................................................................ 31
4.3.1
AZD5718.......................................................................................................... 31
4.3.2
Dapagliflozin.................................................................................................... 31
4.4
End of Study Definition.................................................................................... 31
5
STUDY POPULATION.................................................................................... 31
5.1
Inclusion Criteria .............................................................................................. 31
5.2
Exclusion Criteria ............................................................................................. 34
5.3
Lifestyle Considerations ................................................................................... 36
5.3.1
Meals and Dietary Restrictions ......................................................................... 36
5.3.2
Caffeine and Alcohol ........................................................................................ 36
5.3.3
Activity............................................................................................................. 36
5.3.4
Reproductive Restrictions ................................................................................. 37
5.3.5
Other Restrictions ............................................................................................. 37
5.4
Screen Failures ................................................................................................. 37
6
STUDY INTERVENTION ............................................................................... 37
6.1
Study Intervention(s) Administered................................................................... 37
6.1.1
Investigational Products.................................................................................... 37
6.2
Preparation/Handling/Storage/Accountability ................................................... 38
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 39


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6.3.1
Methods for Assigning Treatment Groups......................................................... 39
6.3.2
Methods for Ensuring Blinding......................................................................... 40
6.3.3
Methods for Unblinding.................................................................................... 40
6.4
Study Intervention Compliance......................................................................... 40
6.4.1
E-Diary............................................................................................................. 41
6.5
Concomitant Therapy........................................................................................ 41
6.5.1
Prohibited Concomitant Medications ................................................................ 42
6.5.2
SGLT2 Inhibitors.............................................................................................. 42
6.5.3
Rescue Medicine............................................................................................... 43
6.6
Dose Modification ............................................................................................ 43
6.7
Intervention After the End of the Study............................................................. 43
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 43
7.1
Discontinuation of Study Drugs ........................................................................ 43
7.1.1
Temporary Discontinuation............................................................................... 45
7.2
Participant Withdrawal from the Study.............................................................. 45
7.3
Lost to Follow-up ............................................................................................. 46
7.4
Study Termination............................................................................................. 47
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 47
8.1
Efficacy Assessments........................................................................................ 47
8.1.1
Primary Efficacy Assessment............................................................................ 47
8.1.2
Secondary Efficacy Assessments....................................................................... 48
8.1.3
............................... 48
8.2
Safety Assessments........................................................................................... 49
8.2.1
Physical Examinations...................................................................................... 49
8.2.2
Vital Signs ........................................................................................................ 49
8.2.3
Electrocardiograms........................................................................................... 50
8.2.4
Clinical Safety Laboratory Assessments............................................................ 50
8.2.5
Ambulatory Blood Pressure Monitoring............................................................ 52
8.2.6
Glycated Haemoglobin ..................................................................................... 52
8.3
Adverse Events and Serious Adverse Events..................................................... 53
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 53
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 53
8.3.3
Causality Collection.......................................................................................... 54
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 54
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 54
8.3.6
Hy’s Law.......................................................................................................... 55
8.3.7
Reporting of Serious Adverse Events ................................................................ 55
8.3.8
Pregnancy......................................................................................................... 56
8.3.9
Medication Error............................................................................................... 57
8.4
Overdose .......................................................................................................... 57
8.4.1
AZD5718.......................................................................................................... 57
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8.4.2
Dapagliflozin.................................................................................................... 57
8.5
Human Biological Samples............................................................................... 58
8.5.1
Pharmacokinetics.............................................................................................. 58
8.5.2
Immunogenicity Assessments ........................................................................... 59
8.5.3
Pharmacodynamics........................................................................................... 59
8.6
Human Biological Sample Biomarkers ............................................................. 60
8.6.1
............. 60
8.6.2
Collection of Optional Biomarker Samples for Future Use................................ 60
8.7
Optional Genomics Initiative Sample................................................................ 60
8.8
Health Economics............................................................................................. 60
9
STATISTICAL CONSIDERATIONS................................................................ 61
9.1
Statistical Hypotheses....................................................................................... 61
9.2
Sample Size Determination............................................................................... 61
9.3
Populations for Analyses................................................................................... 61
9.4
Statistical Analyses ........................................................................................... 62
9.4.1
General Considerations..................................................................................... 62
9.4.2
Efficacy ............................................................................................................ 63
9.4.3
Safety ............................................................................................................... 64
9.4.4
Other Analyses.................................................................................................. 65
9.5
Interim Analyses............................................................................................... 65
9.6
Data Monitoring Committee ............................................................................. 66
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ........................................................................................ 67
11
REFERENCES................................................................................................. 98
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 17
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 18
Table 2
Objectives and Endpoints......................................................................... 27
Table 3
Investigational Products........................................................................... 37
Table 4
Laboratory Safety Variables..................................................................... 51
Table 5
Populations for Analysis .......................................................................... 61
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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 68
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 73
Appendix C
Handling of Human Biological Samples .................................................. 78
Appendix D
Optional Genomics Initiative Sample....................................................... 80
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 83
Appendix F
COVID-19 Specifics................................................................................ 89
Appendix G
Abbreviations .......................................................................................... 92
Appendix H
Protocol Amendment History................................................................... 95


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1 
PROTOCOLSU1\1MARY 
Ll 
Synopsis 
AstraZeneca 
Protocol Title: A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centi·e, 
Dose-Ranging Study of AZD5718 in Pa1iicipants with Proteinuric Chronic Kidney Disease 
Short Title: Dose Response Effect, Efficacy, and Safety of AZD5718 in Reducing 
Albuminuria in Paiiicipants with Proteinuric Chronic Kidney Disease 
Rationale: 
Chronic kidney disease (CKD) is a worldwide public health problem associated with 
significant morbidity and mortality; diabetes mellitus (DM) is the leading cause of end-stage 
renal disease. The pathophysiology of diabetic kidney disease (DKD) is multifactorial, with 
both haemodynamic effects conti·ibuting to glomerulai· fibrosis and inflammation emerging as 
major contributors to disease progression. 5-lipoxygenase activating protein (FLAP) is paii of 
the 5-lipoxygenase (5-LO) pathway that generates biologically active lipid mediators, 
While it is anticipated that sodium-glucose coti·anspoiier-2 
inhibitors (SGLT2i) will be a key component of standard of care for proteinuric CKD in the 
future, definitive evidence in non-diabetic CKD is anticipated, but not yet available, and 
cmTent uptake in DKD is limited with fewer than 5% of patients on SGLT2i treatment. The 
prima1y endpoint for this study is based on anticipated future standai·d of cai·e with all 
paiiicipants on the SGLT2i dapagliflozin. Efficacy, safety, and phaimacokinetics (PK) on 
cmTent standai·d of care with limited use of SGLT2i ai·e secondaiy endpoints. This Phase 2b 
study will investigate if AZD5718, a FLAP inhibitor, can reduce albuminuria in participants 
with proteinuric CKD both on ti·eatment with dapagliflozin as future standai·d of cai·e and on 
cmTent standard of care with minimal SGLT2i use. The dose response relationship, and the 
safety and PK profile of AZD5718 will also be evaluated in these paiiicipants. The result of 
the study will f01m the basis for the future clinical development programme for AZD5718. 
Objectives and Endpoints 
Objectives 
Estimand Description/Endpoints 
Prima1y 
To evaluate the dose response 
Reduction of urine ACR from baseline to Week 20 compared 
effect of AZD5718 on urine ACR 
with placebo. 
at 20 weeks in pa1ticipants with 
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Objectives 
proteinuric CKD ( on treatment 
with dapagliflozin as future 
standard of care from Weeks 12 to 
20) 
Seconda1y 
To evaluate the dose response 
effect of AZD5718 on urine ACR 
at 12 weeks (on cunent standard of 
care) 
To evaluate the safety and 
tolerability of AZD5718 in 
pa1ticipants with proteinmic CKD 
To evaluate the effect of AZD5718 
on ambulato1y blood pressure in 
pa1ticipants with proteinmic CKD 
To assess the PK of AZD5718 
after repeated oral dosing for 20 
weeks in pa1ticipants with 
proteinuric CKD 
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Estimand Description/Endpoints 
The p1ima1y 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 per protocol population. The endpoint being 
assessed is the change in log-transfo1med urine ACR from 
baseline to Week 20. For the intercunent event, if a pa1ticipant 
discontinues treatment due to AE or lack of efficacy, or uses 
prohibited medication, the mine ACR data are treated as 
missing after the event and no imputation is perfo1med. The 
summary measure being evaluated is the geometiic mean 
reduction of urine ACR from baseline to Week 20. 
Reduction of mine ACR from baseline to Week 12 compared 
with placebo. 
The clinical quantity of interest to be estimated is defined by 
the following 3 components: 
• Population 
Randomised paiticipants who meet all eligibility 
c1ite1ia and have valid non-missing mine ACR records 
at baseline and at least one post-treatment visit. 
• Endpoint 
Change in log-t1·ansfo1med urine ACR from baseline 
to Week 12. 
• Summaiy measure 
Geometiic mean reduction of urine ACR from 
baseline to Week 12 compared with placebo. 
• AEs/SAEs 
• Vital signs 
• Clinical chemistiy/haematology/coagulation/urinalysis 
pai·ameters 
• ECG assessments 
Change in 24-hour mean SBP from baseline to Week 12 
AZD5718 plasma concentrations 
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Objectives 
To assess the effect of AZD5718 
on renal function in pruticipants 
with proteinmic CKD with and 
without the addition of 
dapagliflozin 
-
Overall Design 
AstraZeneca 
Estimand Description/Endpoints 
Change in eGFR from baseline to Week 12 and from Week 12 
to Week20 
This is a Phase 2b, randomised, double-blind, placebo-controlled, multi-centre, dose-ranging 
study to evaluate the efficacy, safety and PK of AZD5718 in paiiicipants with proteinuric 
CKD. 
The study will be conducted in approximately 118 study centres across 12 counti·ies. 
Approximately 632 paiiicipants comprising of 67% DKD and 33% non-DKD participants will 
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be randomised 1:1:1:1 to receive once daily oral doses of 
mg AZD5718, 
mg AZD5718, 
mg AZD5718, or placebo, for the first 12 weeks with an add-on therapy of 8 weeks of 
dapagliflozin for all participants, to have 158 participants per group. The plan is to have 
approximately 568 evaluable participants (142 per group) completing the study.
Disclosure Statement: This is a double-blinded placebo-controlled treatment study with 
4 arms.
Number of Participants:
Approximately 632 participants will be enrolled to achieve 568 evaluable participants
(142 per group).
Intervention Groups and Duration:
The study will include 4 intervention groups:
mg AZD5718, 
mg AZD5718, 
mg 
AZD5718, and placebo for the first 12 weeks followed by the addition of dapagliflozin to all 
participants from Week 12 to 20.
The study will include 4 periods:

Screening Period of up to 4 weeks

Treatment Period 1 consisting of 12 weeks where the participants will receive a once 
daily oral dose of the assigned dose of study drug to be taken with approximately 200 mL 
water in the morning with no restrictions on food intake.

Treatment Period 2 consisting of 8 weeks where the participants will receive a treatment 
of once daily oral dose of dapagliflozin 10 mg in addition to the assigned dose of study 
drug. Only participants still taking their assigned treatment from Treatment Period 1 will 
progress to Treatment Period 2. Any participant with urine albumin to creatinine ratio 
(ACR) < 30 mg/g at Week 12 will be excluded from Treatment Period 2. The eligibility 
check to enter Treatment Period 2 will be done at Visit 7 (Week 12) using the last 
available urine ACR result, calculated as the geometric mean of the replicated 
measurements using 3 sequential first morning urine voids.

Follow-up Period of up to 4 weeks.
The study will include a total of 10 visits which includes 2 visits during the Screening Period, 
5 visits during the Treatment Period 1, 2 visits during the Treatment Period 2, and 1 visit 
during the Follow-up Period.
The expected total study duration, including the Screening Period, for each participant will be 
at least 28 weeks.
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Data Monitoring Committee: Not applicable
Statistical Methods
The primary efficacy variable is the change from baseline in urine ACR at 20 weeks compared 
to placebo. Primary analyses will be based on the per protocol population where participants 
are evaluated according to the randomised treatment assignment. Urine ACR will be 
log-transformed and analysed using mixed model repeated measures method. 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 (urine ACR) and 
baseline log (urine ACR)-by-visit interaction. An unstructured covariance structure will be 
used for the within-participant errors. A homogeneity assessment between the DM and the 
non-DM sub-populations will be performed.
The change from baseline in urine ACR at 12 and 20 weeks will be analysed using the 
Multiple Comparison Procedure Modelling approach. Multiple candidate dose response 
models will be assessed. The best fitting model based on Akaike’s Information Criteria will be 
used as a reference for dose selection.
Efficacy on current standard of care will be based on the Full Analysis population up to 
Week 12. The change in urine ACR from baseline to Week 12 will be log-transformed and be 
analysed similarly as the primary variable.
Estimated glomerular filtration rate (eGFR) will be analysed, comparing eGFR at baseline 
with that at 12 weeks, to determine whether there is any acute change with the introduction of 
AZD5718 to inform planning for an eGFR slope analysis in Phase 3. This will be analysed 
using a by-visit analysis of covariance (ANCOVA), adjusting for DM stratification factor, 
treatment group and baseline eGFR. The Full Analysis population will be used for this 
analysis and eGFR will be evaluated on the original scale, if appropriate.
The principal endpoint for ambulatory blood pressure (BP) is the change from baseline in 
24-hour mean systolic BP (SBP) at Week 12. It will be analysed using an ANCOVA model 
with terms for treatment and stratification factor plus the baseline 24-hour mean SBP and 
body mass index (BMI) as covariates.
The secondary efficacy variable is the change from baseline of eGFR at Week 12 and from 
Week 12 to Week 20. It will be analysed using by-visit ANCOVA with terms for treatment, 
stratification factor and baseline eGFR.
Safety analysis will be based on the Safety Analysis population where participants are 
evaluated according to the actual treatment received. Serious adverse event (SAE) collection 
will begin after the participant signs the informed consent document, and all adverse event 
(AE) collection will begin after the participant has received the first dose of the study drug. 


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The SAE/AE collection will last until the end of the participant's follow-up period. Adverse 
events will be coded using the Medical Dictiona1y for Regulato1y Activities (MedDRA) by 
system organ class and prefened te1m. Specific AEs will be counted once for each paiiicipant 
for calculating rates, but will be presented in total in paiiicipant listings. In addition, if the 
same AE occurs multiple times within a paiiiculai· paiiicipant, the highest severity and level of 
causality will be repo1ied. All treatment emergent AEs will be summai·ised overall and by 
deaths and SAEs. Treatment discontinuations due to AEs will be provided. For AEs, 
Treatment Periods 1 and 2 will be analysed sepai·ately, and then overall. 
Clinical laborato1y safety tests including sennn chemistiy, haematology, coagulation, and 
urinalysis parameters will be summai·ised using descriptive statistics at each time point by 
ti·eatment group. Change from baseline to each post baseline time point in these data will also 
be summai·ised, where appropriate. A shift table will be provided for these clinical laborato1y 
pai·ameters as well, where possible. 
Vital sign results and electi·ocai·diograms will be summai·ised using descriptive statistics at 
each time point by ti·eatment group. 
AZD5718 plasma concenti·ation data will be summai·ised by descriptive statistics for each visit 
and each sample collection time point for each dose coho1i . 
will be summai·ised by ti·eatment group and will be 
repo1ied outside of the clinical study repo1i. 
Interim analysis: An administi-ative interim analysis will be conducted when approximately 
200 paiiicipants have completed the 20-week ti·eatment period. 
1.2 
Schema 
Figure 1 
4 Weeks 
Screening 
Study Design 
12 Weeks Treatment 
8 Weeks Add-on 
4 Weeks 
Follow-up 
AZD5718 ._m_g ____ 
__._ __ 
+_D_a_pa_g_li_fl_oz_in_l0_ m_g_...._ ____ _. 
Screening 
R 
AZD5718• mg 
• ,---------- --------.------------r-------, 
AZD57181 mg 
+ Dapagliflozin 10 mg 
+ Dapagliflozin 10 mg 
Placebo 
+ Dapagliflozin 10 mg 
R = randomisation 
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1.3
Schedule of Activities
Table 1
Schedule of Activities
Study Period
Screening
Treatment Period 1
Treatment Period 2
Discontinuation
Follow-up
Details in CSP 
Section or 
Appendix
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-32 to -3
1
15±3
29±3
57±3
85±3
113±3
141±3
169±5
Study Week
-4 to 0
1
2
4
8
12
16
20
24
Informed consent (main)
X
Section 5.1
Informed consent (optional) for 
genetic and biomarker research
X
Section 5.1
Verify eligibility criteria
X
X
X
Xa
Sections 5.1
and 5.2
Demography
X
Section 5.1
Full physical examination 
including height, weight, and BMI
Xb
X
X
X
X
X
X
Section 8.2.1
Physical examination (abbreviated)
X
X
Section 8.2.1
Medical history
X
Section 5.1
Serum hCG, FSH, and LHc
X
Section 5.1
Pregnancy testc
X
Section 5.2
Drug and alcohol screen
X
Section 5.2
Hepatitis B and C screening
X
Section 5.2
Spot urine for ACR
X
Section 5.1
Safety laboratory assessments 
(Clinical chemistry, haematology, 
coagulation, urinalysis)d
X
Xe
X
X
X
X
X
Xe
Xe
X
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Study Period
Screening
Treatment Period 1
Treatment Period 2
Discontinuation
Follow-up
Details in CSP 
Section or 
Appendix
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-32 to -3
1
15±3
29±3
57±3
85±3
113±3
141±3
169±5
Study Week
-4 to 0
1
2
4
8
12
16
20
24
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Section 8.2.3
Vital signsf
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
Randomisation
X
Section 6.3
Retinal sub study (optional, DKD 
sub-group only)g
X
X
Section 8.1.3
HbA1ch
X
X
Section 8.2.6
Calculation of eGFR
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.1
Blood sample for cystatin-C
X
X
X
X
X
X
X
X
X
X
Section 8.5.3
Pharmacokinetics plasma sample 
for AZD5718
X
(pre-dose)
Xi
(pre-dose)
X
(pre-dose)
X
(pre-dose)
X
(pre-dose)
X
(pre-dose)
X
(pre-dose)
Section 8.5.1
Pharmacokinetics plasma sample 
for dapagliflozin
X
(pre-dose)
X
(pre-dose)
Section 8.5.1
 
X
X
X
X
X
Section 8.6
 
X
X
X
X
X
X
Section 8.5.3
Plasma, serum, and urine for future 
use (optional)j, h
X
X
X
X
X
Section 8.6.2
Blood sample for Genomics
Initiative (optional)j
X
Section 8.7
and 
Appendix D
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Study Period
Screening
Treatment Period 1
Treatment Period 2
Discontinuation
Follow-up
Details in CSP 
Section or 
Appendix
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-32 to -3
1
15±3
29±3
57±3
85±3
113±3
141±3
169±5
Study Week
-4 to 0
1
2
4
8
12
16
20
24
Dispense supply of containers for 
urine samples
X
X
X
X
X
X
X
X
X
Section 
8.1.1.1
E-Diary, dispensation and 
completion of diaryk
X
X
X
X
X
X
X
X
X
Section 6.4
Reminder to collect first morning 
void urine samples, 3 days before 
visitl
X
X
X
X
X
X
X
X
X
X
Section 
8.1.1.1
Urine samples for ACRh, m
X
X
X
X
X
X
X
X
X
X
Section 
8.1.1.1
24-hour ABPM, provision and 
completion
Xn
Xo
Xn
Xo
Section 8.2.5
Study drug dispensationp
X
X
X
X
X
Section 6.4
Study drug returnedpq,r
X
X
X
X
X
X
Section 6.4
Study drug intake in study centre
X
X
X
X
X
X
X
Section 6.4
Assessment of AEs/SAEs
Only SAEs
X
X
X
X
X
X
X
X
X
Section 8.3
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Abbreviations: ABPM = ambulatory blood pressure monitoring; ACR = albumin to creatinine ratio; AEs = adverse events; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase; BMI = body mass index; CSP = clinical study protocol; DKD = diabetic kidney disease; ECG = electrocardiogram; 
e-Diary = electronic Diary; eGFR = estimated glomerular filtration rate; FSH = follicle stimulating hormone; fT3 = free triiodothyronine; fT4 = free thyroxine;
HbA1c = glycated haemoglobin; hCG = human chorionic gonadotropin; LH = luteinising hormone; 
; PK = pharmacokinetics; SAEs = 
serious adverse events; TSH = thyroid stimulating hormone
a
Any participant with urine ACR < 30 mg/g at Week 12 will be excluded from Treatment Period 2. The eligibility check to enter Treatment Period 2 will be 
done at Visit 7 (Week 12) using the last available urine ACR result, calculated as the geometric mean of the replicated measurements using 3 sequential first 
morning urine voids. 
b
Full physical examination will be completed at the indicated visits, with the exception that height will only be taken at Screening Visit 1.
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c
Serum hCG, FSH, and LH tests, and a urine dipstick pregnancy test are required for all women.
d
Except for Screening Visit 1, participants should be requested to be in a fasting state (except water) for at least 8 hours prior to sample collection and 
samples should be collected in the morning.
e
To include thyroid function tests (TSH, fT4 and fT3).
f
All vital signs (blood pressure, heart rate, respiratory rate, body temperature, and pulse oximetry) will be measured with the participant is in a supine 
position having rested for at least 10 minutes before each reading and should be taken before any bloods draws. Vital signs should be collected pre-dose on 
the days of study drug dosing.
g
Optional, to be conducted only at study centres who agree to participate and have the appropriate facility to conduct the assessment. There is no requirement 
for all participants at centres undertaking the sub study to participate.
h
To be collected prior to study drug administration.
i
At specific PK sampling sites, for a sub-group of at least 80 participants (20 per dose group including placebo), 4 additional PK samples will be collected at 
Visit 5 within 1-2 h, 2-5 h, 5-8 h, and 8-12 h post-dose. Pre-dose samples will be collected for all participants. Each PK sample must be separated by at least 
1 h. 
j
Only if consent is obtained. The blood sample for Genomics Initiative will be obtained from the participants at Visit 3 prior to study drug administration (at 
or after randomisation). If for any reason the sample is not drawn at Visit 3, it may be taken at any visit until the last study visit. Only 1 sample should be 
collected per participant.
k
Participants will be requested to download an e-Diary application on their smartphones starting from Visit 3, in order to set study reminders and capture 
drug accountability throughout the treatment period, at sites where applicable. If needed, participants may be provided with a smartphone in order to use the 
application. Participants will be trained on how to use the application/device and the site will help the participants to login into the application for the first 
time. Data will be available to the site/Sponsor in real time. The participants who received a smartphone to use the e-Diary will return the smartphones at 
the last visit. Prior to deleting the e-Diary application from their personal smartphone, or returning a site provided smartphone, the participants will be 
requested to complete a satisfaction survey through the application (this survey is only applicable for e-Diary). Where completion of an e-Diary is not 
applicable, participant will be requested to complete a paper dosing diary.
l
Phone call will occur after results from Screening Visit 1 are available and the participant is confirmed eligible in order to remind the participants to collect 
the first morning void urine samples and schedule the Screening Visit 2. If scheduled Visit 3 (Week 1) or Visit 7 (Week 12) will need to be delayed due to 
the need to repeat ABPM recording there is no need to repeat collection of the 3 urine samples.
m
Participants to collect first morning void urine samples on 3 consecutive days (ideally day of visit and each of the preceding 2 days [refrigerated overnight] 
which are returned on the day of visit). This collection may be repeated once during the course of screening. 
n
Participants will be provided an ABPM cuff at Screening Visit 2 and Visit 6 (Week 8) and instructed to perform ABPM 24-hours before their next visit ie,
Visit 3 (Week 1) and Visit 7 (Week 12), respectively. Site will be asked to call the participant the day prior to next visit as a reminder to complete 
assessments. The participant may also visit the site for APBM cuff placement 1 day before their next visit of scheduled assessment (ie, Visit 3 [Week 1] and 
Visit 7 [Week 12] respectively).
o
Sites should ensure that the validity criterion described in Section 8.2.5 is met prior to completing any other assessments at the visit. If the validity criterion 
is not met, the associated study visit may be rescheduled to allow for a repeat ABPM recording only if the rescheduled visit can be completed within the 
specified tolerance period for study visits:
•
Visit 3: up to 72 hours following the originally scheduled visit for Visit 3 but no more than 32 days from Screening Visit 1
•
Visit 7: ± 72 hours from Day 85
If a repeat ABPM session is not possible, the study visit should proceed as indicated. In addition, the visit should also continue if the ABPM session does 
not meet the validity criterion after the repeat session.


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p
Study drug refers to AZD5718/placebo during Treatment Period 1 and AZD5718/placebo + dapagliflozin during Treatment Period 2.
q
Site should follow-up directly with the participant via phone to remind the participant.
r
Participants to return all study drug dispensed at previous visits and only use the newly dispensed study drug. Participants should be reminded not to take 
study drug on the days of a study visit until instructed by the study site.
NOTE: All laboratory assessments are to be performed in central laboratories, except for tests completed using dipsticks and drug and alcohol screen tests which 
will be done locally. Laboratory kits used locally will be provided by the central laboratory.
NOTE: Where the values for the following investigations are outside the usual range for a participant during screening, based on their medical history, retesting 
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2
INTRODUCTION
2.1
Study Rationale
The current Phase 2b study is being conducted to assess functional improvement, as defined 
by change in urine albumin excretion, in participants with proteinuric CKD when dosed with 
AZD5718. Additionally, the dose response relationship, and the safety and PK profile of
AZD5718 will be evaluated in these participants. Furthermore, the additive effect of the 
SGLT2i dapagliflozin taken together with AZD5718 on albuminuria will be assessed in an 
8-week extension period where participants will be treated with AZD5718/placebo and 
dapagliflozin.
2.2
Background
Chronic kidney disease is a worldwide public health problem associated with significant 
morbidity and mortality; DM is the leading cause of end-stage renal disease (Mills et al, 2015, 
Koye et al, 2018). The pathophysiology of DKD is multifactorial, with both haemodynamic 
effects contributing to glomerular fibrosis and inflammation emerging as major contributors to 
disease progression (Hickey and Martin 2018). Angiotensin converting enzyme inhibitors and 
ARBs have been standard of care for treatment of CKD for decades, but these drug classes 
have been shown to confer incomplete protection (Ku et al, 2018). Sodium-glucose 
cotransporter-2 inhibitors have been shown to slow down CKD progression by lowering 
glomerular pressure in patients with CKD, with or without Type 2 Diabetes Mellitus (T2DM)
(Wanner et al, 2016, Heerspink et al, 2020[b]).
Five-lipoxygenase activating protein (FLAP) is part of the 5-LO pathway that generates
biologically active lipid mediators called leukotrienes. The 5-LO pathway is expressed by 
white blood cells and has a primary role in host defence. Five-lipoxygenase activating protein 
is located within nuclear membranes and facilitates transfer of substrate (arachidonic acid) 
from membrane phospholipids to 5-LO for the generation of 
 
 
 Inflammation has been recognised as 
a key component of diabetic nephropathy and increased expression of the 5-LO and FLAP 
genes in the tubulointerstitial compartment in patients with CKD indicating the potential for 
an increased inflammatory leukotriene drive (ERCB cohort renal transcriptomics data in 
collaboration with University of Michigan, Yasuda et al, 2006). 
 and 
 can cause endothelial dysfunction, increasing glomerular permeability to 
albumin. This may explain the reduced urinary albumin excretion seen in a number of 
experimental models with leukotriene inhibition including in-house data on aged monkeys 
with metabolic syndrome treated with a FLAP inhibitor similar to AZD5718. Short term 
treatment with a FLAP inhibitor reduced proteinuria associated with glomerulonephritis in 
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human subjects (Gausch et al, 1999). 
 are also 
vasoconstrictive reducing renal perfusion which can be improved by leukotriene antagonists.
AZD5718, previously identified as AZ13702997, is a reversible FLAP inhibitor. Inhibition of 
FLAP activity will attenuate production of pro-inflammatory and vasoactive leukotrienes by 
leukocytes (eg, neutrophils) and is hypothesised to reduce albuminuria in the CKD population 
with and without DM.
While it is anticipated that SGLT2i will be a key component of standard of care for proteinuric 
CKD in the future, based on data from DAPA-CKD (Heerspink et al, 2020[b]), this is not yet a 
licensed indication. Current uptake in DKD is limited with fewer than 5% of patients on 
SGLT2i treatment. The primary endpoint for this study is based on anticipated future standard 
of care with all participants on the SGLT2i dapagliflozin. Efficacy, safety, and PK on current 
standard of care with limited use of SGLT2i are secondary endpoints.
Dapagliflozin is a highly potent, selective, and reversible inhibitor of SGLT2 that improves 
glycaemic control in patients with DM and provides cardio-renal benefits in patients with 
T2DM and without DM. Dapagliflozin is currently approved in 100 countries for the 
treatment of T2DM as an adjunct to diet and exercise and in some countries for the treatment 
of T1DM as an adjunct to insulin, when insulin does not provide adequate glycaemic control.
Dapagliflozin is commercially available as 5 mg and 10 mg tablet formulations.
This Phase 2b study will investigate if AZD5718, a FLAP inhibitor, can reduce albuminuria in 
participants with proteinuric CKD both on treatment with dapagliflozin as future standard of 
care and on current standard of care with minimal SGLT2i use. The dose response 
relationship, and the safety and PK profile of AZD5718 will also be evaluated in these 
participants. The result of the study will form the basis for the future clinical development 
programme for AZD5718.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD5718 and 
dapagliflozin are provided in the respective IBs.
2.3
Benefit/Risk Assessment
2.3.1
AZD5718
As of 31 March 2020, 4 clinical studies with AZD5718 in healthy volunteers are complete 
(D7550C00001, D7550C00002, D7550C00004, and D7550C00005), 3 studies in healthy 
volunteers are ongoing (D7550C00007, D7550C00008, and D7550C00009), and 1 study is 
ongoing in participants with CAD (D7550C00003). AZD5718 has been administered to 
healthy volunteers (in completed studies) in single doses up to 
 mg, and in repeated doses 
up to 
 mg for 10 days. AZD5718 has been administered to 122 healthy volunteers (in 
completed studies) in single doses up to 
 mg, and in repeated doses up to 
 mg for 10 
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days.
The safety and tolerability of AZD5718 in fasting and fed male healthy volunteers following
single and multiple ascending doses have been evaluated in the single-multiple ascending dose
(SMAD; D7550C00001), Japanese SMAD (JSMAD; D7550C00004), combined drug-drug 
interaction/bioavailability (DDI/BA; D7550C00002) and BA (D7550C00005) studies.
AZD5718 has been well tolerated in male healthy volunteers. No clinically meaningful
differences for changes over time in clinical laboratory tests, vital signs or electrocardiograms
(ECGs) were observed between healthy volunteers who received AZD5718 and those who 
received placebo. There were no deaths or SAEs and all healthy volunteers completed the 
studies. The most common AE in healthy volunteers receiving AZD5718 across the SMAD 
(D7550C00001), DDI/BA (D7550C00002) and BA (D7550C00005) studies was headache; the 
most common AE in Study D7550C00004 was contact dermatitis (reported in Japanese 
healthy volunteers receiving both placebo and AZD5718). No safety concerns were raised 
during the studies.
More detailed information about the known and expected benefits and potential risks of
AZD5718 may be found in the Investigator’s Brochure (IB).
2.3.2
Dapagliflozin
The safety profile of dapagliflozin has been evaluated in clinical development programmes for
T2DM, T1DM, and heart failure. This includes more than 15000 participants treated with
dapagliflozin for T2DM, more than 1000 participants treated with dapagliflozin for Type 1 
Diabetes Mellitus (T1DM) and more than 2000 participants treated with dapagliflozin for 
heart failure. Overall, treatment with dapagliflozin 5 mg was similar to treatment with 
dapagliflozin 10 mg in both T1DM and T2DM. The safety profile of dapagliflozin was overall 
consistent across the studied indications. Dapagliflozin is authorised for treatment of T2DM,
T1DM, and heart failure with reduced ejection fraction, and is under development for 
treatment in patients with CKD and heart failure with preserved ejection fraction.
The most commonly reported AEs associated with the use of dapagliflozin include genital 
infections, urinary tract infections, back pain, and polyuria. In addition, rash has been 
identified as an AE of unknown frequency in marketed use of dapagliflozin.
Diabetic Ketoacidosis
In the cardiovascular outcomes study, DECLARE, 8574 participants received dapagliflozin 
(FORXIGA) 10 mg and 8569 participants received placebo for a median exposure time of 
48 months. Events of diabetic ketoacidosis (DKA) were reported in 27 participants in the 
dapagliflozin 10 mg group and 12 participants in the placebo group.
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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.
More detailed information about the known and expected benefits and potential risks of 
dapagliflozin may be found in the IB.
2.3.3
Other Risks
See Appendix F for details on background information, risks and mitigations plans, and 
impact of coronavirus disease-2019 (COVID-19) on the current study.


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3 
OBJECTIVES AND ENDPOINTS 
Table 2 
Objectives and Endpoints 
Objectives 
Estimand Description/Endpoints 
Prima1y 
To evaluate the dose response 
Reduction of mine ACR from baseline to Week 20 compared 
effect of AZD5718 on mine ACR 
with placebo. 
at 20 weeks in pa1ticipants with 
The p1ima1y estimand is a hypothetical estimand such that the 
proteinmic CKD ( on treatment 
treatment effect is quantified in the optimal situation where 
with dapagliflozin as futme 
any potential confounder is avoided. The population of 
standard of care from Weeks 12 to 
interest is the per protocol population. The endpoint being 
20) 
assessed is the change in log-transfo1med mine ACR from 
baseline to Week 20. For the intercmTent event, if a pa1ticipant 
discontinues treatment due to AE or lack of efficacy, or uses 
prohibited medication, the mine ACR data are treated as 
missing after the event and no imputation is perfo1med. The 
summary measme being evaluated is the geometiic mean 
reduction of mine ACR from baseline to Week 20. 
Seconda1y 
To evaluate the dose response 
Reduction of mine ACR from baseline to Week 12 compared 
effect of AZD5718 on mine ACR 
with placebo. 
at 12 weeks (on cunent standard of The clinical quantity of interest to be estimated is defined by 
care) 
the following 3 components: 
• Population 
Randomised paiticipants who meet all eligibility 
c1ite1ia and have valid non-missing mine ACR records 
at baseline and at least one post-treatment visit. 
• Endpoint 
Change in log-transfo1med mine ACR from baseline 
to Week 12. 
• Summaiy measme 
Geometiic mean reduction of mine ACR from 
baseline to Week 12 compared with placebo. 
To evaluate the safety and 
• AEs/SAEs 
tolerability of AZD5718 in 
• Vital signs 
pa1ticipants with proteinmic CKD 
• Clinical chemistiy/haematology/coagulation/minalysis 
pai·ameters 
• ECG assessments 
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Objectives 
AstraZeneca 
Estimand Description/Endpoints 
To evaluate the effect of AZD5718 
on ambulatory blood pressure in 
pa1ticipants with proteinmic CKD 
Change in 24-hour mean SBP from baseline to Week 12 
To assess the PK of AZD5718 
after repeated oral dosing for 20 
weeks in participants with 
proteinuric CKD 
To assess the effect of AZD5718 
on renal function in participants 
with proteinmic CKD with and 
without the addition of 
dapagliflozin 
-
AZD5718 plasma concentrations 
Change in eGFR from baseline to Week 12 and from Week 12 
to Week20 
·e ia i 
s: -L = 5-lipoxygenase; ACR = albumin to creatinine ratio; AEs = adverse events· 
; CKD = chronic kidne disease· CSR = clinical study repo1t; 
; DKD = diabetic kidney disease; 
· ECG = electroc 
e FR = estimated _lomemlar filtration rate; 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, randomised, double-blind, placebo-controlled, multi-centre, dose-ranging 
study to evaluate the efficacy, safety and PK of AZD5718 in participants with proteinuric 
CKD. Furthermore, the additive effect of the SGLT2i dapagliflozin taken together with 
AZD5718 on albuminuria will be assessed in an 8-week extension period where participants 
will be treated with AZD5718/placebo and dapagliflozin.
The study will be conducted in approximately 118 study centres across 12 countries.
Approximately 632 participants comprising of 67% DKD and 33% non-DKD participants will 
be randomised 1:1:1:1 to receive once daily oral doses of 
mg AZD5718, 
mg AZD5718, 
mg AZD5718, or placebo, for the first 12 weeks with an add-on therapy of 8 weeks of 
10 mg dapagliflozin for all participants, to have 158 participants per group. The plan is to 
have approximately 568 evaluable participants (142 per group) completing the study.
The study will include 4 periods:

Screening Period of up to 4 weeks.

Treatment Period 1 of 12weeks where the participants will receive a once daily oral dose 
of the assigned dose of study drug to be taken with approximately 200 mL water in the 
morning with no restrictions on food intake.

Treatment Period 2 of 8 weeks where the participants will receive a treatment of once 
daily oral dose of dapagliflozin 10 mg in addition to the assigned dose of study drug.
Only participants still taking their assigned treatment from Treatment Period 1 will 
progress to Treatment Period 2. Any participant with urine albumin to creatinine ratio 
(ACR) < 30 mg/g at Week 12 will be excluded from Treatment Period 2. The eligibility 
check to enter Treatment Period 2 will be done at Visit 7 (Week 12) using the last 
available urine ACR result, calculated as the geometric mean of the replicated 
measurements using 3 sequential first morning urine voids.

Follow-up Period of up to 4 weeks.
The study will include a total of 10 visits which includes 2 visits during the Screening Period, 
5 visits during the Treatment Period 1, 2 visits during the Treatment Period 2, and 1 visit 
during the Follow-up Period.
The expected total study duration, including the Screening Period, for each participant will be 
at least 28 weeks.
The SoA to be conducted during the study is presented in Table 1 and a schematic 
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representation of the study is presented in Figure 1.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design
This study is randomised and double-blinded to prevent bias in treatment allocation and in the 
subjective assessment of effect of the study drug in the intended study population. A 
randomised, blinded, multi-centre, placebo-controlled study design is considered the best 
design to achieve the objectives of the study, from both safety and efficacy perspectives.
Additionally, the study is designed to demonstrate efficacy versus placebo and thus, a placebo 
control arm in the study will enable placebo-corrected analysis of safety and efficacy.
4.2.2
Rationale for Study Endpoints
Change in urine albumin excretion during the Treatment Periods provides information about 
renal efficacy (predictive of meeting hard renal endpoints in Phase 3 clinical studies) both on 
anticipated future standard of care and current standard of care, and a sustained effect 
following study drug washout would suggest benefit to renal structure. The treatment duration 
allows a suitable assessment of safety following multiple dose administration and is of 
sufficient length to evaluate the effects of the study drug on urine albumin excretion 
(Levey et al, 2020).
The study also intends to evaluate the effect of AZD5718 on ambulatory BP in participants 
with proteinuric CKD in line with FDA recommendation to understand the temporal changes 
in BP and changes in risk. As elevated BP is known to increase the risk of stroke, heart attack, 
and death, the effect of any drug during the clinical development phase on BP can therefore be 
an important consideration in benefit-risk assessment. A 24-hour ambulatory blood pressure 
monitor (ABPM) is shown to provide precise estimates of BP changes to assess the effects of 
drug on BP and lack a pronounced placebo response (Garnett et al, 2020).
Additionally, this study will assess the PK of AZD5718 to support the dose selection for future 
development in this participant population. 
 
hese biomarkers may include, but are not limited to 
 
 
In addition, blood samples for potential current and future 
 will be collected in participants who have given a separate 
consent for genetic research.
4.2.3
Rationale for Study Population
The study population with CKD (eGFR 20 - 75 mL/min/1.73m2) and albuminuria 
(200 – 5000 mg albumin/g creatinine) enables assessment of the clinical efficacy and safety as 
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well as supporting dose selection in a population at risk for progression to renal failure (Go et 
al, 2018).
4.3
Justification for Dose
4.3.1
AZD5718
The AZD5718 doses selected for this study are based on the goal of characterising the dose
response for urine ACR and evaluating safety in a proteinuric CKD participant population.
The doses have been selected based on data from human volunteer studies with the aim of 
suppressing production of both
Single doses of up to 
mg AZD5718 and once daily repeated doses of 
mg, 
mg, 
mg and 
mg for 10 days have been well tolerated in healthy volunteers. In an ongoing 
Phase 2a study in coronary artery disease (CAD) participants with a recent myocardial 
infarction, doses of 
mg and 
mg are being evaluated.
A study in non-human primates with a similar compound to AZD5718 showed a beneficial 
and clinically relevant reduction in urine ACR at exposures aiming for an 80% reduction of 
production in blood. Model predicted relationship between inhibition of ex vivo
 
production in blood and exposure in healthy subjects has shown that a 
mg once daily dose 
at steady state gives > 80% inhibition during the whole dosing interval. A 
mg dose is 
predicted to result in a 30% reduction by the end of the dosing interval and the 
mg dose is 
between the lowest and the highest dose evaluated.
4.3.2
Dapagliflozin
A once daily dose of 10 mg dapagliflozin has been established as having the optimal effect on 
albuminuria in DKD (Heerspink et al, 2020[a]).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the Follow-up Visit as shown in the Schedule of Activities (SoA; Table 1).
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
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Age
1
Participants must be ≥18 years of age inclusive, at the time of signing the informed 
consent.
For participants who haven’t reached the age of maturity according to local regulations in 
their country, a written informed consent should be obtained from the participant and his 
or her legally acceptable representative.
Type of Participant and Disease Characteristics
2
Participants with proteinuric CKD defined as 

eGFR 20 – 75 mL/min/1.73m2 based on chronic kidney disease epidemiology 
collaboration (CKD-EPI) equation at Screening Visit 1 and

albuminuria defined as 200 -5000 mg albumin/g creatinine based on the geometric 
mean of the replicated measurements using 3 sequential first morning void urine at 
Visit 2.
and

with diagnosis of T2DM (for DKD sub-group only).
Weight
3
Body weight within 50-150 kg and BMI within the range 18 to 45 kg/m2 (inclusive).
Sex
4
Male or female
5
Female participants must be of non-childbearing potential and must have been surgically 
sterilised (ie, bilateral oophorectomy, and/or complete hysterectomy, and/or bilateral 
salpingectomy; tubal ligation is not sufficient) or be postmenopausal (amenorrhoeic for 
12 months or more following cessation of exogenous hormonal treatments and assessed 
by serum follicle stimulating hormone [FSH] and luteinising hormone [LH] levels at 
Screening Visit 1). All female participants must have a negative serum pregnancy test at 
Screening Visit 1 and negative urine pregnancy test at Visit 3 (Day 1) prior to study drug 
administration.
6
Male participants must be surgically sterile or agree to use highly effective 
contraceptives. Non-sterilised male participants who are sexually active with a female 
partner of childbearing potential must use a male condom with spermicide from Day 1 to 
3 months after the last dose of the study drug. It is strongly recommended for the female 
partner of a male participant to also use a highly effective method of contraception 
throughout this period.
Note: In case a male condom with spermicide is not available in a country or region, 
non-sterilised male participants who are sexually active with a female partner of 
childbearing potential must use a male condom without spermicide and the female partner 
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Note: Highly effective birth control methods for female partners of male participants 
include: total sexual abstinence (true abstinence in line with the preferred and usual 
lifestyle choice of the participant), vasectomised partner, tubal occlusion, intrauterine 
device (provided coils are copper banded), levonorgestrel intrauterine system (eg, 
Mirena®), medroxyprogesterone injections (eg, Depo-Provera®), etonogestrel implants 
(eg, Implanon®, Norplan®), normal and low dose combined oral pills, 
norelgestromin/ethinylestradiol transdermal system (eg Evra® Patch), intravaginal device 
(eg, NuvaRing®), and Cerazette® (desogestrel) pills.
Approved/Certified measurements in Japan are as below:
Vasectomy, tubal occlusion, intrauterine device (provided coils are copper banded),
levonorgestrel intrauterine system (eg, Mirena®).
These measurements are acceptable forms of highly effective birth control in Japan.
Not Approved/Certified measurements in Japan are as below:
Cerazette® (desogestrel) pills, medroxyprogesterone injections (eg, Depo-Provera®),
etonogestrel implants (eg, Implanon®, Norplan®), normal and low dose combined oral
pills, norelgestromin/ethinylestradiol transdermal system (eg, Evra® Patch), intravaginal
device (eg, NuvaRing®).
Informed Consent
7
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 CSP.
8
 
 
.
Other Criteria
9
Participants should have a stable BP meeting all of the following criteria:
(a) BP ≤150/100 mmHg at Screening Visit 1 and Visit 3.
(b) Stable dose of angiotensin converting enzyme inhibitor (ACEi) or angiotensin 
receptor blocker (ARB) for at least 4 weeks prior to Screening Visit 1 with ACEi and 
ARB dosing according to local guidelines. Participants who have been deemed 
unable to tolerate ACEi or ARB therapy due to allergy or complications may be 
enrolled.
10 For participants on any additional antihypertensive medication (including diuretic 
therapy), the doses must be stable for at least 4 weeks prior to Screening Visit 1.
11 If on SGLT2i or glucagon-like peptide-1 receptors agonists (GLP1-RA) treatment, the 
participants must have been on a stable dose for at least 4 weeks prior to randomisation 
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visit. No new additional SGLT2i or GLP1-RA therapy is permitted until the 8-week 
extension period.
12 If on treatment with other drugs with potential to influence albuminuria, eg non-steroidal 
anti-inflammatory drug (NSAID)s, the participants must have been on a stable dose for at 
least 4 weeks prior to Screening Visit 1.
13 Renin inhibitor or an aldosterone antagonist in combination with an ACEi or an ARB 
(dual renin angiotensin aldosterone system inhibitor therapy) is permitted and participants 
must have been on a stable dose for at least 4 weeks prior to Screening Visit 1.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Recent hepatitis, or positive screening test for hepatitis B (hepatitis B virus surface 
antigen) or hepatitis C (hepatitis C antibody).
2
Diagnosis of polycystic kidney disease or anatomical causes of CKD.
3
Diagnosis of T1DM.
4
Participants with severe hepatic impairment (Child-Pugh class C).
5
Abnormal laboratory findings at Screening Visit 1
(a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper 
limit of normal (ULN) or total bilirubin > 2 × ULN (unless due to Gilbert’s disease) 
or evidence of chronic liver disease.
(b) Serum potassium > 5.5 mmol/L that cannot be adjusted to values ≤5.5 mmol/L by 
appropriate management.
6
Any of the following concomitant conditions or diseases at Screening Visit 1
(a) History of QT prolongation associated with other medications that required 
discontinuation of that medication.
(b) Congenital long QT syndrome.
(c) Acute coronary syndrome, percutaneous coronary intervention, coronary artery 
bypass grafting within 6 months.
(d) High degree atrioventricular block II-III, sinus node dysfunction with significant 
sinus pause, untreated with pacemaker.
(e) Stroke within 3 months.
(f) Heart failure New York Heart Association classification III-IV.
(g) Anticipated dialysis or renal transplantation within 1 year.
(h) History of substance dependence or a positive screen for drugs or alcohol abuse, 
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discretion of the Investigator. Alcohol and drug screening to be completed for all 
participants locally with laboratory kits provided by the central laboratory.
(i)
Prior malignancy other than non-melanoma skin cancer or cervical cancer in situ 
treated with apparent success with curative therapy (response duration of > 5 years).
(j)
Any other condition or clinically relevant abnormal findings in physical examination, 
laboratory results or ECG during screening period that, in the opinion of the 
Investigator, may compromise the safety of the participant in the study, reduce the 
participant’s ability to participate in the study, or interfere with evaluation of the 
study drug.
7
Participant who had severe course of COVID-19 (extracorporeal membrane oxygenation, 
mechanically ventilated), and/or had a confirmed case of COVID-19 within 4 weeks of 
Screening Visit 1 (for further details See Appendix F).
Prior/Concomitant Therapy
8
Ongoing use of any biologic drug and/or small molecule targeting the immune system 
(for example, tumour necrosis factor blockers, anakinra, rituximab, abatacept, 
azathioprine, mycophenolate, cyclophosphamide, tocilizumab, corticosteroids other than 
topical or inhaled).
9
Any serum creatinine-altering drugs within 1 month prior to Screening Visit 1 including 
but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, 
probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins.
10 Treatment with any concomitant medications known to be associated with Torsades de 
Pointes or potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of Visit 3 
(Randomization).
11 Treatment with zileuton, cilastatin (dipeptidase-1 [DPEP1] inhibitor), or leukotriene 
receptor antagonists (eg, montelukast) within 4 weeks of Screening Visit 1.
12 Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 
1 month prior to Screening Visit 1.
Prior/Concurrent Clinical Study Experience
13 Concurrent enrolment in another clinical study involving an investigational treatment or 
drug or participation in a device study within 3 months prior to Screening Visit 1.
14 Participants with a known hypersensitivity to AZD5718 or any of the excipients of the 
product.
Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the
product.
Other Exclusions
15 Donation of blood or significant blood loss in excess of 500 mL within 3 months prior to 
Day 1 (or > 1200 mL in the year prior to Day 1).


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16 Plasma donation within 60 days prior to Day 1.
17 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study centre).
18 Judgement by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
19 For women only - currently pregnant (a negative serum pregnancy test is required at 
Screening Visit 1 and urine pregnancy test at Day 1 [Visit 3]) or breast-feeding.
20 An employee, or close relative of an employee, of AstraZeneca, the Contract Research 
Organisation (CRO), or the study site, regardless of the employee’s role.
21 Participants who are legally institutionalised.
22 Participants working night shifts, and who cannot avoid strenuous manual labour during 
the study.
Note: Where the values for the following investigations are outside the usual range for a 
participant during screening, based on their medical history, retesting may be undertaken on 
one occasion without requiring a re-screen: Blood pressure, eGFR, spot urine for ACR, ALT, 
AST, bilirubin, and serum potassium.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
1
Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, pomelos, 
exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the start of study 
drug until after the final dose.
2
Participant should only be requested to arrive at the clinic after fasting for at least 8 hours 
(no food or liquid [except for water] intake permitted) for all study visits except for 
Screening Visit 1.
5.3.2
Caffeine and Alcohol
1
Participants will abstain from ingesting caffeine- or xanthine-containing products (eg,
coffee, tea, cola drinks, and chocolate) for at least 12 hours before each visit to study 
centre.
2
Participants will abstain from alcohol for at least 48 hours before each visit to study 
centre.
5.3.3
Activity
1
Participants will abstain from strenuous exercise for at least 24 hours before each blood 
collection for clinical laboratory tests.
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5.3.4
Reproductive Restrictions
1
Male participants should agree to use highly effective method of contraception from 
Day 1 until 3 months after the final dose of the study drug.
5.3.5
Other Restrictions
1
Male participants will abstain from donating the sperm throughout the duration of the 
study and for 3 months after the final dose of the study drug.
2
Participants will abstain from donating blood or plasma throughout the duration of the 
study and for 3 months after the final dose of the study drug.
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 the study drug. 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 SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants should be assigned the same participant number as 
for the initial screening.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, intended to be administered to or medical device(s) utilised by a study participant 
according to the CSP.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Table 3
Investigational Products
Intervention 
name
AZD5718
Dapagliflozin
Placeboa
Type 
Drug
Drug
Drug
Dose 
formulation
Tablets
Tablets
Tablets
Unit dose 
strength(s)
mg, 
mg, and 
mg
10 mg
Not applicable
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Intervention 
name
AZD5718
Dapagliflozin
Placeboa
Dosage 
level(s)
mg, 
mg (
mg + 
mg), and 
mg, 
once daily
10 mg, once daily 
Once daily
Route of 
administration
Oral
Oral
Oral
Use
Experimental
Experimental
Placebo- comparator
IMP and 
NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Packaging and 
labelling
Study drug will be 
provided in blisters that 
will be packed in a 
wallet. There will be 2
blisters packed in one 
wallet. Each wallet will 
be labelled in accordance 
with GMP and local 
regulatory guidelines. 
The labels will fulfil 
GMP Annex 13 
requirements for 
labelling. Label text will 
be translated into local 
language as required.
Study drug will be 
provided in bottle. Each 
bottle will contain 
35 tablets and will be 
labelled in accordance 
with GMP and local 
regulatory guidelines. 
The labels will fulfil 
GMP Annex 13 
requirements for 
labelling. Label text will 
be translated into local 
language as required.
Study drug will be 
provided in blisters that 
will be packed in a 
wallet. There will be 2
blisters packed in one 
wallet. Each wallet will 
be labelled in accordance 
with GMP and local 
regulatory guidelines. 
The labels will fulfil 
GMP Annex 13 
requirements for 
labelling. Label text will 
be translated into local 
language as required.
Abbreviations: GMP = Good Manufacturing Practice; IMP = Investigational medicinal product; 
NIMP = Non-investigational medicinal product
a
As comparator to AZD5718 only.
6.2
Preparation/Handling/Storage/Accountability
1
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drugs received and any discrepancies are reported 
and resolved before use of the study drugs.
2
Only participants enrolled and randomised into the study may receive study drugs and 
only authorised site staff may supply or administer study drugs. All study drugs 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.
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3
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drugs accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
6.3.1
Methods for Assigning Treatment Groups
All participants will be centrally assigned to randomised study drug using Interactive 
Response Technology/Randomization and Trial Supply Management (IRT/RTSM). Before the 
study is initiated, the telephone number and call-in directions for the Interactive Voice 
Response System (IVRS) and/or the log-in information and directions for the Interactive Web 
Response System (IWRS) will be provided to each study centre. 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.
Randomisation will be stratified by participants with and without DM at the time of 
randomisation in order to ensure approximate balance between treatment groups within each 
sub-population.

Stratum 1: DKD participants without SGLT2i background outside Japan

Stratum 2: DKD participants with SGLT2i background outside Japan

Stratum 3: Non-DKD participants outside Japan

Stratum 4: DKD participants without SGLT2i background in Japan

Stratum 5: DKD participants with SGLT2i background in Japan

Stratum 6: Non-DKD participants in Japan
The number of randomised DKD and non-DKD participants will be monitored in order to 
ensure that the non-DKD sub-population is 30%-35% of the total participants randomised. At 
least 72 Japanese participants will be included.
At randomisation, the IRT/RTSM will assign eligible participant a unique randomisation code 
and blinded study drug kit number(s). Specific information concerning the use of the 
IRT/RTSM will be provided in the separate user manual at each study centre.
Study drugs will be dispensed at the study visits as summarised in the SoA (Table 1). Returned 
study drugs should not be re-dispensed to the participants.
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to receive AZD5718 (
mg), AZD5718 (
mg), AZD5718 (
mg), or placebo in 
Treatment Period 1 followed by add-on 10 mg of dapagliflozin to the randomised dose level in 
Treatment Period 2. Upon completion of the randomisation request form, the randomisation 
will be produced by Parexel Informatics using the AstraZeneca randomisation solution 
(AZRand).
6.3.2
Methods for Ensuring Blinding
The study will have a double-blind design. Placebo tablets will match appearance of each of 4
dosage levels: 
mg AZD5718, 
mg AZD5718, 
mg AZD5718 and placebo.
No member of the study team at AstraZeneca, or representative, personnel at study centres, or 
any CRO handling data will have access to the randomisation scheme prior to unblinding for 
the primary analysis, with the exception of the Parexel Informatics personnel generating the 
randomisation scheme as well as AstraZeneca Supply Chain, and the CRO companies 
conducting PK sample analyses, providing the IRT/RTSM and carrying out the packaging and 
labelling of the study drug. This documentation will be kept in a secure location until the end 
of the study. Separate personnel with no other involvement in the study will be unblinded for 
the interim analysis.
6.3.3
Methods for Unblinding
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the participant requires knowledge of the study drug. The Investigator 
documents and reports the action to AstraZeneca, without revealing the treatment given to the 
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 the blinded study drug and that potentially require 
expedited reporting to regulatory authorities.
For the administrative interim analysis, separate personnel with no other involvement in the 
study will be unblinded. A detailed description of the interim analysis to be conducted will be 
provided in the Statistical Analysis Plan (SAP).
6.4
Study Intervention Compliance
AZD5718 and placebo will be provided in blisters packed in child-resistant wallets. Enough 
tablets will be dispensed for daily dosing at home until the participant returns for the next 
study visit. Dapagliflozin will be provided in 75 cc high-density polyethylene bottle.
When the participants are dosed at the study centre, they will receive the study drugs directly 
from the Investigator or designee, under medical supervision. The date, and time if applicable,
of dose administered in the clinic will be recorded in the source documents and recorded in 
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the electronic Case Report Form (eCRF). The dose of the study drugs and study participant 
identification will be confirmed at the time of dosing by a member of the study centre staff 
other than the person administering the study drug.
When the participants self-administer study drugs at home, compliance with study drugs will 
be assessed at each visit. Compliance will be assessed by direct questioning, counting returned 
tablets etc., during the study centre 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 AZD5718/placebo and dapagliflozin tablets dispensed to and taken 
by each participant must be maintained and reconciled with study drugs and compliance 
records. Study drugs start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
6.4.1
E-Diary
The participants will be requested to download an e-Diary application on their smartphone 
during Visit 3, in order to set up study reminders, (ie, reminder to take their medication or 
collect the first morning void) as well as capture drug accountability throughout the treatment 
period, at sites where applicable. If needed, participants will be provided with a smartphone in 
order to use the application. Participants will be trained on how to use the application/device 
and the site will help the participants to login into this application for the first time. Data will 
be available to the site/Sponsor in real time. The participants who received a smartphone to 
use the e-Diary will return the smartphones at the last study visit.
Where completion of an e-Diary is not applicable, participant will be requested to complete a 
paper dosing diary.
Prior to deleting the e-Diary application from their personal smartphone, or returning a site 
provided smartphone, the participants will be requested to complete a satisfaction survey 
through the application (this survey is only applicable for e-Diary). 
6.5
Concomitant Therapy
Any medication or vaccine (including over the counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrolment
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
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prior therapy.
6.5.1
Prohibited Concomitant Medications
Use of OTC medications, herbal supplements, vitamins, etc, from Screening through to the 
early discontinuation visit is discouraged. Participants must be instructed not to take any 
medications, including OTC products, without first consulting with the Investigator. 
Non-study SGLT2i or GLP1-RA should not be initiated after enrolment in the study.
Participants are not permitted to receive any of the following medications during the study.
1
Systemic (oral or injectable) corticosteroids within 28 days of Screening Visit 1 until the 
end of the Follow-up Period.
2
Any other immunosuppressive therapy within 3 months of randomisation until the end of 
the Follow-up Period.
3
Any immunotherapy within 3 months of randomisation, except for stable maintenance 
dose allergen-specific immunotherapy started 28 days prior to Screening Visit 1 until the 
end of Follow-up Period.
4
Interferon gamma within 3 months of randomisation until the end of the Follow-up 
Period.
5
Investigational products other than AZD5718 within 4 months or 5 half-lives of 
randomisation until the end of the Follow-up Period.
6
Immunoglobulin or blood products within 28 days of Screening Visit 1 until the end of 
the Follow-up Period.
7
Ongoing use of any biologic drug or small molecule targeting the immune system (for 
example, tumour necrosis factor blockers, anakinra, rituximab, abatacept, azathioprine,
tocilizumab, mycophenolate, corticosteroids other than topical or inhaled).
8
Any serum creatinine-altering drugs within 1 month prior to Screening Visit 1 including 
but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, 
probenecid, ranolazine, trimethoprim, cyclophosphamide, aminoglycosides, or 
cephalosporins until the end of the Follow-up Period.
9
Any medication that alters leukotriene levels or actions within 4 weeks of Screening 
Visit 1, eg, zileuton cilastatin, and montelukast until the end of the Follow-up Period.
10 Simvastatin, lovastatin, or atorvastatin at doses > 40 mg per day within 1 month of 
Screening Visit 1 until the end of the Follow-up Period.
6.5.2
SGLT2 Inhibitors
If the participants are on SGLT2i treatment prior to enrolment into this study, they must have 
been on a stable dose for at least 4 weeks prior to randomisation visit. No new additional 
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Participants receiving SGLT2i treatment prior to randomisation as standard of care will have 
to continue the treatment at the same dose through the study and it must not be changed unless 
prescribed by the Investigator.
In general, any dose changes of SGLT2i treatment should be avoided during the study unless 
due to medical necessity. If the participant needs to interrupt SGLT2i treatment for any reason, 
they should be allowed to re-start it again once the respective medical condition gets resolved.
For Treatment Period 2, any existing SGLT2i treatment, including fixed-dose combination 
preparations, will be discontinued and replaced by dapagliflozin 10 mg once daily until the 
end of the treatment period. For participants on fixed-dose combinations, the non-SGLT2i 
drugs should be prescribed as single agent preparations, at the discretion of the PI.
6.5.3 Rescue Medicine
If a participant’s medical condition requires rescue therapy, the participant should be treated 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 dapagliflozin to avoid hypoglycaemia.
6.6
Dose Modification
No dose modifications are permitted during the study due to its short duration. However, study 
drug dose(s) may be withheld if clinically necessary.
In the case of delayed or missed dose for any reason, subsequent doses should be administered 
according to the original schedule (ie, at the planned timepoint relative to first dose of the 
study drug).
6.7
Intervention After the End of the Study
After completing dosing with study drugs at Week 20 and the Follow-up Visit at Week 24, the 
participants will have completed the study. AZD5718 will not be provided for post-study use.
Both the study drugs (AZD5718 and dapagliflozin) will be withdrawn after Week 20 and 
participants should be returned to their previously prescribed treatment regimen, at the 
discretion of the Investigator.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Drugs
Participants are free to discontinue study drugs at any time, without prejudice to further 
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
Participants who choose to discontinue AZD5718 prior to the end of Treatment Period 1
will not proceed to Treatment Period 2 and are expected to complete the assessments per 
Discontinuation Visit and Follow-up Visit.

Participants who choose to discontinue either AZD5718 or dapagliflozin prior to the end 
of Treatment Period 2 are expected to continue in the study on the remaining study 
therapy and are expected to complete the study assessments according to the schedule of 
study procedures for the remainder of the study.

Participants who choose to discontinue both AZD5718 and dapagliflozin prior to the end 
of Treatment Period 2 are expected to complete the study assessments according to the 
schedule of study procedures for the remainder of the study.
See the SoA (Table 1) for data to be collected at the time of discontinuation of study drugs and 
follow-up and for any further evaluations that need to be completed.
The Investigator and/or Study Physician may determine that an individual participant will not 
receive any further study drug if any of the following occur in that participant:

Withdrawal of consent from further treatment with study drugs.

Lost to follow-up.

Safety reasons as judged by the Investigator and/or Sponsor where continued treatment 
may put the participant at undue risk.

Incorrectly randomised participant in whom inclusion/exclusion criteria violation would 
put the participant at undue risk.

Participant noncompliance that, in the opinion of the Investigator or Sponsor, warrants 
treatment discontinuation for safety reasons (eg, refusal or inability to adhere to scheduled 
visits).

Pregnancy.

Any of the following liver function abnormalities:

ALT or AST > 8 × ULN

ALT or AST > 5 × ULN for more than 2 weeks

ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or international normalised 
ratio [INR] > 1.5); see Appendix E for additional details regarding reporting of 
participants with ALT or AST ≥3 × ULN and total bilirubin ≥2 × ULN with 
unknown aetiology (ie, Hy’s Law [HL] cases)

ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
If an unexpected, acute decline in GFR is observed (> 15% decrease in eGFR from the 


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Screening Visit values), the participant should be promptly evaluated. Volume depletion, 
hypotension, inter-current medical problems, and concomitant drugs may cause increases in 
blood creatinine. Urinary tract infection and urinary obstruction should be considered. Several 
drugs may cause a decline in GFR, especially NSAIDs and certain antibiotics such as 
trimethoprim. If any drug is suspected of causing or contributing to worsening kidney 
function, their use should be re-considered. The Investigator together with the Study Physician 
should consider the discontinuation of the investigational medicinal product (IMP) if eGFR 
decreases by more than 30% of Screening Visit values.
Consider temporary interruption of dapagliflozin if DKA is suspected. The participant should 
be promptly evaluated. If DKA is confirmed, dapagliflozin should be discontinued 
permanently.
Note that discontinuation from study drugs is NOT the same thing as a withdrawal from the 
study.
Participants who are permanently discontinued from receiving the study drugs will be 
followed for protocol-specified assessments, including follow-up of any AEs, unless consent 
is withdrawn specifically from further study participation (Section 7.2), the participant is lost 
to follow-up (Section 7.2), or the participant is enrolled in another clinical study.
A participant who decides and/or is recommended by the treating physician or the Investigator 
to permanently discontinue the study drugs will always be asked about the reason(s) for 
discontinuation and about the presence of any AEs. All efforts must be taken to ensure that the 
participant will be seen and assessed by an Investigator and, as scheduled for other 
participants, all end of treatment visit assessments should be completed at the time of 
discontinuation of study drug.
7.1.1
Temporary Discontinuation
For participants needing treatment with prohibited concomitant medications, study drugs must
be discontinued or interrupted temporarily.
For decisions around discontinuation, the Study Physician can be consulted as appropriate.
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 
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
At the time of withdrawal from the study, if possible, an Early Study Drug
Discontinuation Visit should be conducted, as shown in the SoA. See SoA (Table 1) for 
the 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 drugs 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 is 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 centre.
The following actions must be taken if a participant fails to return to the study centre for a 
required study visit:

The study centre 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.

Study centre personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants 
randomised, including those who did not get investigational product. Public sources may 
be searched for vital status information. If vital status is determined as deceased, this will 
be documented, and the participant will not be considered lost to follow-up. Sponsor 
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7.4
Study Termination
AstraZeneca may terminate the entire study prematurely if concerns for safety arise within this 
study or in any other study with AZD5718. 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 timing are summarised in the SoA (Table 1). Protocol waivers 
or exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study drug.

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 or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will be included in the ICF.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Efficacy Assessments
8.1.1
Primary Efficacy Assessment
8.1.1.1
Urinary Albumin Creatinine Ratio
The urine ACR is a key marker for assessing kidney function. Urine ACR is a ratio between 
2 measured substances (albumin and creatinine), which estimates 24-hour urine albumin 
excretion.
During this clinical study, a spot urine sample is collected during the Screening Visit 1 and at 
the remaining timepoints, participants are required to collect first morning void urine samples 
on 3 consecutive days (ideally day of visit and preceding 2 days [refrigerated overnight] 


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which are returned on the day of visit) as described in SoA (Table 1). If scheduled Visit 3 
(Week 1) or Visit 7 (Week 12) will need to be delayed due to the need to repeat ABPM 
recording there is no need to repeat collection of the 3 urine samples. The containers to collect 
the urine samples are dispensed to the participant during Screening Visit 1 and as required at 
other visits during the course of the study. Urine ACR will be calculated as follows.
Urine ACR (mg/g) = urine albumin (mg/dL) / urine creatinine (g/dL)
At each visit, the geometric mean of the triplicate measurements will be computed centrally
and used for all analyses of urine ACR.
8.1.2
Secondary Efficacy Assessments
8.1.2.1
Estimated Glomerular Filtration Rate
Estimated GFR is another marker that is considered as a standard for assessment of kidney 
function. It 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 are collected at various timepoints during the course of the study as shown in SoA 
(Table 1). Estimated GFR is then calculated as follows.
 (	
/	/1.73 	²)
= 141 × 	 (/, 1)  × 	 (/, 1) −0.209 × 0.993 #$
× (1.018 & &	') × (1.159 & )'*)
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.
Estimated GFR calculations will be performed by the central laboratory.
Alternatively, serum cystatin-C alone 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 (Stevens et al, 2008). Blood samples will also be collected 
for measurement of cystatin-C at specified time points in the SoA (Table 1).
8.1.3
 
 
 
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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Physical Examinations

A complete physical examination will be performed and include assessments of the 
following; general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose, and throat), lymph nodes, thyroid, muscular-skeletal 
(including spine and extremities) and neurological systems.

A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Physical examination will be performed at timepoints as specified in the SoA (Table 1).
8.2.2
Vital Signs
Vital signs will be performed at time points as specified in the SoA (Table 1). Vital signs will 
include BP, heart rate (HR), respiratory rate, body temperature, and pulse oximetry. Vital signs 
will be measured with the participant in a supine position having rested for at least 10 minutes 
before each reading and should be taken before any bloods draws. Vital signs should be 
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collected pre-dose on the days of study drug dosing and before blood draws. Blood pressure 
and pulse measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available. Route of body 
temperature and pulse oximetry measurements will be conducted according to local 
procedures but should be consistent throughout the study for an individual participant.
8.2.3
Electrocardiograms
Triplicate 12-lead ECGs will be performed at timepoints as specified in the SoA, Table 1
using an ECG machine that automatically calculates the heart rate and measures PR interval, 
QRS, QT, and QTc intervals. 
The ECGs should be performed after the participant has rested for at least 10 minutes in 
supine position. Three individual ECG tracings should be obtained in succession, no more 
than 2 minutes apart. The full set of triplicates should be completed within 10 minutes.
The Investigator will make an overall evaluation of the ECG as normal or abnormal. If 
abnormal, it will be decided whether or not the abnormality is clinically significant or not 
clinically significant and the reason for the abnormality will be recorded on the eCRF. 
Abnormal values shall not be recorded as AEs unless deemed clinically significant. The 
printout of the ECG is to be signed, dated and filed in participant medical record as source 
document.
8.2.4
Clinical Safety Laboratory Assessments
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the visits indicated in the SoA (Table 1). Safety sampling will 
be done after at least 8 hours of fasting, except for Screening Visit 1.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
The clinical chemistry, haematology, coagulation, and urinalysis will be performed at the
central laboratory, except for tests completed using urine dipsticks which will be done locally 
(see Table 4 for details of these tests). Laboratory kits used locally will be provided by the 
central laboratory.
Where values for the following investigations are outside the usual range for a participant
during screening, based on their medical history, retesting may be undertaken on one occasion 
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
Blood pressure, eGFR, spot urine for ACR, ALT, AST, bilirubin, serum potassium.
The following laboratory variables will be measured.
Table 4
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-White blood cell count
S/P-Sodium
B-Red blood cell count
S/P-Potassium
B-Haemoglobin
S/P-Urea
B-Haematocrit
S/P-Creatinine
B-Mean corpuscular volume
S/P-Creatine kinase
B-Mean corpuscular haemoglobin
S/P-Albumin
B-Mean corpuscular haemoglobin concentration
S/P-Calcium
B-Neutrophils absolute count
S/P-Phosphate
B-Lymphocytes absolute count
S/P-Glucose (fasting) (Non-fasting at Screening 
Visit 1)
B-Monocytes absolute count
S/P-Alkaline phosphatase 
B-Eosinophils absolute count
S/P-Alanine aminotransferase 
B-Basophils absolute count
S/P-Aspartate aminotransferase 
B-Platelets
S/P-Total bilirubin 
B-Reticulocytes absolute count
S/P-Follicle stimulating hormonea,b
Coagulation
S/P-Luteinising hormonea,b
B-International normalised ratio
S/P-Thyroid stimulating hormone (TSH)
B-Activated partial thromboplastin time
S/P-Free triiodothyronine (fT3)
B-Fibrinogen
S/P-Free thyroxine (fT4)
Urinalysisc
S/P-Creatinine (for eGFR quantification)
U-Glucose (dipstick)
S/P-Chloride
U-Albumin (quantification/semi-quantification)
S/P-Bicarbonate
U-Glucose 
S/P-Magnesium
U-Blood (dipstick)
S/P-Human chorionic gonadotropin hormoneb
U-White blood cells
S/P-Albumin
U-human chorionic gonadotropin hormone (dipstick)b
S/P-Total protein
Other Clinical Safety Panelsa (serum or plasma)
S/P-Hepatitis B surface Antigen 
S/P-Hepatitis C virus antibody
Abbreviations: B = whole blood; eGFR = estimated glomerular filtration rate; P = plasma; S = serum; U = urine
a
Screening Visit 1 only
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c
If urinalysis is positive for blood or white blood cells then microscopy through central laboratory, including 
white blood cells, red blood cells, and casts, should be completed
NOTE: 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 HL, for 
further instructions.
8.2.5
Ambulatory Blood Pressure Monitoring
24-hour ABPM will be performed at timepoints as specified in the SoA (Table 1). Participants
will be provided the ABPM cuff and instructed to use the device 24 hours prior to the next 
visit.
Training for Application and Wearing of ABPM Device:
Participants will be given training at their local study site about how to set up and apply the
ABPM device. In brief, an appropriate size BP cuff will be selected, and the device will be
fitted to the nondominant arm of the participant, with the bladder placed over the artery and an
initial test reading performed. The participants will be advised that for the first reading, the 
device will inflate to a pressure of 180 mmHg, and thereafter the device will adapt to inflate to 
a pressure just above the last recorded BP. The participant will be advised to undergo normal 
daily activities while wearing the cuff, and he/she will be advised to avoid any strenuous form 
of activity, bathing or showering while wearing the cuff. The participant will be advised to 
remain still during a measurement with the arm relaxed at heart level. The participant will also 
be given advice on how to wear the device during the day and at night while sleeping, and 
what to expect in terms of frequency of readings during the day and overnight. During ABPM, 
systolic BP, diastolic BP, heart rate pressure, HR, and mean arterial pressure readings will be 
recorded over a period of 24 hours. The participant may also visit the site for APBM cuff 
placement 1 day before their next assessment visit, as scheduled in the SoA (Table 1).
The site should ensure that the following validity criterion of the ABPM session is met prior to 
completing any other study assessments at the visit. An ABPM session may be repeated once 
if the following validity criterion has not been met:

A minimum 20 h recording with at least 70% of expected measurements being successful
If the validity criterion is not met, the associated study visit may be rescheduled to allow for a 
repeat ABPM recording only if the rescheduled visit can be completed within the specified 
tolerance period for study visits, as described in the SoA (Table 1).
If a repeat ABPM session is not possible, the study visit should proceed as indicated. In 
addition, the visit should also continue if the ABPM session does not meet validity criterion
after the repeat session.
8.2.6
Glycated Haemoglobin
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timepoints as specified in the SoA (Table 1).
8.3
Adverse Events and Serious Adverse Events
The 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).
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 Adverse Event and Serious 
Adverse Event Information
Serious AEs will be recorded from time of signature of the ICF and all AEs will be collected 
after the participant has received the first dose of study drug. The collection of AEs/SAEs will 
continue throughout the treatment period and including the Follow-up Period.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
drug 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 Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment 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 study drugs (yes or no)

Action taken with regard to study drugs

AE caused participant’s withdrawal from study (yes or no)


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
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

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 study drug 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 study drug?’
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/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol (CSP) mandated laboratory tests and vital signs 
will be summarised in the Clinical Study Report (CSR). 


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Deterioration as compared to baseline in CSP-mandated laboratory values and vital signs
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the study drug 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 drug, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE 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 total bilirubin ≥ 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 HL.
8.3.7
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study drug, or 
to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day 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 
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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 centre staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study centre staff how to proceed.
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 the AstraZeneca 
drug AZD5718.
8.3.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
drugs.
8.3.8.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drugs 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 one day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.8) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
When the eCRF module is used include the following: The PREGREP module in the eCRF is 
used to report the pregnancy and the paper-based PREGOUT module is used to report the 


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outcome of the pregnancy.
8.3.8.2
Paternal Exposure 
As a precaution, all male participants should avoid fathering a child by either true abstinence 
or the use of 2 effective means of contraception (a male condom with spermicide; see 
Inclusion Criterion #6, Section 5.1, for regions where male condoms with spermicide are not 
available) with their partner from the time of study drug administration (Day 1) until 3 months 
after the last dose of study drugs.
Sperm donation
Male participants should not donate sperm for the duration of the study and for at least 
3 months after the last day of study drugs.
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 one day, ie,
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.7) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B.
8.4
Overdose
8.4.1
AZD5718
For this study, any dose of the AZD5718 greater than that specified in this CSP will be 
considered an overdose.
8.4.2
Dapagliflozin
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 T2DM. 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. If an overdose is suspected, monitoring of vital functions as well as 
treatment should be performed as appropriate.


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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study drug occurs 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 
one or 5 calendar days for overdoses associated with an SAE (see Section 8.3.7) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific Laboratory Manual. Samples should be stored in a secure storage space with 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. 

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

Venous blood samples will be collected for measurement of plasma concentrations of 
AZD5718 and dapagliflozin as specified in the SoA (Table 1).

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 based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring.


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
Plasma samples will be used to analyse the PK of AZD5718 and dapagliflozin. Samples 
collected for analyses of AZD5718 and/or dapagliflozin plasma concentration may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or after 
the study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.

The actual date and time (24-hour clock time) of each sample and date and time (24-hour 
clock time) of previous dose taken will be recorded in the eCRF. Site may refer to e-Diary 
or home dosing diary for time of last dose taken by the participant prior to dosing in 
clinic, if available.
A sub-group of at least 80 participants (20 per dose group including placebo) will have 
4 additional PK samples taken within 1-2 h, 2-5 h, 5-8 h, and 8-12 h post-dose (one sample 
taken at each time window with the additional requirement of at least 1 hour between 
2 subsequent samples) for analysis of AZD5718. As indicated in the SoA (Table 1), the 
additional samples will be taken at Visit 5 for only the sub-group of 80 participants, while 
pre-dose PK samples for analysis of AZD5718 will be collected from all study participants.
8.5.1.1
Determination of Drug Concentration
Samples for determination of AZD5718 and dapagliflozin concentration in plasma will be 
assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the analytical method used will be 
described in a separate Bioanalytical Report.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis or additional assay development work, if any, will be 
performed alongside the bioanalysis of the test samples. The results from the evaluation, if 
performed, will be reported in a separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Immunogenicity analysis will not be assessed in this study.
8.5.3
Pharmacodynamics
8.5.3.1
Collection of Samples
Plasma and urine samples for measurement of
 will be collected at specified time points 
in the SoA (Table 1). For urine samples, creatinine level will also be measured to allow the 
 level to be normalised.
For storage, re-use and destruction of pharmacodynamics (PD) samples see Section 8.5 and 
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Appendix C.
8.6
Human Biological Sample Biomarkers
 
 
 
 
.
8.6.2
Collection of Optional Biomarker Samples for Future Use
Collection of optional samples for biomarker research is also part of this study as specified in 
the SoA and is subject to agreement to optional consent. 
 
For storage, re-use and destruction of biomarker samples see Section 8.5.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA (Table 1) and is subject to agreement in the ICF addendum.
Blood sample for deoxyribonucleic acid (DNA) isolation will be collected from participants 
who have consented to participate in the genetic analysis component of the study. 
Participation is optional. Participants who do not wish to participate in the genetic research 
may still participate in the study.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in
the appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples see Appendix D.
8.8
Health Economics
This section is not applicable.
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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary hypothesis for this study is that AZD5718 will reduce urine ACR compared with 
placebo on treatment with dapagliflozin as future standard of care. Dose response will be 
evaluated.
The secondary hypotheses of this study are:

AZD5718 will reduce urine ACR compared with placebo on current standard of care.

AZD5718 will exhibit an acceptable safety profile in participants with proteinuric CKD.

AZD5718 will exhibit an acceptable ambulatory BP in participants with proteinuric CKD.

AZD5718 will exhibit an acceptable PK profile in participants with proteinuric CKD.
9.2
Sample Size Determination
For the primary endpoint, a total of 142 evaluable participants per group will provide 
 
power to detect a placebo adjusted
 reduction in urine ACR from baseline between 
AZD5718 
mg and placebo group with 
, assuming a SD of
 on 
the natural log-scale. It will also assure at least 
 power to detect the same urine ACR 
reduction and the significance of dose response over multiple dose response models in the 
DKD sub-population. To account for approximately 
 discontinuation, 158 participants per 
group will be enrolled.
The sample size was calculated using nQuery (version 8.2.0.0) and validated using EAST 
(version 6.4.1).
9.3
Populations for Analyses
The following populations are defined:
Table 5
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who sign the informed consent form.
Full Analysis Population
All participants who are randomised and receive any study drug. 
Participants are evaluated according to the treatment assigned at 
randomisation.
The Full Analysis Population will be used for all analyses of demographic 
baseline characteristics and efficacy data.
Per Protocol Population
A subset of the Full Analysis Population consisting of all participants who
receive the additional treatment with dapagliflozin post Week 12 and do not 
violate the terms of the protocol in a way that may affect the primary 
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Population/Analysis set
Description
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 Population
All participants who are randomised and receive any study drug. 
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 study drug from the wrong 
kit for only part of the treatment duration, they will be analysed according 
to their randomisation dose.
The Safety Analysis Population will be used for all safety analyses.
Ambulatory Blood Pressure 
Monitoring Population
All participants in the Full Analysis Population who have valid ambulatory 
blood pressure data for change from baseline analyses.
Pharmacokinetic Population
All participants in the Full Analysis Population who have at least one 
detectable AZD5718 plasma concentration measurement post-treatment.
The Pharmacokinetic Population will be used for all PK analyses.
9.4
Statistical Analyses
The SAP will be finalised prior to first participant in and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the primary, secondary and safety endpoints.
9.4.1
General Considerations
Relevant demographic and baseline characteristics will be summarised descriptively for each 
study treatment group and overall.
There are 4 planned study periods:

Screening period (4 weeks)

Treatment Period 1 (12 weeks)

Treatment Period 2 (8 weeks)

Follow-up period (4 weeks)
All efficacy and safety variables will be summarised by study treatment group using 
descriptive statistics (n, geometric mean, SD, median, minimum and maximum for continuous 
data and n, frequencies and percentages for categorical data). Data will be summarised by visit 
as applicable. Safety outputs will also include a pooled AZD5718 group.
The statistical methods and how the variables are presented will be further detailed in the SAP. 


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The potential impact of missing data and methods will be described fully in the SAP.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
The primary efficacy endpoint for this study is the reduction of urine ACR from baseline to 
Week 20 compared to placebo (on treatment with dapagliflozin as future standard of care).
As urine ACR is assumed to follow a log-normal distribution, it will be log-transformed for 
statistical analysis purposes. The mean log changes in urine ACR at Week 20 (+,-, +,., +,/, +,0) for 
each of the 3 AZD5718 doses and placebo will be estimated in a mixed model for repeated 
measures (Weeks 2, 4, 8, 12, 16, and 20). The values will be back transformed onto the 
original scale to give the geometric mean relative change from baseline at Week 20. 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 (urine 
ACR) and baseline log (urine ACR)-by-visit interaction. An unstructured covariance structure 
will be used for the within-participant errors. A homogeneity assessment between the DM and 
the non-DM sub-populations will be performed. Baseline urine ACR is taken to be the mean 
of urine ACR measurements taken at Visit 2 (Screening Visit 2) and Visit 3 (Study Day 1).
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 per protocol population. The endpoint being assessed is the change in log-transformed 
urine ACR from baseline to Week 20. For the intercurrent event, if a participant discontinues
treatment due to AE or lack of efficacy, or uses prohibited medication, the urine ACR data are 
treated as missing after the event and no imputation is performed. The summary measure 
being evaluated is the geometric mean reduction of urine ACR from baseline to Week 20.
9.4.2.2
Secondary Endpoints
Urine ACR will be analysed to determine the dose response effect of AZD5718 at 12 weeks 
(on current standard of care). The population of interest are randomised participants who meet 
all eligibility criteria and have valid non-missing urine ACR records at baseline and at least 
one post-treatment visit. The mean log change from baseline in urine ACR will be analysed 
using a mixed model for repeated measures. The summary measure being evaluated is the 
geometric mean reduction of urine ACR from baseline to Week 12.
Estimated GFR will be analysed, comparing eGFR at baseline with that at 12 weeks, to 
determine whether there is any acute change with the introduction of AZD5718 to inform 
planning for an eGFR slope analysis in Phase 3. This will be analysed using a by-visit 
ANCOVA, adjusting for DM stratification factor, treatment group and baseline eGFR. The 
Full Analysis population will be used for this analysis and eGFR will be evaluated on the 
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Ambulatory BP will be analysed to determine the effect of AZD5718 on BP. This will be 
assessed by the change in 24-hour mean SBP at Week 12. It will be analysed using ANCOVA, 
adjusting for DM stratification factor, treatment group, plus baseline 24-hour mean SBP and 
BMI as covariates. The Full Analysis population will be used for this analysis.
The AZD5718 plasma concentrations will be summarised by descriptive statistics for each 
visit and each sample point for AZD5718-treated participants by dose cohort. Further details 
of this will be provided in the SAP. Additional PK analyses may be conducted as appropriate. 
If the data allow, population PK analysis will be performed, but will not be reported in the 
CSR.
 
 
 
 
 
 
9.4.3
Safety
All safety analyses will be performed on the Safety Analysis population.
Adverse events (and also separately SAEs) will be summarised by study treatment group in 
incidence summaries by MedDRA System Organ Class (SOC) and Preferred Term (PT). All 
AEs will be listed and assigned to on/off treatment period as:

Prior treatment: The SAE occurred before the first administration of study drug. Only 
applicable for SAEs.

On treatment: The AE occurred on or after the first administration until 7 days after last 
dose of AZD5718 and/or dapagliflozin.

Off treatment: The AE occurred more than 7 days after the last dose of study drug.
Adverse events will be assigned to the period where they start. Serious adverse event 
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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 drug. The 
SAE/AE collection will last until the end of the participant’s follow-up period. Adverse events 
will be coded using the MedDRA by SOC and PT. Specific AEs will be counted once for each 
participant for calculating rates but will be presented in total in participant listings. In 
addition, if the same AE occurs multiple times within a particular participant, the highest 
severity and level of causality will be reported. All treatment emergent AEs will be 
summarised overall and by deaths and SAEs. Treatment discontinuations due to AEs will be 
summarised.
Clinical laboratory safety tests including serum chemistry, haematology, coagulation, and 
urinalysis parameters will be summarised using descriptive statistics at each time point by 
treatment group. Change from baseline to each post baseline time point in these data will also 
be summarised, where appropriate. A shift table will be provided for these clinical laboratory 
parameters as well, where possible.
Vital signs and clinical laboratory data and ECG will be summarised at each time point. 
Change from baseline to each post baseline time point will also be summarised, where 
appropriate.
9.4.4
Other Analyses 
The change from baseline in urine ACR at 12 and 20 weeks will be analysed using the 
Multiple Comparison Procedure – Modelling approach (Pinheiro et al, 2006). Multiple 
candidate dose response models will be assessed. The best fitting model based on Akaike’s 
Information Criteria will be used as a reference for dose selection. This will be assessed on the 
Full Analysis population.
 will be summarised by treatment group.
 
 
 
 
9.5
Interim Analyses
An interim analysis will be conducted when approximately 200 participants have completed 
the 20-week treatment period. A separate review committee of AstraZeneca representatives 
will review the unblinded interim outputs. The design and the conduct of the study will not be 
impacted regardless of the interim results.
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The SAP will describe the planned interim analyses in greater detail.
9.6
Data Monitoring Committee
Not applicable.


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight 
Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

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), 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 drug under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.

For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.

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review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

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 or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC of study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
All rescreened participants are required to sign a new consent form.
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.


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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.
A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 6
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 
noncompliance 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).


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
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for as outlined in Clinical Study Agreement 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 7
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 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 source data agreement and 
computerised data check list for electronic source data.
A 8
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 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 centres 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 centre closure visit has been performed.
The Investigator may initiate study centre 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:


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
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 drug development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CROs 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.
A 9
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multi-centre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating Investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a participant or clinical 
study participant administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study drug has been administered.
B 2
Definitions of Serious Adverse Event
An SAE 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 judgement on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a non-serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.


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


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intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 


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


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
Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
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 


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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
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.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and: Provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
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 


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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 3. Although DNA is stable, early sample collection is preferred to avoid introducing 
bias through excluding participants who may withdraw due to an AE. If for any reason 
the sample is not drawn at Visit 3, it may be taken at any visit until the last study visit. 
Only one sample should be collected per participant for genetics during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A.
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 


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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 Investigator(s) is 
responsible for ensuring that consent is given freely, and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
Investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management

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 PHL cases and 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 total 
bilirubin from a local laboratory. 
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study drug.
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 or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN at any 
point during the study following the start of study medication irrespective of an increase in 
ALP.
Hy’s Law 
Aspartate aminotransferase or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN, 
where no other reason, other than the study medication, 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 total bilirubin, but there is no specified timeframe within which the 
elevations in transaminases and total bilirubin 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:


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
Inform the AstraZeneca representative that the participant has not met PHL 
criteria.

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:

Determine whether PHL criteria were met at any study visit prior to starting study 
medication (See Section E 4.2).

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 who met PHL criteria prior to starting study drug, 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.

Complete the 3 Liver eCRF Modules as information becomes available 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or 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


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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 
study drug, to ensure timely analysis and reporting to health authorities within 15 calendar 
days from 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 total bilirubin
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 PHL 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 total 
bilirubin elevations other than the study drug:

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 PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to study drug and seriousness 
criteria is medically important, according to CSP process for SAE reporting.


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
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.
E 6
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT (Gamma-glutamyl transferase)
LDH (Lactate dehydrogenase)
Prothrombin time
INR (International Normalised Ratio)
Viral hepatitis
IgM anti-HAV (Hepatitis A Virus)
IgM and IgG anti-HBc
HBsAg (Hepatitis B Surface Antigen)
HBV DNA a(Hepatitis B Virus DNA)
IgG anti-HCV (Hepatitis C Virus)
HCV RNA a(Hepatitis C Virus RNA)
IgM anti-HEV (Hepatitis E Virus)
HEV RNA (Hepatitis E Virus RNA)
Other viral infections
IgM & IgG anti-CMV (Cytomegalovirus)
IgM & IgG anti-HSV (Herpes Simplex Virus)
IgM & IgG anti-EBV (Epstein Barr Virus)
Alcoholic hepatitis
Carbohydrate deficient transferrin 
(CD-transferrin) b
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 b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly


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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 WHO to declare a pandemic situation on 
12 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden including new outbreaks, locally or globally, 
will impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect participants, 
site staff, and society as a whole.
Both EMA and FDA as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at high pace. 
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in future, special attention will be paid to protect participants
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline.
F 2
Risk Assessment for COVID-19 Pandemic
There are 2 study drugs with different mechanisms of action that are unlikely to impact on the 
course of infection with SARS-CoV-2. AZD5718 does have an anti-inflammatory mode of 
action with inhibition of leukotriene production. While, this poses a theoretical risk of 
adversely influencing the antiviral response, this is judged to be unlikely. Dapagliflozin is an 
anti-glycaemic agent and is believed not to cause immune suppression. Therefore, risk of the 
participants 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 as those in the study, in particular 
CKD and T2DM. 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).
Measures to mitigate the additional risks caused by COVID-19 are:

This study is going to start enrolling only when the Sponsor and CRO in collaboration 
deem it is safe to start the study. In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic 
imposed by the local authorities are compatible with safe conduct of the study.


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
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.

Participants will be closely monitored for any signs and symptoms of COVID-19, 
including fever, dry cough, dyspnoea, sore throat and fatigue throughout the study during 
the pandemic. Once clinical signs of infection are reported by participants, the 
Investigator needs to determine whether samples can be collected, and safety data can be 
recorded on site. If not, AEs and concomitant medications will be obtained via phone 
calls. The decision to continue with dosing the participant with the study drugs in the 
event of him/her showing symptoms of COVID-19 infection will be per Investigator’s 
discretion.

The probability of virus transmission will be controlled as much as possible by:

Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory.

Confirmation of COVID-19 infection by optional laboratory assessment will be 
conducted based on availability (test capacity and turnaround time) of approved tests 
and on Investigator’s discretion.

Requesting all participants are contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and are asked not to attend the site in case 
of suspected reports. In addition, participants are asked for any contact with a person 
who has tested positive for SARS-CoV-2. If applicable, participants will be referred 
to the local health care system for further follow-up and treatment.

Physical distancing and person-to-person contact restrictions will be applied during 
site visits and in-house confinement.

Where physical distancing is not possible, PPE 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.
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 
participants will be asked to use surgical face masks and/or gloves if deemed appropriate by 


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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.
In addition, where possible, other measures for carrying out protocol related activities, such as 
but not limited to home nursing, may be employed as required.
F 5
References
1. 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
2. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency, March 2020, Updated on April 16, 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
5-LO
5-lipoxygenase 
ABPM
Ambulatory Blood Pressure Monitoring
ACEi
Angiotensin Converting Enzyme Inhibitors
ACR
Albumin to Creatinine Ratio
AE
Adverse Event
ALT
Alanine Aminotransferase
ALP
Alkaline Phosphatase
ANCOVA
Analysis of Covariance 
AST
Aspartate Aminotransferase
ARB
Angiotensin Receptor Blocker
AZRand
AstraZeneca randomisation solution
BA
Bioavailability
BMI
Body Mass Index
BP
Blood Pressure
CAD
Coronary Artery Disease
CONSORT
Consolidated Standards of Reporting Trials
COVID-19 
Coronavirus Disease-2019
CKD
Chronic Kidney Disease
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DDI
Drug-Drug interaction
DILI
Drug-Induced Liver Injury
DKA
Diabetic Ketoacidosis
DKD
Diabetic Kidney Disease
DNA
Deoxyribonucleic Acid 
DM
Diabetes Mellitus
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
CCI
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Abbreviation or special 
term
Explanation
eCRF
electronic Case Report Form
EDC
Electronic Data Capture 
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
FDA
U.S. Food and Drug Administration
FLAP
5-Lipoxygenase Activating Protein
FSH
Follicle Stimulating Hormone
fT3
Free triiodothyronine
fT4
Free thyroxine
GCP
Good Clinical Practice
GLP1-RA
Glucagon-like peptide-1 Receptors Agonists
HbA1c
Glycated Haemoglobin
hCG
Human Chorionic Gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HL
Hy’s Law
HR
Heart rate
IATA
International Airline Transportation Association 
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICF
Informed Consent Form
IgG
Immunoglobulin G
IMP
Investigational Medicinal Product
INR
International Normalised Ratio
IRT
Interactive Response Technology
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LH
Luteinising Hormone
 
 
 
 
MedDRA
Medical Dictionary for Regulatory Activities 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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-
• 
-
1111 
1111 
1111 
1111 


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Abbreviation or special 
term
Explanation
NSAID
Non-Steroidal Anti-Inflammatory Drug
OTC
Over the Counter
PD
Pharmacodynamics
PHL
Potential Hy’s Law
PK
Pharmacokinetic
 
PT
Preferred Term
QTc
Corrected QT interval
RTSM
Randomization and Trial Supply Management
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SBP
Systolic Blood Pressure
SCr
Serum Creatinine
SD
Standard Deviation
SMAD
Single-Multiple Ascending Dose
SoA
Schedule of Activities
SOC
System Organ Class
SGLT2i
Sodium-Glucose Cotransporter-2 inhibitor
SUSARs
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TSH
Thyroid stimulating hormone
ULN
Upper Limit of Normal
WHO
World Health Organisation
CCI
CCI-
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Appendix H
Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Version 2.0, Amendment 1
05-Aug-2020
Version 1.0 
29-May-2020
The Protocol Amendment Summary of Changes Table for the current amendment
(Amendment 2) is located directly before the Table of Contents.
Amendment 1 (05-August-2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The original CSP, Final 1.0, dated 29 May 2020, is updated following the FDA safety review 
(10 Jul 2020) and updates have been made to correct errors and further clarify processes. 
Section # and Name
Description of Change
Brief Rationale
Section 1.1, Synopsis
Section 3, Objectives and 
Endpoints 
Coagulation is included to the 
laboratory parameters for the secondary 
endpoint: To evaluate the safety and 
tolerability of AZD5718 in participants 
with proteinuric CKD
Omitted in error, included for 
consistency
Section 1.1, Synopsis
Section 4.1, Overall 
design
The number of countries included in 
the study are updated from 10 to 12 
Additional countries will be included in 
the study 
Section 1.1, Synopsis
Section 1.3, Table 1
Schedule of Activities
Section 4.1, Overall 
design
Section 8.1.1.1, Urinary 
Albumin Creatinine 
Ratio
Clarification of how the ACR result is 
calculated to determine exclusion of 
participants from Treatment Period 2
Process clarification 
Section 1.3, Table 1
Schedule of Activities 
Abbreviated physical examinations are 
not completed at Visits 5 and 7 
(X removed)
A full physical examination is required 
at these visits; both abbreviated and full 
were included at these visits in error
Section 1.3, Table 1
Schedule of Activities
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments, Table 4
Footnotes to clarify that serum hCG, 
FSH, and LH tests, and a urine 
pregnancy test are required for all 
women, not only women with intact 
uterus 
Increasing clarity of pregnancy testing 
approach in response to feedback from 
trial sites


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Section # and Name
Description of Change
Brief Rationale
Section 1.3, Table 1
Schedule of Activities
Coagulation is included in the safety 
laboratory assessments row 
Omitted in error 
Deletion of duplicate row for urinalysis 
assessments (safety laboratory 
assessments)
Duplicate row included in error
Section 1.3, Table 1
Schedule of Activities
Sampling timepoints for plasma and 
urine 
 are reduced; samples will 
not be collected at Visits 2, 4, 6, and 10
Changes to the plan for analysis of 
 
The correct footnote is applied to the 
row: Reminder to collect first morning 
void urine samples, 3 days before visit 
(Site should follow-up directly with the 
participant via phone to remind the 
participant) 
Incorrect footnote included in error
The correct footnote is applied to the 
row: Study drug dispensation (Study 
drug refers to AZD5718/placebo 
during Treatment Period 1 and 
AZD5718/placebo + dapagliflozin 
during Treatment Period 2) 
Incorrect footnote included in error
Section 1.3, Table 1
Schedule of Activities
Section 8.2.4, Clinical 
safety laboratory 
Assessments 
Note is included to clarify the local and 
central laboratory assessment 
procedures. Section 8.2.4 is updated to 
clarify the use of local urine dipstick 
tests 
Process clarification 
Section 1.3, Table 1
Schedule of Activities
Section 8.2.2, Vital Signs 
Pulse oximetry is included in the vital 
signs assessments 
FDA request to monitor oxygen 
saturation to check for respiratory 
depression 
Section 1.3, Table 1
Schedule of Activities
Section 8.1.3, 
 
 
 
 
 
Process clarification
Section 1.3, Table 1
Schedule of Activities
Section 6.4.1
Text added to clarify that where 
completion of an e-Diary is not 
applicable, participant will be requested 
to complete a paper dosing diary
Details of an e-Diary satisfaction 
survey added 
Process clarification
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Section # and Name
Description of Change
Brief Rationale
Section 5.1, Inclusion 
Criterion #5
Clarification that females must be of 
non-childbearing potential and that a 
pregnancy test is required for all female 
participants
Process clarification 
Section 5.1, Inclusion 
Criterion #6
Section 8.3.8.2, Paternal 
Exposure
Text added to clarify the contraceptive 
requirements for male participants in 
regions where male condoms with 
spermicide are not available
Process clarification
Section 5.2, Exclusion 
Criterion #6 (h)
Clarification that alcohol and drug 
screening is completed locally using 
laboratory kits provided by the central 
laboratory, and that screening must be 
completed for all participants 
Process clarification 
Section 6.1.1
Investigational Products, 
Table 3
Table updated stating that 
Dapagliflozin is taken once daily 
Clarification 
Section 6.5.2, SGLT2 
Inhibitors 
Clarification of SGLT2i fixed-dose 
combination treatments allowed during 
Treatment Period 2
Clarification
Section 7.1, 
Discontinuation of Study 
Drugs 
Greater than (>) is changed to ≥for 
ALT, AST, and total bilirubin where 
the CSP refers to Hy’s Law
Consistency with Hy’s Law 
Appendix E
Section 8.2.4, Clinical 
Laboratory Assessments 
Additional safety samples do not need 
to be recorded in the eCRF 
Process clarification
Section 9.4.3, Safety 
(Statistical Analyses)
Coagulation and urinalysis are included 
in the description of the statistical 
analysis for laboratory safety tests 
Omitted in error, included for 
consistency
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not been 
summarised


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11
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Hickey FB, Martin F. Role of the Immune System in Diabetic Kidney Disease. Curr Diab Rep. 
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Document Name: d7551c00001-csp-v3-amendment-2
Document Title:
D7551C00001 Clinical Study Protocol version 3 Amendment
2
Document ID:
Doc ID-004248931
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
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Meaning of Signature
29-Jan-2021 09:39 UTC
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Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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SAP_001.pdf: 
Parexel International
AstraZeneca
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 3.0
Effective Date: 26 Nov 19
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 1 of 43
Parexel International
AstraZeneca
D7551C00001
A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Dose-Ranging Study of 
AZD5718 in Participants with Proteinuric Chronic Kidney Disease
Statistical Analysis Plan
Version: 3.0
Parexel Project Number: PXL248068


Parexel International
AstraZeneca
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 3.0
Effective Date: 26 Nov 19
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 2 of 43
TABLE OF CONTENTS
1
INTRODUCTION................................................................................................................... 7
2
STUDY OBJECTIVES............................................................................................................ 8
2.1
Primary Objective................................................................................................................ 8
2.2
Secondary Objectives .......................................................................................................... 8
2.3
Exploratory Objectives ........................................................................................................ 9
3
INVESTIGATIONAL PLAN .................................................................................................. 9
3.1
Overall Study Design and Plan ............................................................................................ 9
3.2
Endpoints .......................................................................................................................... 10
3.2.1
Efficacy Variables........................................................................................................... 11
3.2.1.1
Urine ACR.................................................................................................................... 11
3.2.1.2
Estimated GFR.............................................................................................................. 11
3.2.1.3
Ambulatory Blood Pressure........................................................................................... 11
3.2.1.4
AZD5718 Plasma Concentrations.................................................................................. 11
3.2.2
Safety Variables .............................................................................................................. 12
3.2.2.1
Adverse Events/Serious Adverse Events ....................................................................... 12
3.2.2.2
Vital Signs .................................................................................................................... 12
3.2.2.3
Clinical Laboratory Parameters (Clinical Chemistry, Haematology, and Urinalysis)...... 12
3.2.2.4
Electrocardiogram Assessments .................................................................................... 13
3.2.2.5
Physical Examinations .................................................................................................. 13
3.2.3
Exploratory Variables...................................................................................................... 14
3.2.3.1
Retinal Sub-study.......................................................................................................... 14
4
STATISTICAL METHODS .................................................................................................. 14
4.1
Data Quality Assurance ..................................................................................................... 14
4.2
General Presentation Considerations.................................................................................. 14
4.3
Software............................................................................................................................ 15
4.4
Study Participants.............................................................................................................. 16
4.4.1
Disposition of Participants............................................................................................... 16
4.4.2
Protocol Deviations ......................................................................................................... 16
4.5
Analysis Populations ......................................................................................................... 17
4.5.1
Analysis Sets................................................................................................................... 18
4.6
Demographic and Other Baseline Characteristics............................................................... 18
4.7
Concomitant Medication.................................................................................................... 19
4.8
Treatment Compliance....................................................................................................... 20
4.9
Efficacy Evaluation ........................................................................................................... 21
4.9.1
Analysis and Data Conventions ....................................................................................... 21
4.9.1.1
Dose-response Testing .................................................................................................. 21
4.9.1.2
Multi-centre Studies...................................................................................................... 21
4.9.1.3
Adjustments for Covariates ........................................................................................... 21
4.9.1.4
Handling of Dropouts or Missing Data.......................................................................... 22
4.9.1.5
Interim Analyses........................................................................................................... 22
4.9.1.6
Examination of Sub-groups........................................................................................... 23
4.9.2
Primary Efficacy Variable – UACR ................................................................................. 23
4.9.2.1
Primary Analysis........................................................................................................... 23
4.9.3
Secondary Efficacy Variables.......................................................................................... 24


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Statistical Analysis Plan
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Project Document Version No. 3.0
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4.9.3.1
UACR at 12 Weeks....................................................................................................... 24
4.9.3.2
Estimated GFR.............................................................................................................. 24
4.9.3.3
Ambulatory Blood Pressure Monitoring ........................................................................ 25
Primary ABPM Analysis ............................................................................................... 25
Sensitivity ABPM Analysis – 24-hour Mean SBP.......................................................... 26
Secondary ABPM Analysis ........................................................................................... 26
4.10
Safety Evaluation............................................................................................................... 26
4.10.1
Extent of Exposure.......................................................................................................... 27
4.10.2
Adverse Events................................................................................................................ 27
4.10.3
Deaths, Serious Adverse Events, and Other Significant Adverse Events .......................... 29
4.10.4
Clinical Laboratory Evaluation........................................................................................ 29
4.10.5
Vital Signs, Physical Findings and Other Observations Related to Safety ........................ 30
4.10.6
Safety Monitoring ........................................................................................................... 31
4.11
Other Analyses .................................................................................................................. 31
4.11.1
Pharmacokinetics ............................................................................................................ 31
4.11.2
Retinal Sub-Study ........................................................................................................... 31
4.12
Interim Analysis ................................................................................................................ 32
4.12.1
Early Termination of Study ............................................................................................. 32
4.13
Determination of Sample Size............................................................................................ 32
4.14
Changes in the Conduct of the Study or Planned Analysis ................................................. 32
5
REFERENCES...................................................................................................................... 34
6
APPENDIX ........................................................................................................................... 35
Appendix A: Schedule of Activities .............................................................................................. 36
Appendix B: Interim Analysis Plan ............................................................................................... 39
Appendix C: Treatment-Emergent Laboratory and Vital Signs Criteria limits ............................... 42
Appendix D: Exclusion from Per-Protocol Analysis...................................................................... 43


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Page 4 of 43
REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
15 OCT 2020
Original document
2.0
26 APR 2022
Addition of Ambulatory Blood Pressure Monitoring (ABPM) analyses for 
day-time/night-time, and hourly ABPM Mixed Models for Repeated 
Measures. Sub-group and sensitivity analyses added.
Appendix D added to include Multiple Imputation (MI) for ABPM data.
Update to Appendix D to clarify that MI will be performed using hourly
mean Systolic Blood Pressure (SBP) measurements.
Statistical modelling for the hourly mean SBP will be based on the change 
of hourly mean SBP.
Sensitivity analysis of the ABPM analysis for participants with treatment 
compliance ≥80% added.
By-strata efficacy analysis added for urine albumin to creatinine ratio 
(UACR) and estimated glomerular filtration rate (eGFR).
3.0
27 SEP 2022
Following early termination of study, planned analysis is updated to reflect 
analysis of interest for final clinical study report. Removal of AZD5718 
pharmacokinetic (PK) analysis, Dapagliflozin PK analysis, biomarker 
analysis and ABPM sensitivity analysis. 
Addition of Changes from Planned Analysis section which outlines the 
differences between the study protocol and the statistical analysis plan 
following the study termination.








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2
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective
Estimand Description
To evaluate the dose-response effect of AZD5718 
on urine ACR at 20 weeks in participants with 
proteinuric CKD (on treatment with dapagliflozin 
as future standard of care from Weeks 12 to 20)
Reduction of urine ACR from baseline to Week 20 compared 
with placebo.
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 
Per-Protocol population. The endpoint being assessed is the 
change in log-transformed urine ACR from baseline to Week 20. 
For the intercurrent event, if a participant discontinues treatment 
due to AE or lack of efficacy, or uses prohibited medication, the 
urine ACR data are treated as missing after the event and no 
imputation is performed. The summary measure being evaluated 
is the geometric mean reduction of urine ACR from baseline to 
Week 20.
Abbreviations: ACR = albumin to creatinine ratio; AE = adverse event; CKD = chronic kidney disease.
2.2
Secondary Objectives
Secondary Objectives
Endpoints
To evaluate the dose-response effect of AZD5718 
on urine ACR at 12 weeks (on current standard of 
care)
Reduction of urine ACR from baseline to Week 12 compared 
with placebo.
The clinical quantity of interest to be estimated is defined by the 
following three components:

Population
Randomised participants who meet all eligibility criteria 
and have valid non-missing urine ACR records at 
baseline and at least one post-treatment visit.

Endpoint
Change in log-transformed urine ACR from baseline to 
Week 12.

Summary measure
Geometric mean reduction of urine ACR from baseline 
to Week 12 compared with placebo.
To evaluate the safety and tolerability of AZD5718 
in participants with proteinuric CKD

AEs/SAEs

Vital signs

Clinical chemistry/ haematology/urinalysis parameters

ECG assessments
To evaluate the effect of AZD5718 on ambulatory 
blood pressure in participants with proteinuric 
CKD
Change in 24-hour mean SBP from baseline to Week 12.
To assess the PK of AZD5718 after repeated oral 
dosing for 20 weeks in participants with 
proteinuric CKD
AZD5718 plasma concentrations
[Note: following the termination of FLAIR study, the PK 
analyses will not be performed]
To assess the effect of AZD5718 on renal function 
in participants with proteinuric CKD with and 
without the addition of dapagliflozin
Change in eGFR from baseline to Week 12 and from Week 12 to 
Week 20.
Abbreviations: ACR = albumin to creatinine ratio; AE = adverse event; CKD = chronic kidney disease; ECG =
electrocardiograms; eGFR = estimated glomerular filtration rate; PK = pharmacokinetic(s); SBP = systolic blood pressure; 
SAE = serious adverse event. 






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3.2.1
Efficacy Variables
3.2.1.1
Urine ACR
Urine ACR is a key marker for assessing kidney damage. Urine ACR is a ratio between measured 
albumin and measured creatinine, which estimates 24-hour urine albumin excretion. See the SoA in 
Appendix A for timing of collection.
Urine ACR will be calculated as:
 	
 (mg/g) =   (mg/dL)
  (g/dL)
Spot urine samples are collected during the Screening Visit and at the remaining timepoints, 
participants are required to collect first morning void urine samples on 3 consecutive days. At each 
visit, the geometric mean of the triplicate ACRs will be computed centrally and used for all analysis 
of urine ACR.
Baseline urine ACR is taken to be the geometric mean of urine ACR geometric mean measurements 
taken at Visit 2 (Screening Visit 2) and Visit 3 (Study Day 1).
3.2.1.2
Estimated GFR
Estimated GFR is a marker for assessing kidney function. Estimated GFR is calculated based on 
serum creatinine values and will be calculated by the central laboratory using the CKD-EPI equation
as follows:
 (mL/min/1.73m#)
= 141 × min(&
/κ, 1)( × max(&
/κ, 1)+,.#,- × 0.993 	0
× (1.018 2 2) × (1.159 2 45)
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.
3.2.1.3
Ambulatory Blood Pressure
24-hour ambulatory blood pressure monitoring (ABPM) will be performed at timepoints as specified 
in the SoA in Appendix A. During ABPM, systolic blood pressure (SBP), diastolic BP (DBP), heart 
rate (HR), and mean arterial pressure readings will be recorded over a period of 24 hours.
3.2.1.4
AZD5718 Plasma Concentrations
Venous blood samples will be collected for the measurement of plasma concentrations of AZD5718 
as specified in the SoA in Appendix A. The actual date and time (24-hour clock time) of each sample 
and date and time (24-hour clock time) of previous dose taken will be recorded in the eCRF. Site may 
refer to e-Diary or home dosing diary for time of last dose taken by the participant prior to dosing in 
clinic, if available.
A sub-group of at least 80 participants (20 per dose group including placebo) will have four additional 
PK samples taken within 1-2 hours (h), 2-5 h, 5-8 h, and 8-12 h post-dose (one sample taken at each 
time window with the additional requirement of at least 1 h between 2 subsequent samples) for 
analysis of AZD5718. As indicated in the SoA in Appendix A, the additional samples will be taken 
at Visit 5 for only the sub-group of 80 participants, while pre-dose PK samples for analysis of 
AZD5718 will be collected from all study participants.


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Samples for determination of AZD5718 (and dapagliflozin) concentration in plasma will be assayed 
by bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately validated 
bioanalytical method. Full details of the analytical method used will be described in a separate 
Bioanalytical Report.
Drug concentration information that may unblind the study will not be reported to investigative sites 
or blinded personnel until the study has been unblinded.
3.2.2
Safety Variables
Safety will be assessed by descriptive analysis of adverse events (AEs) (including serious adverse 
events [SAEs]), vital signs, laboratory assessments, ECGs, and physical examinations.
3.2.2.1
Adverse Events/Serious Adverse Events
Adverse events are collected from time of first dose through to the Follow-Up Period. Serious adverse 
events will be collected from the time of signed informed consent through to the Follow-up Period.
3.2.2.2
Vital Signs
Vital signs will be performed at timepoints as specified in the SoA in Appendix A. Vital signs will 
include BP, HR, respiratory rate, pulse oximetry, and body temperature. Vital signs should be 
collected pre-dose on the days of study drug dosing and before blood draws.
3.2.2.3
Clinical Laboratory Parameters (Clinical Chemistry, Haematology, and Urinalysis)
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, and 
urinalysis will be taken at the visits indicated in the SoA in Appendix A. 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.
Clinical chemistry, haematology, and urinalysis will be performed at the central laboratory, except 
for the pregnancy test at Visit 3 which will be done locally via urine dipstick. Any other tests 
performed by urine dipstick are also performed locally, shown in Table 1. The laboratory variables 
to be measured are presented in Table 1.


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Table 1 Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-White blood cell count
S/P-Sodium
B-Red blood cell count
S/P-Potassium
B-Haemoglobin
S/P-Urea
B-Haematocrit
S/P-Creatinine
B-Mean corpuscular volume
S/P-Creatine kinase
B-Mean corpuscular haemoglobin
S/P-Albumin
B-Mean corpuscular haemoglobin concentration
S/P-Calcium
B-Neutrophils absolute count
S/P-Phosphate
B-Lymphocytes absolute count
S/P-Glucose (fasting) (Non-fasting at Screening Visit 1)
B-Monocytes absolute count
S/P-Alkaline phosphatase
B-Eosinophils absolute count
S/P-Alanine aminotransferase
B-Basophils absolute count
S/P-Aspartate aminotransferase
B-Platelets
S/P-Total bilirubin
B-Reticulocytes absolute count
S/P-Follicle stimulating hormone^
S/P-Luteinising hormone^
Coagulation
S/P-Thyroid stimulating hormone
B-International normalised ratio
S/P-Free triiodothyronine
B-Activated partial thromboplastin time
S/P-Creatinine (for eGFR quantification)
B-Fibrinogen
S/P-Chloride
S/P-Bicarbonate
Urinalysis *
S/P-Magnesium
U-Glucose (dipstick)
S/P-Human chorionic gonadotropin hormone#
U-Albumin (quantification/semi-quantification)
S/P-Albumin
U-Glucose
S/P-Total Protein
U-Blood (dipstick)
U-White blood cells
U-human chorionic gonadotropin hormone@
Other Clinical Safety Panels^ (serum or plasma)
S/P-Hepatitis B surface Antigen (HBsAg)
S/P-Hepatitis C virus antibody
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.
* If urinalysis abnormal Microscopy through central laboratory – including white blood cells, red blood cells, and casts.
^ Screening Visit 1 only.
@ Via urine dipsticks.
3.2.2.4
Electrocardiogram Assessments 
Triplicate 12-lead ECGs will be performed at timepoints as specified in the SoA in Appendix A. The 
Investigator will make an overall evaluation of the ECG as normal or abnormal. If abnormal, it will 
be decided whether or not the abnormality is clinically significant or not clinically significant and the 
reason for the abnormality will be recorded on the eCRF. 
3.2.2.5
Physical Examinations
Physical examination will be performed at timepoints as specified in the SoA in Appendix A and will 
include:

A complete physical examination will be performed and include assessments of the following: 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including 
ears, eyes, nose and throat), lymph nodes, thyroid, muscular-skeletal (including spine and 
extremities) and neurological systems. Weight and body mass index (BMI) will also be 
collected.




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Confidence intervals (CIs) will be presented to one more decimal place than the raw data.
Data will be summarised by-visit as applicable. 
‘Baseline’ is defined as the last value obtained prior to the first dose of study medication, unless 
otherwise stated. ‘End of Study’ is defined as the last available post-treatment assessment. ‘Study
Day’ will be calculated relative to the date of randomisation, ie:
If Assessment Date < Randomisation Date, then
&67 87 = 	9999 8 −6;9; 8
If Assessment Date ≥ Randomisation Date then
&67 87 = 	9999 8 −6;9; 8 + 1
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 2.
Table 2 Analysis Visit Windows
eCRF Visit
Target Day
Protocol Visit 
Window
Actual assessment 
day
Analysis visit
Visit 3 
(randomisation)
D1
D1
D1
Randomisation
Visit 4 (Wk 2)
D15
D12 to D18
D2 to D21
Week 2
Visit 5 (Wk 4)
D29
D26 to D32
D22 to D42
Week 4
Visit 6 (Wk 8)
D57
D54 to D60
D43 to D71
Week 8
Visit 7 (Wk 12)
D85
D82 to D88
D72 to D88
Week 12
Visit 8 (Wk 16)
D113
D110 to D116
D89 to D127
Week 16
Visit 9 (Wk 20)
D141
D138 to D144
D128 to D144
Week 20
Visit 10 (Wk 24)
D169
D164 to D174
D145 to D183
Follow-up
Abbreviations: D = day; eCRF = electronic Case Report Form; Wk = week.
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 
nominal visit date. The listings will highlight the value for that participant that went into the summary 
table, wherever feasible.
The Coronavirus Disease of 2019 (COVID-19) pandemic was declared by the World Health 
Organisation on 11 March 2020. Due to this, some COVID-19 specific summaries will be presented 
to summarise the impact of the pandemic.
4.3
Software
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and validated 
environment. 


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4.4
Study Participants
4.4.1
Disposition of Participants
A clear accounting of the disposition of all participants who enter the study will be provided, from 
screening to study completion.
The following summaries will be provided:

A summary of the number of participants screened, screen failures, enrolled into the study, 
randomised, treated, completing Treatment Period 1, completing Treatment Period 2 and 
completing the study, by treatment group and overall. In addition, reasons for not being 
treated, not completing Treatment Period 1, not completing Treatment Period 2 and not 
completing the study will be summarised by treatment group and overall (Analysis set: All
participants).

A summary of the number of participants randomised per region, country and centre, by 
treatment group and overall (Analysis Population: Randomised participants).

A summary of Interactive Voice Recognition System (IVRS) stratification factors ie, DKD 
status (DKD participants, non-DKD participants), SGLT2i history (with SGLT2i background, 
without SGLT2i background) and region (Japan, Rest of World) at randomisation by 
treatment group and overall (Analysis Population: Randomised participants).
By-participant listings of disposition details for discontinued participants and participants 
completing the study will be provided. In addition, a by-participant listing of the randomisation 
scheme and codes will be provided.
4.4.2
Protocol Deviations
Important protocol deviations (IPDs) are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments. The impact of IPDs on the 
efficacy and/or safety 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 
IPDs.
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.

Deviation 3: Participant received prohibited medication during study treatment period.

Deviation 4: Met study treatment discontinuation criteria but continued study treatment and 
potentially had major impact to participants’ safety according to clinical judgement.


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
Deviation 5: Missed visits, assessments, or treatments that, in the Investigator’s opinion, were 
due to the COVID-19 global 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.

Deviation 6: Data in CRF not consistent with source documents and/or discrepancies are not 
explained.
The number and percentage of participants with any IPD will be summarised for each IPD category 
based on the full analysis set (FAS). 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 protocol deviations, 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 protocol deviations will be detected from the data recorded in the clinical database 
and will be reviewed at regular protocol deviation review meetings. At this meeting, the 
programmatically-derived protocol deviations will be checked to ensure that they have been correctly 
classified as important or not important protocol deviations. 
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.
A by-participant listing of important protocol deviations will be provided.
4.5
Analysis Populations
The following summaries will be provided:

A summary of the number of participants in each analysis set by treatment group and 
overall. Exclusions from each analysis population 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 3 Populations for Analysis
Analysis Populations
Description
Enrolled 
All participants who sign the informed consent form.
Full Analysis Population
All participants who are randomised and receive any study drug. 
Participants are evaluated according to the treatment assigned at 
randomisation. The Full Analysis Population will be used for all analyses 
of demographic data, baseline characteristics and efficacy data.
Per Protocol Population
A subset of the Full Analysis Population consisting of all participants who 
receive the additional treatment with dapagliflozin post-Week 12 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 Population
All participants who are randomised and receive any study drug. 
Participants are evaluated according to the actual treatment they received. 
If a participant received a different treatment dose than randomised 
throughout the study, they will be analysed according to the treated dose, 
not the randomisation dose. If a participant received study drug from the 
wrong kit for only part of the treatment duration, they will be analysed 
according to their randomisation dose. The Safety Analysis set will be 
used for all safety analyses, unless otherwise specified.
Extended Safety Analysis Population
A subset of the Safety Analysis Population consisting of all participants 
who receive the additional treatment with dapagliflozin post-Week 12.
Ambulatory Blood Pressure Monitoring 
Population
All participants in the Full Analysis Population who have valid 
ambulatory blood pressure data for change from baseline analyses.
4.5.1
Analysis Sets
Analysis sets consist of two components: (1) analysis population (See Section 4.5), which specifies 
the participants included in an analysis; (2) data period, defining the time period during which data 
will be included in the analysis.
Analysis Set
Analysis Population
Data Period
Full Analysis Set
Full Analysis Population
Day 1 to the end of the follow-up period
Per-Protocol Set
Per-Protocol Population
Day 1 to the end of the follow-up period
Safety Analysis Set
Safety Analysis Population
Day 1 to the end of the follow-up period
Monotherapy Safety Analysis Set
Safety Analysis Population
Day 1 to the end of the first treatment period
Extended Safety Analysis Set
Extended Safety Analysis
Population
Day 1 to the end of the follow-up period with 
flag to subset Week 12 to the end of the 
follow-up period
The Extended Safety Analysis Set includes participants who entered the second treatment period. The 
Week 12 flag is added to the Extended Safety Analysis Set to allow subsetting of participant data to 
be from Week 12 to end of study. 
4.6
Demographic and Other Baseline Characteristics
Age will be calculated as the number of complete years between a participant's birth date and the date 
of informed consent.


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Demographic and other baseline characteristics will be listed for all participants and summarised for 
the Full Analysis Population, as:

Demographics 
o
age (years), 
o
age group (< 50, ≥50 to < 65, ≥65 to < 85, ≥85 years),
o
sex, race (if collected), 
o
country,
o
ethnicity.

Participant characteristics at baseline 
o
height [cm], 
o
weight [kg], 
o
weight groups (< 40, ≥40 - < 75, ≥75 - < 90, ≥90 - < 120, and ≥120 kg), 
o
body mass index (BMI), 
o
BMI groups: 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).

Baseline disease characteristics
o
Type 2 Diabetes Mellitus (T2DM) diagnosis (Y/N)
o
T2DM duration (years), 
o
CKD stage (eGFR category): Stage 2 (60–89 mL/min)/Stage 3a (45–59 mL/min)/ 
Stage 3b (30–44 mL/min)/Stage 4 (15–29 mL/min)/Stage 5 (<15 mL/min),
o
eGFR (mL/min/1.73m2),
o
albuminuria (defined as 200 -5000 mg albumin/g creatinine; count and percentage of 
participants meeting criteria), 
o
SGLT2i history (background/no background),
o
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),
o
Chronic 
glomerulonephritis 
type:
IgA 
nephropathy, 
Focal 
segmental 
glomerulosclerosis (FSGS), Lupus nephritis, Membranous nephropathy, Minimal 
change, Other primary or secondary glomerulonephritis, 
o
Angiotensin Converting Enzyme Inhibitors (ACEi)/ Angiotensin II Receptor Blockers 
(ARB) history (Y/N))

A summary and a list of participants by site and country will be provided.
Medical history and relevant surgical history will be coded using 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.
4.7
Concomitant Medication
Any medication or vaccine (including over-the-counter or prescription medications, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrolment or receives during the 
study will be recorded as concomitant. Medications starting after the completion/withdrawal date of 
study will be listed but will not be classified or summarised.


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If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of enrollment. Medications will be assumed to be concomitant only, unless 
there is clear evidence (through comparison of partial dates) to suggest that the medication started 
prior to enrollment. If there is clear evidence to suggest that the medication started prior to enrollment, 
the medication will be assumed to be both prior and concomitant, unless there is clear evidence to 
suggest that the medication stopped prior to enrollment. If there is clear evidence to suggest that the 
medication stopped prior to enrollment, the medication will be assumed to be prior only.
The frequency and percentage of participants receiving rescue medication during the treatment 
periods will be presented by treatment group. A by-participant listing will also be presented for all 
rescue medications taken during the treatment periods, by treatment group.
Concomitant medications will be summarised 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

disallowed concomitant medication taken during the study
The type of medication in terms of common concomitant, anti-diabetic, and heart failure related 
medication will be derived from the CRF module assigned to the respective type of medication. A 
by-participant listing of concomitant medications at study entry and taken during treatment will be 
presented. 
A by-participant listing of medications not started due to the COVID-19 pandemic will be presented.
4.8
Treatment Compliance
Treatment compliance will be assessed using two methods:

Counting the number of AZD5718/placebo and dapagliflozin tablets dispensed to and taken 
by each participant, providing an overall percentage of treatment compliance for the study.

Summarising instances of dose interruptions lasting 3 or more consecutive days.
Participants will be requested to return all unused study medication and empty packages to the clinic 
at each visit. The amount of dispensed and returned study medication will be recorded in the eCRF. 
The percentage treatment compliance will be calculated from the dose as:
=> ; ;2 6;9 7 5
=> ; ;2 6;9 ?6
× 100
Participants taking ≥80% and ≤120% of planned study medication are considered to be compliant.
Overall study compliance percentage will be summarised as follows:

Descriptive statistics will be summarised by the four treatment groups and overall.

Percent compliance will be categorised according to the following three categories:

< 50% or ≥150% (significant drug non-compliance)

≥50% and < 80% or > 120% and < 150% (moderate drug non-compliance)

≥80%, ≤120% (drug compliance)


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A by-participant listing of treatment compliance data will be provided. 
A separate compliance measure is to be defined as dose interruptions which last three or more days. 
This will indicate severe non-compliance.
A summary of the number of occurrences of drug interruptions lasting three or more consecutive 
days, by treatment group and treatment period. A by-participant listing of all participants who have 
at least one instance of a dose interruption of three or more consecutive days will be presented.
4.9
Efficacy Evaluation
4.9.1
Analysis and Data Conventions
This study is designed to test for superiority and assess the dose-response relationship. The null 
hypothesis for the treatment comparison will be that there is no difference between AZD5718 with 
dapagliflozin and placebo with dapagliflozin on urine ACR. The alternative hypothesis will be that 
there is a difference. Symbolically, this is expressed as follows:
H(0): (AZD5718+dapagliflozin) = (placebo + dapagliflozin)
H(1): (AZD5718+dapagliflozin) ≠ (placebo + dapagliflozin)
A 2-sided test with = 0.1 will be used to test this hypothesis.
4.9.1.1
Dose-response Testing
Not applicable for this study. See Section 4.14 for further details.
4.9.1.2
Multi-centre Studies
No per centre (where the term ‘centre’ defines each investigator site) summaries or analyses will be 
made.
4.9.1.3
Adjustments for Covariates
The primary efficacy analysis will be adjusted for the following baseline covariates:
1.
DKD status (stratification variable) 
2.
SGLT2i history (stratification variable)
3.
Visit
4.
Baseline measure of log (urine albumin to creatinine ratio [UACR])
5.
Treatment-by-visit interaction
6.
Baseline log (UACR)-by visit interaction


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Strata with low counts (<5 participants in a stratum) will be pooled with adjacent strata. 
4.9.1.4
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values. For analyses of UACR, if a measurement is 
missing it will not be imputed. 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 of “< x” (ie, below the lower limit of quantification) or > x (ie, 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” or “> x” will be imputed by Covance Central Laboratory in order to effectively 
calculate the geometric mean.
Partial or missing dates
If the start date of the concomitant medication, medical history relating to T2DM diagnosis 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 stop 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 last 
dose of study treatment.

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 (eg, 28, 29, 30, or 31).

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.
4.9.1.5
Interim Analyses
An administrative interim analysis will be conducted when approximately 211 participants have 
completed the 20-week treatment period. See Section 4.12 and Appendix B for further details


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4.9.1.6
Examination of Sub-groups
Sub-group analyses for the primary efficacy endpoint by SGLT2i background and by DKD status 
will be presented. Summaries of the primary efficacy variable by treatment group and sub-group will 
also be produced. No formal statistical analysis will be performed within these sub-group.
A forest plot will present the least-squares mean and 90% CI overall and for each sub-group
individually. These will be taken from the primary analysis model. 
4.9.2
Primary Efficacy Variable – UACR
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 per 
protocol population. The endpoint being assessed is the change in log-transformed urine ACR from 
baseline to Week 20. For the intercurrent event, if a participant discontinues treatment due to AE or 
lack of efficacy, or uses prohibited medication, the urine ACR data are treated as missing after the 
event and no imputation is performed. The summary measure being evaluated is the geometric mean 
reduction of urine ACR from baseline to Week 20.
4.9.2.1
Primary Analysis
The primary efficacy endpoint for this study is the reduction of urine ACR from baseline to Week 20 
compared to placebo (on treatment with dapagliflozin as future standard of care). As urine ACR is 
assumed to follow a log-normal distribution, it will be log-transformed for statistical analysis 
purposes. The mean log changes in urine ACR at Week 20 (@AB, @A#, @AC, @AD) for each of the 3 AZD5718 
doses and placebo will be estimated in a mixed model for repeated measures [MMRM] (Weeks 2, 4, 
8, 12, 16, and 20). The values will be back transformed onto the original scale to give the geometric 
mean relative change from baseline at Week 20. 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 (urine ACR) and baseline log (urine ACR)-by-visit interaction. An 
unstructured covariance structure will be used for the within-participant errors. A homogeneity 
assessment between the DM and the non-DM sub-populations will be performed. 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 heterogeneous Toeplitz covariance 
structure will be evaluated, followed by the heterogeneous autoregressive of first order, 
heterogeneous compound symmetry, and homogeneous compound symmetry covariance structures 
in the case of further non-convergence. If none of the models converge, the analysis will be altered 
to use an analysis of covariance (ANCOVA) with last observation carried forward (LOCF) imputation 
method implemented.
The point estimates from the model, including the 95% CIs and p-values will be presented. The point 
estimate and 95% CI for the geometric mean ratio will be converted to the percentage change as 
follows:
[(; F ; −1) × 100]
The UACR will be summarized by treatment group and visit in terms of absolute values and changes 
from baseline.


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The primary analysis will be repeated by strata (DKD without SGLT2i background, DKD with 
SGLT2i background, non-DKD), with the analysis model will include the fixed categorical effects of 
treatment, visit, and treatment-by-visit interaction, plus the continuous covariates of baseline log 
(urine ACR) and baseline log (urine ACR)-by-visit interaction. 
A plot showing the mean percentage change from baseline in UACR over time within each treatment 
group will be provided.
A by-participant listing of the UACR data will be provided.
4.9.3
Secondary Efficacy Variables
4.9.3.1
UACR at 12 Weeks
Urine ACR will be analysed to determine the dose-response effect of AZD5718 at 12 weeks (on 
current standard of care). The population of interest are randomised participants who meet all 
eligibility criteria and have valid non-missing urine ACR records at baseline and at least one post-
treatment visit. The mean log change from baseline in urine ACR will be analysed using a mixed 
model for repeated measures. The summary measure being evaluated is the geometric mean reduction 
of urine ACR from baseline to Week 12. This will be evaluated using the same methods for the 
primary efficacy endpoint. The analysis will be repeated on the Per-Protocol Analysis Population.
The results of the model parameters (estimates, p-values, and 95% CIs) will be presented. The point 
estimate and 95% CI for the geometric mean ratio will be converted to the percentage change as 
follows:
[(; F ; −1) × 100]
UACR will be summarized by treatment group and visit in terms of absolute values and changes from 
baseline.
The analysis will be repeated by strata (DKD without SGLT2i background, DKD with SGLT2i 
background, non-DKD), with the analysis model will include the fixed categorical effects of 
treatment, visit, and treatment-by-visit interaction, plus the continuous covariates of baseline log 
(urine ACR) and baseline log (urine ACR)-by-visit interaction. 
4.9.3.2
Estimated GFR
Estimated GFR will be analysed, comparing eGFR at baseline with that at 12 weeks, to determine 
whether there is any acute change with the introduction of AZD5718 to inform planning for a GFR 
slope analysis in Phase 3. This will be analysed using a by-visit ANCOVA, adjusting for DM 
stratification factor, treatment group and baseline eGFR. The FAS will be used for this analysis and 
eGFR will be evaluated on the original scale. The analysis will be repeated on the Per-Protocol 
Analysis Population.
The results of the by-visit ANCOVA will be presented by treatment group. A summary of change 
from baseline of eGFR results will be presented by treatment group and a by-participant listing 
provided of eGFR results at each visit. Plots of the least-squares mean by treatment group over time, 
and the mean eGFR over time up to follow-up visit will be presented.
An ANCOVA model will be produced for eGFR up to Week 20, analysed on the Per-Protocol 
Analysis set, similarly to that described above.


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The analysis will also be repeated by strata (DKD without SGLT2i background, DKD with SGLT2i 
background, non-DKD), adjusting for treatment group and baseline eGFR. 
4.9.3.3
Ambulatory Blood Pressure Monitoring
For drugs intended for chronic use, the US Food and Drug Administration (FDA) recommended use 
of ambulatory blood pressure monitoring (ABPM) to assess the sustained BP effect (FDA guidance 
on Assessment of Pressor Effects of Drugs, May 2018). The collection and the analysis of the ABPM 
data in this study is aimed to delineate differential BP effect of AZD5718 relative to placebo.
The device will be provided to the participants at the visits outlined in the SoA in Appendix A
(Screening Visit 2 and Visit 6 [Week 8]). They will be instructed to perform the ABPM 24-hours 
before their next visit, ie, Visit 3 (Week 1) and Visit 7 (Week 12), respectively. The ABPM recording 
must have finished prior to dosing at each specified visit. 
If the 24-hour ABPM assessment session provided at a visit is confirmed to not meet the validity 
criteria, the associated study visit may be rescheduled to allow for a repeat ABPM recording only if 
the rescheduled visit can be completed within the specified tolerance period for study visits, as 
described in the SoA in Appendix A. An assessment session is valid if there is a minimum of 20 hours 
of the recording with at least 70% of expected measurements being successful. If the repeated 
assessment session is not valid using the same validity criteria, no further repeats will be performed 
for that visit. This criterium for the validity of measurements will only be used on site to reschedule 
the ABPM assessment session. The inclusion criteria for the statistical analysis are separate and are
described in the following paragraph.
Recordings will be done every 20 minutes during the day-time (06:01 to 22:00) and every 30 minutes 
during the night-time (22:01 to 06:00). These definitions of day-time and night-time are only to be 
used on site for collecting recordings; they will be defined differently for the purpose of statistical 
analyses.
For the purpose of inclusion in the statistical analyses, the session needs to satisfy two conditions:
1. There should be at least 50% of successful measurements in both day-time (06:01 to 22:00) 
and night-time (22:01 to 06:00). If both the scheduled and repeat assessment sessions have 
more than 50% of successful measurements in the respective timeframes, the assessment 
session with a higher overall percentage of successful measurements will be included in the 
analyses. In the unlikely event that both the scheduled and repeated assessment sessions have 
the same percentage of successful measurements (and both above 50%), the scheduled 
assessment session will be taken as the visit assessment. 
2. There are not more than two consecutive hours with no available measurements in an ABPM 
assessment session.
Primary ABPM Analysis
The primary endpoint in the analysis is the change from baseline in 24-hour mean SBP at Week 12. 
Participants with missing mean 24-hour SBP at Week 12 will be excluded from the analysis.
In order to derive the mean SBP over various time periods, the hourly mean SBP is derived for each 
participant for each hour using the available data at the visit. This is the sum of the successful non-
missing SBP measurements in the hour, divided by the number of non-missing SBP measurements 
in the respective hour. This derivation will be used to further derive the endpoints of interest.


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The 24-hour mean SBP is derived as the sum of the non-missing hourly mean SBP measurements, 
divided by the number of hours with non-missing hourly mean SBP. Missing hourly mean SBP
derivations will not be counted towards the 24-hour mean.
For the ABPM analysis, baseline for the 24-hour mean ABPM parameter (or mean day-time, mean 
night-time, mean hourly) is defined as the 24-hour mean value (or corresponding mean day-time
value, mean night-time value, mean hourly value) during the Screening Visit 2.
The change from baseline in 24-hour mean SBP at Week 12 will be analysed using an ANCOVA
model, with change from baseline in 24-hour mean SBP as the dependent variable, adjusting for DM 
stratification factor, treatment group (AZD5718 
mg, AZD5718 
mg, AZD5718 
mg, 
placebo), plus baseline 24-hour mean SBP and BMI as covariates. The ambulatory blood pressure
monitoring population will be used for this analysis. The least squares (LS) mean difference between 
each of the AZD5718 doses and placebo (ie, placebo-corrected change from baseline in 24-hour mean 
SBP) will be derived from the model. The 2-sided 90% CI for these differences will be presented. 
If the proportion of participants within a sub-group category is too small for effective analyses, sub-
group categories can be collapsed or removed from the sub-group analyses, where appropriate.
The change from baseline in 24-hour mean DBP at Week 12 will be analysed similarly to the primary 
endpoint using an ANCOVA model. The 2-sided 90% CI for the difference between each of the 
AZD5718 doses and placebo will be derived from the model and presented. 
Sensitivity ABPM Analysis – 24-hour Mean SBP
The proportion of missingness of ABPM data (the number of participants who did not meet either of 
the statistical validity criteria at baseline and Week 12) will be summarised by treatment group and 
by key baseline characteristics (age group, race, BMI group, and randomisation strata). 
Secondary ABPM Analysis
The secondary ABPM endpoints are change from baseline in mean day-time and mean night-time 
ABPM metrics (SBP and DBP), these will be evaluated similarly to the primary ABPM endpoint
using ANCOVA models, presenting only the 90% CI between each of the AZD5718 doses and 
placebo. No formal hypothesis testing will be performed. Day-time is defined as 09:00 to 21:00, 
night-time is defined as 01:00 to 06:00.
The mean day-time SBP will be derived as the sum of the hourly mean SBP from 09:00 to 21:00 
divided by the total number of hours with non-missing data. The mean night-time SBP will be derived 
as the sum of the hourly mean SBP from 01:00 to 06:00 divided by the total number of hours with 
non-missing data. The same derivations will be performed for DBP. Summary statistics will be 
presented for mean day-time and night-time values.
By-participant listing for ambulatory blood pressure monitoring values and derivations will be 
presented by treatment group and visit.
4.10 Safety Evaluation
All safety summaries and analyses will be based upon the Safety analysis set as defined in Section 4.5, 
unless otherwise specified. Safety summaries will be presented by treatment group and with a pooled 
AZD5718 group, where appropriate.
CCI
CCI
CCI


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Change from baseline will be calculated as the differences between the post-dose value at each time 
point and the value prior to administration of the study medication.
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 blood pressure) 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 too.
Outputs presented on the Extended Safety Analysis Set will include the Week 12 flag to subset for 
data in the second treatment period. These outputs may be repeated without the Week 12 flag if 
deemed appropriate by the study team, thereby including all data for participants who continued into 
the second treatment period only.
4.10.1 Extent of Exposure
The extent of exposure (days) will be derived as follows for AZD5718 and for dapagliflozin:
8; ;2 H?;9[	I85718] (679)
= 8 ;2 9 6;9[	I85718] −8 ;2 29 6;9[	I85718] + 1
8. ;2 H?. ; 6?02;J (679)
= 8 ;2 9 6;9[6?02;J] −8 ;2 29 6;9[6?02;J]
+ 1
The following extent of exposure summaries will be provided separately for AZD5718 and for 
dapagliflozin:

A summary of the duration of exposure to treatment (days) and cumulative exposure over 
time (≥1 day, ≥28 days, ≥57 days, ≥85 days, ≥120 days), by treatment group.

Total exposure to study treatment (days) = (min(last dose date, death date) - first dose date 
+1) / (365.25)

Time on study – defined as the time in days from the start date of treatment to the date of 
last study assessment or the date of withdrawal. 
A summary of duration of exposure to treatment (days) will also be presented for the Monotherapy 
Safety Analysis Set and the Extended Safety Analysis Set with Week 12 flag.
The following summaries will be produced for the Safety Analysis Set, by treatment group:

Number of and reasons for dose interruptions
4.10.2 Adverse Events
Adverse events will be coded using MedDRA version 23.0 or later. 


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An AE (classified by preferred term) started during the treatment period will be considered a 
treatment-emergent adverse event if it was not present prior to the first dose of randomised 
treatment. An AE that starts more than 7 days after the last dose of study medication will not be 
counted as a treatment-emergent AE. AEs which worsen after the start of treatment will not be 
included as a treatment-emergent AE but will be recorded.
Adverse events (and also separately SAEs) will be summarised by study treatment group in incidence 
summaries by MedDRA SOC and PT. Adverse events will be assigned to the period where they start
and will be summarised for the Safety Analysis Set, with selected outputs summarized for the 
Monotherapy Safety Analysis Set and Extended Safety Analysis Set with Week 12 flag. Serious 
adverse event 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 drug. 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 drug. Only 
applicable for SAEs.

On treatment: The AE occurred on or after the first administration until 7 days after last dose 
of AZD5718 and/or dapagliflozin.

Off treatment: The AE occurred more than 7 days after the last dose of study drug.
The number, percentage and percentage per participant exposure year (PEY) of participants 
reporting treatment-emergent AEs in each treatment group will be tabulated by SOC and PT; by 
SOC; by SOC, PT, and relationship to study medication as assessed by the Investigator. If more 
than one event occurs with the same preferred term for 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 severity and by relationship to the study medication. 
The event rate per 100 PEY is defined as:
K
 ;2 9L9 Mℎ	O
9 ;2 679  95 2; 	O   ?;6 + 7 679P × 365.25 × 100
The denominator is calculated per participant then summed. The distribution of treatment-emergent 
AEs by severity and relationship to study medication will be summarized by treatment group.
A summary of AEs in any category will be presented by treatment. The incidence of common (≥5% 
of participants in any treatment group) treatment-emergent AEs, common treatment-emergent serious 
AEs, and AEs leading to discontinuation of study medication will be summarized by SOC, PT and 
treatment group, sorted in decreasing overall (across treatments) frequency. Treatment-emergent AEs
with outcome of deaths will also be presented. In addition, all fatal SAEs (ie, events that caused death) 
will be summarized. 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 a treatment-emergent AE in the same participant 
will only be counted once overall. Non-serious treatment-emergent AEs occurring in more than 5% 
of participants will be presented by treatment.
The number and percentage of participants reporting AEs by treatment group, SOC and PT will also 
be presented for the Monotherapy Safety Analysis Set and the Extended Safety Analysis Set with 
Week 12 flag.


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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 categorization.
4.10.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events
The following summaries will be provided:

A summary of the number and percentage of participants reporting a treatment-emergent AE 
with outcome of death by treatment group, SOC and PT

A summary of key participant information for participants reporting treatment-emergent AE 
with outcome of death

A summary of the number of SAEs reported by treatment group, SOC and PT

A summary of the number and percentage of participants reporting a SAE by treatment group, 
SOC and PT

A summary of key participant information for participants reporting a SAE 
The number and percentage of participants reporting a treatment-emergent AE leading to death, and 
SAEs by treatment group, SOC and PT will also be presented for the Monotherapy Safety Analysis 
Set and the Extended Safety Analysis Set with Week 12 flag.
4.10.4 Clinical Laboratory Evaluation
The following summaries will be provided:

A summary of the observed absolute values and change from baseline in each haematology and 
clinical chemistry laboratory parameter by treatment group and time point.

A summary of baseline versus maximum observation on treatment in each laboratory parameter 
by treatment group (shift table)

A summary of baseline versus minimum observation on treatment in each laboratory parameter 
by treatment group (shift table)

A summary of key participant information for participants reporting changes outside reference 
ranges in each laboratory parameter

A summary of the number and percentage of participants reporting changes outside reference 
ranges in each laboratory parameter

A plot of alanine aminotransferase (ALT) versus total bilirubin, expressed as multiples of upper 
limit of normal (ULN)

A plot of aspartate aminotransferase (AST) versus total bilirubin, expressed as multiples of ULN

A plot of liver biochemistry over time, for participants with potential Drug Induced Liver Injury 
(ie, ALT/AST ≥ 3 x ULN and total bilirubin (BILI) ≥ 2 x ULN, and in which the elevation in 
transaminases precede or coincide with (that is, on the same day as) the elevation in BILI or 
ALT/AST ≥ 5 x 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 ie, participants 
with combined ALT or AST, and bilirubin elevations

A summary of treatment-emergent laboratory changes will be presented for the Safety Analysis 
Set, the Monotherapy Safety Analysis Set (Treatment Period 1) and the Extended Safety 
Analysis Set with Week 12 flag (Treatment Period 2).


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Treatment-emergent laboratory and vitals change (TELVC) limits of interest for this study are 
provided in Appendix C for the laboratory parameters, and in Table 5 for vital signs.
By-participant listings of all laboratory data will be provided including participant identifier, 
treatment, age, sex, race, visit, category, laboratory test name, result, and standard units. Laboratory 
reference ranges will also be listed and out of range values will be flagged.
4.10.5 Vital Signs, Physical Findings and Other Observations Related to Safety
ECG measurements will be evaluated by the clinician at each visit described in the SoA in 
Appendix A as either normal or abnormal. Number and percentage of participants with normal and 
abnormal ECG readings by visit will be presented by treatment group. Abnormal ECG results and 
reasons entered into the CRF will be listed by participant and by visit. 
Potentially clinically significant (PCS) ECG values will be identified from Third Party Vendor data 
collected. The predefined criteria (based on severity) for PCS ECG values are displayed in Table 4.
Table 4 Potentially Clinically Significant 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*
QTcB
ms
< 320
> 450*
< 300
> 480*
> 30*
> 60*
> 500*
* 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, 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) 
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 
ms = milliseconds, bpm = beats per minute: NA= not applicable. 
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 5.
Table 5 Vital Sign Notable Change Predefined Criteria
Vital sign
Observed
value
Notable change from
baseline
Systolic BP (mmHg)
High
≥ 140
Increase of ≥ 20


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Low
< 90
Decrease of ≥ 20
Diastolic BP (mmHg)
High
≥ 90
Increase of ≥ 10
Low
< 60
Decrease of ≥ 10
Pulse Rate (bpm)
High
≥ 110
Increase of ≥ 20
Low
< 50
Decrease of ≥ 20
Pulse Oximetry
High
N/A
N/A
Low
< 90%
Decrease of ≥5% 
BP = blood pressure.
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 of the observed absolute values and change from baseline in each vital sign parameter 
by treatment group and time point.

A summary of key participant information for participants reporting notable changes outside 
predefined criteria in each vital sign parameter.

A summary of the number and percentage of participants experiencing notable changes from 
baseline outside predefined criteria, by vital sign parameter and treatment group.

A summary of the observed absolute values and change from baseline in each ECG parameter by 
treatment group and time point. Both pre- and post-investigational medicinal product (IMP)
measurements will be presented at each time point.

A summary of the number and percentage of participants with QTcF intervals exceeding 
predefined upper limits (as stated in Table 4).

A summary of ECG assessment (normal/abnormal [clinically significant, not clinically 
significant]), baseline versus last observation on treatment. Post-IMP measurement at last 
observation on treatment will be used.

A summary of key participant information for participants reporting PCS ECG values outside 
predefined criteria by treatment group and visit.

A summary of the number and percentage of participants reporting PCS ECG values outside 
predefined criteria, by ECG parameter and treatment group.
By-participant listings of vital sign parameters, abnormal ECG results, and weight, height, and BMI 
will also be provided.
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.
4.10.6 Safety Monitoring 
This is not applicable for this study. 
4.11 Other Analyses
4.11.1 Pharmacokinetics
Following the early termination of the FLAIR study, it was confirmed that all PK analysis (AZD5718 
and Dapagliflozin) is no longer required for Final Analysis. 
4.11.2 Retinal Sub-Study
The retinal study to be performed on eligible DKD study participants will provide descriptive 
summaries of BCVA and OCT, as described in Section 3.2.3.1. Summary statistics and change from 




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Pharmacokinetic analyses of AZD5718 and dapagliflozin were also removed from the final analysis. 
The statistical analysis plan has been updated to reflect this.
Due to the early termination of the study, the total number of randomised participants is 613 with 
340 participants completing treatment. Therefore, efficacy analyses should be evaluated with caution 
due to lack of power.
The total study duration, as highlighted in Section 3.1, will vary following study termination, up to a 
maximum of 28 weeks. 


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5
REFERENCES
FDA, 2018
FDA Guidance: Assessment of Pressor Effects of Drugs, May 2018.


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6
APPENDIX


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Appendix A: Schedule of Activities
Table 6 Schedule of Activities
Study Period
Screening
Treatment Period 1
Treatment Period 2
Discontinuation
Follow-up
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-32 to -3
1
15±3
29±3
57±3
85±3
113±3
141±3
169±5
Study Week
-4 to 0
1
2
4
8
12
16
20
24
Informed consent (main)
X
Informed consent (optional) for 
genetic and biomarker research
X
Verify eligibility criteria
X
X
X
Xa
Demography
X
Full physical examination 
including height, weight and 
BMI
Xb
X
X
X
X
X
X
Physical examination 
(abbreviated)
X
X
Medical history
X
Serum hCG, FSH and LHc
X
Pregnancy testc
X
Drug and alcohol screen
X
Hepatitis B and C screening
X
Spot urine for ACR
X
Safety laboratory assessments 
(Clinical chemistry, 
haematology, coagulation, 
urinalysis)d
X
Xe
X
X
X
X
X
Xe
Xe
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
Randomisation
X
Retinal study (optional DKD 
sub-group only)g
X
X
HbA1ch
X
X
Calculation of eGFR
X
X
X
X
X
X
X
X
X
X
Blood sample for cystatin-C
X
X
X
X
X
X
X
X
X
X




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e
To include thyroid function tests (TSH, fT4 and fT3).
f
All vital signs (blood pressure, heart rate, respiratory rate, body temperature and pulse oximetry) will be measured with the participant in a supine position having rested for at least 10 minutes 
before each reading and should be taken before any blood draws. Vital signs should be collected pre-dose on the days of study drug dosing.
g
Optional, to be conducted only at study centres with the appropriate facility to conduct the assessment. There is no requirement for all participants at centres undertaking the sub-study to 
participate.
h
To be collected prior to study drug administration.
h
Containers to be dispensed at any study visit as required.
i
At specific PK sampling sites, for a sub-group of at least 80 participants (20 per dose group including placebo), 4 additional PK samples will be collected at this visit within 1-2 h, 2-5 h, 5-8 h, 
and 8-12 h post-dose. Pre-dose samples will be collected for all participants. Each PK sample must be separated by at least 1 h.
j
Only if consent is obtained. The blood sample for Genomic Initiative will be obtained from the participants at Visit 3 prior to study drug administration (at or after randomisation). If for any 
reason the sample is not drawn at Visit 3, it may be taken at any visit window until the last study visit. Only 1 sample should be collected per participant.
k
Participants will be requested to download an e-Diary application on their smartphones starting from Visit 3, in order to set study reminders and capture drug accountability throughout the 
treatment period, at sites where applicable. If needed, participants may be provided with a smartphone in order to use the application. Participants will be trained on how to use the 
application/device and the site will help the participants to login into the application for the first time. Data will be available to the site/Sponsor in real time. The participants who received a 
smartphone to use the e-Diary will return the smartphones at the last visit. Prior to deleting the e-Diary application from their personal smartphone, or returning a site provided smartphone, the 
participants will be requested to complete a satisfaction survey through the application (this survey is only applicable for e-Diary). When completion of an e-Diary is not applicable, participant 
will be requested to complete a paper dosing diary.
l
Phone call will occur after results from Screening Visit 1 are available and the participant is confirmed eligible in order to remind the participant to collect the first morning void urine samples 
and schedule the Screening Visit 2. If scheduled Visit 3 (Week 1) or Visit 7 (Week 12) will need to be delayed due to the need to repeat ABPM recording there is no need to repeat collection of 
the 3 urine samples.
m
Participants to collect first morning void urine samples on 3 consecutive dates (ideally day of visit and each of the preceding 2 days [refrigerated overnight] which are returned on the day of 
visit). This collection may be repeated once during the course of screening. 
n
Participants will be provided an ABPM cuff at Screening Visit 2 and Visit 6 (Week 8) and instructed to perform ABPM 24-hours before their next visit ie, Visit 3 (Week 1) and Visit 7 (Week 12), 
respectively. Site will be asked to call the participant the day prior to next visit as a reminder to complete assessments. The participant may also visit the site for ABPM cuff placement 1 day 
before their next visit of scheduled assessment (i.e., Visit 3 [Week 1] and Visit 7 [Week 12], respectively)
o
Sites should ensure that the validity criterion described in Section 8.2.5 (CSP) is met prior to completing any other assessments at the visit. If the validity criterion is not met, the associated study 
visit may be rescheduled to allow for a repeat ABPM recording only if the rescheduled visit can be completed within the specified tolerance period for study visits:

Visit 3: up to 72 hours following the originally scheduled visit for Visit 3 but no more than 32 days from Screening Visit 1.

Visit 7: ±72 hours from Day 85.
If a repeat ABPM session is not possible, the study visit should proceed as indicated. In addition, the visit should also continue if the ABPM session does not meet the validity criterion after the 
repeat session.
p
Study drugs refer to AZD5718/placebo during Treatment Period 1 and AZD5718/placebo + dapagliflozin during Treatment Period 2.
q
Site should follow-up directly with the participant via phone to remind the participant.
r
Participants to return all study drug dispensed at previous visits and only use the newly dispensed study drug. Participants should be reminded not to take study drug on the days of a study visit 
until instructed by the study site.
NOTE: All laboratory assessments are to be performed in central laboratories, except for tests completed using dipsticks and drug and alcohol screen tests which will be done locally. Laboratory kits used 
locally will be provided by the central laboratory. 
NOTE: Where the values for the following investigations are outside the usual range for a participant during screening, based on their medical history, retesting may be undertaken on one occasion without 
requiring a re-screen: Blood pressure, eGFR, spot urine for ACR, ALT, AST, bilirubin, and serum potassium.
Abbreviations: ABPM = ambulatory blood pressure monitoring; ACR = albumin to creatinine ratio; AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = 
body mass index; CKD = chronic kidney disease; CSP = clinical study protocol; DKD = diabetic kidney disease; ECG = electrocardiogram; e-Diary = electronic Diary; eGFR = estimated glomerular 
filtration rate; FSH = follicle stimulating hormone; fT3=free triiodothyronine; fT4=free thyroxine; h = hour, HbA1c = glycated haemoglobin; hCG = human chorionic gonadotropin; LH = luteinising 
hormone; 
; PK = pharmacokinetic(s); SAEs = serious adverse events; TSH=thyroid stimulating hormone.
CCI




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σ = the standard error of the estimate, 
d,.e = f+B(0.8) ie, the 0.8-level quantile of the normal distribution,
d,.- = f+B(0.9) ie, the 0.9-level quantile of the normal distribution,
TV = 0.357 representing a Target Value (TV) of 30%,
LRV = 0.223 representing a Lower Reference Value (LRV) of 20%.
A decision plot will be created for UACR reduction for the placebo-adjusted estimates of 
AZD5718 
, 
 and 
mg at week 20. A schematic example of a decision plot for UACR 
reduction at week 20 for the AZD5718 is illustrated below.
Abbreviations: LRV = Lower Reference Value; TV = Target Value; UACR = urine albumin to creatinine ratio.
Initiation of future studies requires at least one dose to have GO for the placebo-adjusted 
UACR reduction at week 20 and the response of the other doses pointing in the right direction.
Reference:
Paul Frewer, Pat Mitchell Claire Watkins and James Matcham, Decision-making in early 
clinical drug development, Pharmaceutical Statistics 2016, 15 255–263
reduction in UACR (%)
[(5718 + Dapa) vs (placebo + Dapa)]
0
10
20
30
40
50
LRV
(20%)
TV 
(30%)
GO CRITERIA
CCI
CCI
CCI


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B.3.
Safety Analysis
Safety analysis will be based on the Interim Safety Analysis set. Selected safety outputs will be 
presented by treatment group and overall.
The number, percentage and percentage per participant exposure year (PEY) of participants reporting 
TEAEs in each treatment group will be tabulated by SOC and PT, by SOC. A summary of adverse 
events in any category will be presented by treatment. The incidence of common (≥5% of participants 
in any treatment group) treatment-emergent AEs, common treatment-emergent serious AEs, and AEs 
leading to discontinuation of study medication will be summarized by SOC, PT and treatment group, 
sorted in decreasing overall (across treatments) frequency. Moreover, treatment-emergent AEs 
leading to hospitalization will also be presented.
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 resulting in death.
Summary statistics of laboratory data (as described in Section 4.10.4) will be presented. Participants 
with laboratory values which are highlighted as abnormal will be listed. Summary statistics of vital 
signs data may be collected.


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Appendix C: Treatment-Emergent Laboratory and Vital Signs Criteria limits
The treatment-emergent laboratory and vitals change (TELVC) limits of interest for this study are as 
follows:
Laboratory Parameter
Range
TELVC limits
Creatinine
≥1.5 x Baseline Serum Creatinine
≥2 x Baseline Serum Creatinine
Sodium
< 120 mmol/L
< 130 mmol/L
> 150 mmol/L
Potassium
≤2.5 mmol/L
≥6.0 mmol/L
Creatine Kinase
> 5 x ULN
> 10 x ULN


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Appendix D: Exclusion from Per-Protocol Analysis
Participants will be excluded from Per-Protocol analysis if they present with an important protocol 
deviation (IPD) which is deemed to severely impact the validity of the analysis. The IPDs identified 
as leading to exclusion from the Per-Protocol analysis set are outlined in the protocol deviation 
specification. All protocol deviations are reviewed by the study team and IPDs are reviewed on a 
case-by-case basis.
During the study, prior to the interim analysis and interim database lock, it was documented that one 
site in Poland (site 5702) did not have sufficient source documentation or medical validation for 
anomalous laboratory assessments. The data from the site could impact data integrity of the interim 
and final analyses if included in the Per-Protocol analysis set. A specific IPD was created and 
documented as:

Data entered in the eCRF that are transcribed from source documents not being consistent
with the source documents and /or the discrepancies are not explained /and /or medical records 
not available.
Participants from the site in Poland were allocated this IPD and are thereby excluded from the 
Per-Protocol analysis set. Their data will remain in the Full Analysis Set, in line with the 
Intention-to-Treat principles.


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