A Phase 3, International, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on CKD Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia
Phase: PHASE3
Conditions: Renal Insufficiency, Chronic, Hyperkalemia
Sponsor: AstraZeneca

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
1 of 125
Clinical Study Protocol
Study Intervention
Sodium Zirconium 
Cyclosilicate (SZC), Lisinopril, 
and Valsartan
Study Code
D9488C00001
Version
2.0 (Amendment 1)
Date
08Jun2022
A Phase 3, International, Randomised, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of Sodium 
Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) 
Progression in Participants with CKD and Hyperkalaemia or at 
Risk of Hyperkalaemia
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
(Japan) AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s):
IND number 108951
EudraCT number 2021-001911-96
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.
Redacted
ed
se 3
se
for 
Intern
Inter
trolled Stu
trolled S
closilicate 
losilicat
icipan
cip
ublic 
ku, Osaka 530
ku, Osaka
Pub
s wit
s wit
k of Hyper
 of Hyp
k
ub
Disclosure
straZeneca
raZeneca
esults are
sults are
and in
nd in

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
3 of 125
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1 (version 2.0)
08Jun2022
Original protocol (version 1.0)
24Jun2021
Amendment 1 (Version 2.0) 08 June 2022
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The primary reasons for this amendment are the following:
!
Clarify that the primary endpoints (total and chronic eGFR slope) are co-primary and will
be analysed as such, ie, both endpoints must be met for the study to be deemed successful.
!
Implement the use of a race agnostic CKD-EPI eGFR formula (Delgado et al 2022, Inker
et al 2021).
!
Add a third stratification factor of SGLT2 inhibitor and/or finerenone use at
randomisation.
!
Allow inclusion of participants with Type 1 diabetes mellitus.
!
Allow inclusion of participants on stable SGLT2 inhibitors or MRAs.
Changes to the protocol are listed below:
Section number and name
Description of change
Brief rationale
General
Corrected minor typographical and 
spelling errors throughout the 
protocol.
Improve the quality of the 
document.
Title Page
Added IND number 108951.
Provide IND regulatory identifier 
number.
1.1 (Synopsis)
Updated text to reflect changes 
made in the main body of the 
protocol.
Consistency with the main body of 
the protocol
2.1 (Study Rationale)
2.2.1 (Background Information on 
CKD)
2.2.3.1 (Facilitation of RAASi 
Treatment Optimisation)
11 (References)
Updated NICE 2014 link and 
reference to NICE 2021.
New NICE Guidelines for CKD 
(NG203) published 25 August 
2021; last updated 24 November 
2021.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
4 of 125
Section number and name
Description of change
Brief rationale
1.3 (Schedule of Activities)
Table 1 (Schedule of Activities 
During the Screening Period and 
Initiation and Run-in Phases)
4.1.1 (Screening Period [Up to 
13 days])
Removed minimum interval of 
7 days between screening Visit 1 
and Visit 2.
In Table 1, changed the study days 
for screening from -10 (window of 
± 3 days) to -13 to -1 (no window).
Removed minimum interval of 
7 days between Visit 1 and 2, so 
that Visit 2 can start as soon as 
results from the screening 
assessments and blood sampling 
are available.
1.3 (Schedule of Activities)
Table 1 (Schedule of Activities 
During the Screening Period and 
Initiation and Run-in Phases)
4.1.2 (Initiation Phase [Up to 
72 hours])
4.1.3 (Run-in Phase [3 months/up 
to Day 90])
Removed requirement for 
participants who are 
hyperkalaemic at Visit 2 (Day 1) 
to have S-K measured at 24 hours 
post Day 1 dose (Visit 3a) during 
the initiation phase.
Removed Visit 3a from the 
Schedule of Activities.
NOTE: The original visit 
numbering will be retained.
To reduce participant and site 
burden.
1.3 (Schedule of Activities)
Table 2 (Schedule of Activities 
During the Maintenance Phase and 
Follow-up)
Added footnote that “Week refers 
to the end of the week, eg: Week 6 
is the end of the sixth week (ie, 
Day 43 [6 weeks × 7 days + 1 = 
43]); Week 12 is the end of the 
twelfth week (ie, Day 85 
[12 weeks × 7 days + 1 = 85]), 
etc.”
Clarification.
3 (Objectives and Endpoints)
Table 4 (Objectives and 
Endpoints)
4.2.2.1 (Rationale for the Primary 
Endpoints)
9.1 (Statistical Hypotheses)
The primary endpoints are co-
primary.
In Table 4, added footnote that 
“Both of the primary endpoints 
must be met in order for the study 
to be declared successful, ie, co-
primary endpoints”.
In Section 9.1, revised as follows 
(bold indicates added text and 
strikethrough indicates deleted 
text):
“Two co-primary hypotheses 
(corresponding to the evaluation of 
the difference in total and chronic 
eGFR slope, respectively) are 
defined in the study. A fixed 
sequence MTP will be applied to 
the family of the primary 
hypotheses, with the hypothesis 
corresponding to difference in 
total slopes tested first and the 
Total eGFR slope (measurements 
starting at randomisation) and 
chronic eGFR slope 
(measurements starting at 12 
weeks after randomisation) will be 
evaluated as co-primary endpoints 
to mitigate the potential impact of 
the acute pharmacodynamic 
effects on efficacy assessments. 
The study will be deemed 
successful only if statistically 
significant differences in BOTH 
total and chronic eGFR slopes are 
demonstrated (using a 2-sided test 
and a significance level of 0.05 for 
both hypotheses).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
5 of 125
Section number and name
Description of change
Brief rationale
hypothesis corresponding to the 
difference in chronic slopes tested 
second. Provided both of the
primary hypotheses are rejected, 
the testing will proceed to the 
secondary hypotheses. Similar to 
the primary hypotheses, a A fixed 
sequence MTP will also be applied 
to the family of all secondary 
hypotheses, with the order in the 
sequence following the order 
specified in Table 4.”
4.2.3 (Rationale for Placebo 
Control During the Maintenance 
Phase)
Moved text in second paragraph to 
last paragraph and updated to 
“Potentially beneficial 
renoprotective treatments, 
including SGLT2 inhibitors (ie, 
dapagliflozin and canagliflozin), 
finerenone, or any other 
medications in these 2 classes 
that are approved for CKD, will 
not be withheld in the study” (bold 
indicates added text).
Moved text to last paragraph for 
better readability.
Participants will receive SoC for 
any underlying medical conditions 
during the study. Dapagliflozin, 
canagliflozin, and finerenone are 
currently approved for CKD. 
Additionally, any other such 
medications approved for CKD 
subsequent to this amendment are 
allowed.
5.1 (Inclusion Criteria)
Criterion 2: Removed sentence 
specific to Japan, “For participants 
< 20 years of age and enrolled in 
Japan, a written informed consent 
should be obtained from the 
participant and his or her legally 
acceptable representative.”
The age of adulthood in Japan is 
now 18 years, so consent of the 
participant’s legally acceptable 
representative is no longer 
required.
5.1 (Inclusion Criteria)
8.1.1 (Assessments based on 
Laboratory Analyses; Table 9 
[Laboratory Efficacy Variables])
9.4.2.1 (Primary Endpoint[s])
11 (References)
For inclusion in the study 
(criterion 3) and for the analysis of 
the primary endpoint, the race 
agnostic CKD-EPI eGFR formula 
(Delgado et al 2022, Inker et al 
2021) will be used.
The eGFR will also be calculated 
according to the original race 
adjusted CKD-EPI formula (Levey 
et al 2009) and may be used for 
sensitivity or supportive analyses
Revised per current 
recommendation of the NKF-ASN 
Task Force to use formulas that do 
not include race modifiers to 
estimate kidney function.
Since there is a change in the 
eGFR CKD-EPI formula during 
the study, eGFR will be calculated 
using both formulas: the race 
agnostic CKD-EPI formula 
(Delgado et al 2022, Inker et al 
2021) for the primary analysis and 
the race adjusted CKD-EPI 
formula (Levey et al 2009) for 
sensitivity or supportive analyses.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
6 of 125
Section number and name
Description of change
Brief rationale
Added literature references of 
Delgado et al 2022 and Inker et al 
2021 to support CKD-EPI race 
agnostic eGFR formula.
5.1 (Inclusion Criteria)
Criterion 4 for UACR: Added “If 
the first sample does not fulfil 
eligibility criteria, a second sample 
can be obtained during the 
screening period; if so, the UACR 
measurement from the second 
sample must be within the 
eligibility range.”
To mitigate variability in UACR 
measurements.
5.1 (Inclusion Criteria)
Criterion 8: “If on an SGLT2 
inhibitor (ie, dapagliflozin and 
canagliflozin), finerenone, or 
any other medications in these 
2 classes that are approved for 
CKD, the dose must have been 
stable for 3 months prior to 
screening (Visit 1)” (bold indicates 
added text).
Dapagliflozin, canagliflozin, and 
finerenone are currently approved 
for CKD. Criterion also applies to 
any other such medications 
approved for CKD subsequent to 
this amendment.
5.2 (Exclusion Criteria)
Criterion 3: Revised to 
“Participants with a known 
history of systolic blood pressure 
≥160 mmHg or diastolic blood 
pressure ≥95 mmHg (confirmed 
by repeated measurement), within 
2 weeks prior to screening 
(Visit 1) are excluded. In 
addition, any participant with 
systolic blood pressure 
≥160 mmHg or diastolic blood 
pressure ≥95 mmHg as 
measured at screening (Visit 1) 
and confirmed by repeated 
measurement is excluded. 
Participants may be rescreened 
once blood pressure is controlled” 
(bold indicates added text; 
strikethrough indicates deleted 
text).
Revised to clarify exclusion of 
participants for uncontrolled blood 
pressure, ie, within 2 weeks prior 
to screening (history) or as 
measured at screening. Both 
conditions must not be met for 
participants to be eligible for the 
study.
5.2 (Exclusion Criteria)
Criterion 8: Removed exclusion of 
“Type 1 diabetes mellitus”.
NOTE: The original numbering of 
the exclusion criteria will be
retained. (ie, 7, 9, 10, 11, etc).
To allow inclusion of Type 1 
diabetes mellitus population in the 
study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
7 of 125
Section number and name
Description of change
Brief rationale
5.2 (Exclusion Criteria)
Criterion 22: Revised to “Treated 
with an MRA not approved for 
CKD within 3 months prior to 
screening (Visit 1)” (bold indicates 
added text). 
Finerenone, a non-steroidal MRA, 
is approved for CKD. Participants 
on finerenone or any other MRAs 
approved for CKD are eligible for 
the study provided the dose is 
stable as per change to inclusion 
criterion 8.
5.2 (Exclusion Criteria)
Criterion 26: Added “Note: For 
participants taking a fixed 
combination of an ACEi or ARB 
with another agent (eg, calcium 
blockers or diuretics) as SoC, the 
investigator must make a judgment 
that it will be safe and efficacious 
for such participants to change to 
the study ACEi or ARB and to the 
other drug as separate agents.”
All participants are required to 
switch to the study ACEi or ARB 
during the run-in phase. This note 
was added for investigator 
awareness to consider participants 
who are on the fixed combination 
of an ACEi or an ARB with 
another agent (eg, calcium 
blockers or diuretics) as SoC. Such 
participants are not excluded 
unless, based on investigator 
judgment, switching to the study 
ACEi or ARB and the other drug 
(eg, calcium blockers or diuretics) 
as separate agents (rather than a 
fixed combination) during the 
run-in phase could be a safety risk 
or may not be as efficacious.
6.1.1 (Investigational Products; 
Table 5 [Investigational Products])
Added lisinopril 2.5 and 10 mg 
and valsartan 80 mg unit dose 
strength(s) and a footnote that “In 
countries where lisinopril and 
valsartan will be supplied centrally 
through AstraZeneca, specific unit 
dose strengths will be confirmed 
to the countries”.
To allow sourcing of lisinopril and 
valsartan at additional unit dose 
strengths.
6.1.1 (Investigational Products; 
Table 5 [Investigational Products])
Added footnote for single dose 
SZC and placebo “Further 
guidance and information are 
provided in the Pharmacy 
Manual”.
Added footnote for lisinopril and 
valsartan dosage levels that “the 
QD dose can be divided as long as 
the total daily dose is the 
prescribed dose, eg, valsartan 
320 mg QD is equivalent to 
valsartan 160 mg BID.”
For SZC dosage level, revised to:
Clarification

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
8 of 125
Section number and name
Description of change
Brief rationale
“Initiation Phase: S-K > 5 to ≤ 6.5 
mmol/L (measured by L-Lab): 
Single dose contains 10 g SZC that 
should be suspended in 45 mL of 
water and. The 10 g SZC single 
dose should be administered TID 
for up to 72 hours until 
normokalaemic (S-K 3.5-5.0 
mmol/L); the total daily dose is 
30 g SZC” (bold indicates added 
text; strikethrough indicates 
deleted text).
6.3.1 (The Process of Enrolment 
and Randomisation)
Added a third stratification factor 
for randomisation: SGLT2 
inhibitor and/or finerenone use at 
randomisation.
To mitigate any baseline 
imbalance in the use of these 
agents.
6.5.1 (Prohibited and Restricted 
Concomitant Medication)
Table 7 (Examples of Drugs that 
Should be Taken 2 hours Before or 
After SZC/Placebo to Avoid 
Possible Raised Gastric pH Drug 
Interactions)
Added section for “Interaction 
with Other Medicinal Products and 
Other Forms of Interaction” with 
subsections for “Effect of Other 
Medicinal Products on SZC” and 
“Effect of SZC on Other 
Medicinal Products”. Updated text 
in subsection “Effect of SZC on 
Other Medicinal Products”, 
including addition of tacrolimus.
In Table 7, removed the following 
from the list of examples:
•
Anti-HIV drugs of 
amprenavir, delavirdine, and 
fosamprenavir
•
Antibiotics
•
antiepileptics
•
antimycotics of ioriconazole.
•
bisphosphonates
•
cardiac glycosides
•
immunosuppressants
•
intestinal anti-inflammatory 
agents
•
Iron preparations;
•
Tyrosine kinase inhibitors of 
acalabrutinib, gefitinib, 
pazopanib
In Table 7, changed 
“antimyocotics” to “azole 
antifungals”.
The list of examples in Table 7 is 
not exhaustive. The format, 
structure, and content of this 
section were updated to align with 
the SZC Core Data Sheet dated 22 
March 2022.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
9 of 125
Section number and name
Description of change
Brief rationale
8.2.2 (Vital Signs)
Removed requirement for 3 blood 
pressure readings separated by 
2 minutes and for additional 
readings if first 2 readings differ 
by more than 5 mmHg.
To simplify the vital sign 
descriptions in the protocol.
9.2 (Sample Size Determination)
Added subsection for possible 
causes of missing data during the 
randomised treatment phase.
For clarity, to include details on 
the expected reasons for missing 
data, as well as a high-level 
description of the approaches for 
handling missing data in the 
analysis (with further details to be 
provided in the SAP)
9.4.2.1 (Primary Endpoint[s])
Removed the option of switching 
to a hypothetical intercurrent event 
strategy with respect to initiation 
of long-term potassium lowering 
agents.
This intercurrent event strategy
will not be used for the primary 
efficacy analysis.
9.4.2.1 (Primary Endpoint[s])
Revised text to include additional 
details for covariance matrix, for 
sensitivity and subgroup analyses,
and graphical illustrations of 
eGFR profiles over time.
For clarity, to include a high-level 
plan for sensitivity and subgroup 
analyses in the protocol (with 
further details to be provided in 
the SAP).
Appendix A 7 (Data Quality 
Assurance)
Last bullet, revised retention 
period for records and documents 
to 25 years (previously 15 years).
To align with updated 
AstraZeneca global retention and 
disposal schedule.
Appendix B2 (RAASi Dose 
Equivalence Table)
Added losartan starting dose of 
25 mg and lisinopril starting dose 
of 2.5 mg to the list of examples in 
the footnote for doses that may 
differ per local labels.
Clarification.
Appendix B3 (Definitions of 
RAASi Adequate Dose)
Added footnote for adequate daily 
dose that “Normokalaemic 
participants with hypertension or 
primary glomerular diseases with 
nephrotic range proteinuria 
(> 3.5 g/24 hours) who are at high 
risk of hyperkalaemia, not taking 
maximal RAASi doses as per local 
label but currently receiving doses 
in the range considered adequate 
in this table can be included in the 
normokalaemic cohort if in the 
investigator’s judgment the current 
RAASi dose is not optimal for 
their condition. In these 
To provide flexible wording so 
that such participants, eg, those 
with nephrotic range proteinuria 
who can benefit from higher doses 
of RAASi are not excluded 
because they are normokalaemic 
while receiving a dose within 
adequate range (but not maximal).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
10 of 125
Section number and name
Description of change
Brief rationale
participants, it is expected that 
RAASi doses will be up-titrated to 
maximal during the run-in phase.
Appendix B3 (Definitions of 
RAASi Adequate Dose)
Added footnote for adequate daily 
dose column that “Where a range 
is indicated, any daily dose within 
that range is considered an 
adequate daily dose.”
Clarification.
Appendix C (Instructions for Use 
of SZC/Placebo for Management 
of Serum Potassium During the 
Run-in and Maintenance Phases)
Added to the footnote to recheck 
S-K within 2 weeks if RAASi 
therapy is restarted at any dose or 
increased as per KDIGO 2020.
Clarification.
ACEi angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ASN, American Society of 
Nephrology; BID, twice daily; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology 
Collaboration; eGFR, estimated glomerular filtration rate; ESKD, end stage kidney disease; HIV, human 
immunodeficiency virus; IND, investigational new drug; MRA, mineralocorticoid receptor antagonist; 
NICE, National Institute for Health and Care Excellence; MTP, multiple testing procedure; NKF, National 
Kidney Foundation; QD, once daily; RAASi, renin-angiotensin-aldosterone system inhibitor SGLT2, sodium-
glucose cotransporter-2; SAP, statistical analysis plan; S-K, serum potassium; SoC, standard of care;
SZC, sodium zirconium cyclosilicate; TID, three times daily; UACR, urine albumin-to-creatinine ratio.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
11 of 125
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS.................................................................................................... 11
LIST OF FIGURES ............................................................................................................ 14
LIST OF TABLES.............................................................................................................. 14
LIST OF APPENDICES..................................................................................................... 14
1
PROTOCOL SUMMARY................................................................................ 16
1.1
Synopsis ........................................................................................................... 16
1.2
Schema............................................................................................................. 25
1.3
Schedule of Activities....................................................................................... 25
2
INTRODUCTION............................................................................................ 31
2.1
Study Rationale ................................................................................................ 31
2.2
Background ...................................................................................................... 31
2.2.1
Background Information on CKD ..................................................................... 31
2.2.2
Background Information on SZC ...................................................................... 32
2.2.3
Rationale for the Use of SZC in Patients with CKD .......................................... 33
2.2.3.1
Facilitation of RAASi Treatment Optimisation ................................................. 33
2.2.3.2
Increased Serum Bicarbonate............................................................................ 33
2.2.3.3
Correction of Hyperkalaemia with Maintenance of Normokalaemia and 
Reduction in Aldosterone.................................................................................. 34
2.2.3.4
Estimated GFR in Long-term Studies of SZC.................................................... 34
2.3
Benefit/Risk Assessment................................................................................... 34
2.3.1
Risk Assessment............................................................................................... 34
2.3.2
Benefit Assessment........................................................................................... 36
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 36
3
OBJECTIVES AND ENDPOINTS................................................................... 37
4
STUDY DESIGN ............................................................................................. 38
4.1
Overall Design.................................................................................................. 38
4.1.1
Screening Period (Up to 13 Days)..................................................................... 39
4.1.2
Initiation Phase (Up to 72 hours)....................................................................... 39
4.1.3
Run-in Phase (3 months/up to Day 90).............................................................. 40
4.1.4
Maintenance Phase, Double-blind, Parallel Groups (24 months)/104 weeks)..... 41
4.1.5
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 42
4.2
Scientific Rationale for Study Design ............................................................... 42
4.2.1
Rationale for the Study Population.................................................................... 42
4.2.2
Rationale for the Endpoints............................................................................... 43
4.2.2.1
Rationale for the Primary Endpoints ................................................................. 43
4.2.2.2
Rationale for the Secondary Endpoints.............................................................. 44

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
12 of 125
4.2.3
Rationale for Placebo Control During the Maintenance Phase........................... 44
4.3
Justification for Dose........................................................................................ 45
4.3.1
Justification for Dose of SZC............................................................................ 45
4.3.2
Justification for Dose of Lisinopril and Valsartan.............................................. 45
4.4
End of Study Definition.................................................................................... 46
5
STUDY POPULATION ................................................................................... 46
5.1
Inclusion Criteria .............................................................................................. 46
5.2
Exclusion Criteria ............................................................................................. 48
5.3
Lifestyle Considerations ................................................................................... 49
5.3.1
Meals and Dietary Restrictions ......................................................................... 49
5.3.2
Caffeine, Alcohol, and Tobacco........................................................................ 50
5.3.3
Contraception ................................................................................................... 50
5.4
Screen Failures ................................................................................................. 50
6
STUDY INTERVENTION............................................................................... 51
6.1
Study Intervention(s) Administered .................................................................. 51
6.1.1
Investigational Products.................................................................................... 51
6.2
Preparation/Handling/Storage/Accountability ................................................... 54
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 54
6.3.1
The Process of Enrolment and Randomisation .................................................. 54
6.3.2
Break of the Blind............................................................................................. 55
6.3.3
Potentially Treatment-revealing Data................................................................ 56
6.4
Study Intervention Compliance......................................................................... 56
6.5
Concomitant Therapy........................................................................................ 57
6.5.1
Restricted Concomitant Medication .................................................................. 57
6.5.2
Rescue Medication............................................................................................ 58
6.5.3
COVID-19 Vaccination .................................................................................... 59
6.6
Dose Modification ............................................................................................ 59
6.6.1
Monitoring Lisinopril/Valsartan Titration During the Run-in and Maintenance 
Phases............................................................................................................... 60
6.6.2
Lisinopril/Valsartan Dosing Upon Entry to and During the Run-in Phase.......... 60
6.6.3
Strategy for Lisinopril/Valsartan Up-Titration During the Run-in Phase Visits.. 61
6.6.4
Use of SZC/Placebo for Management of Serum Potassium Immediately after 
Randomised Withdrawal (Up to Week 6 of Maintenance Phase)....................... 63
6.6.5
Additional Unscheduled Visits for Titration of Lisinopril/Valsartan Doses 
During the Run-in and Maintenance Phases ...................................................... 65
6.7
Intervention After the End of the Study............................................................. 65
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 65
7.1
Discontinuation of Study Intervention............................................................... 65
7.1.1
Permanent Discontinuation of Study Intervention ............................................. 65
7.1.1.1
Procedures for Permanent Discontinuation of Study Intervention...................... 66
7.1.2
Temporary Discontinuation............................................................................... 68

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
13 of 125
7.1.3
Procedures for Erroneously Dosed or Randomised Participants......................... 68
7.2
Participant Withdrawal from the Study ............................................................. 69
7.3
Lost to Follow up.............................................................................................. 69
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 70
8.1
Efficacy Assessments........................................................................................ 70
8.1.1
Assessments Based on Laboratory Analyses ..................................................... 70
8.1.2
Other Efficacy Assessments.............................................................................. 71
8.2
Safety Assessments........................................................................................... 71
8.2.1
Physical Examinations...................................................................................... 72
8.2.2
Vital Signs........................................................................................................ 72
8.2.3
Electrocardiograms........................................................................................... 72
8.2.4
Clinical Safety Laboratory Assessments............................................................ 73
8.2.4.1
Clinical Safety Central Laboratory Assessments ............................................... 73
8.2.4.2
Clinical Safety Local Laboratory Assessments.................................................. 74
8.3
AEs and SAEs .................................................................................................. 75
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 75
8.3.2
Follow-up of AEs and SAEs ............................................................................. 76
8.3.3
Causality Collection.......................................................................................... 76
8.3.4
AEs Based on Signs and Symptoms.................................................................. 77
8.3.5
AEs Based on Examinations and Tests.............................................................. 77
8.3.6
Reporting of SAEs............................................................................................ 78
8.3.7
Pregnancy......................................................................................................... 78
8.3.7.1
Maternal Exposure............................................................................................ 78
8.3.7.2
Paternal Exposure............................................................................................. 79
8.3.8
Medication Error............................................................................................... 79
8.4
Overdose .......................................................................................................... 79
8.4.1
SZC or SZC/Placebo......................................................................................... 79
8.4.2
Lisinopril/Valsartan .......................................................................................... 80
8.5
Human Biological Samples............................................................................... 80
8.5.1
Pharmacokinetics.............................................................................................. 80
8.5.2
Immunogenicity................................................................................................ 81
8.5.3
Pharmacodynamics........................................................................................... 81
8.6
Human Biological Sample Biomarkers ............................................................. 81
8.7
Optional Genomics Initiative Sample................................................................ 81
8.8
Medical Resource Utilisation and Health Economics ........................................ 81
8.9
Other Assessments............................................................................................ 81
8.9.1
Local Laboratory Measurements....................................................................... 81
8.9.2
Demography and Medical History..................................................................... 82
9
STATISTICAL CONSIDERATIONS............................................................... 82
9.1
Statistical Hypotheses....................................................................................... 82
9.2
Sample Size Determination............................................................................... 82
9.3
Populations for Analyses .................................................................................. 84

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
14 of 125
9.4
Statistical Analyses........................................................................................... 84
9.4.1
General Considerations..................................................................................... 84
9.4.2
Efficacy ............................................................................................................ 84
9.4.2.1
Co-primary Endpoint(s).................................................................................... 85
9.4.2.2
Secondary Endpoint(s)...................................................................................... 87
9.4.3
Safety ............................................................................................................... 87
9.5
Interim Analyses............................................................................................... 88
9.6
Data Monitoring Committee ............................................................................. 88
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 88
11
REFERENCES............................................................................................... 121
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 25
LIST OF TABLES
Table 1
Schedule of Activities During the Screening Period and Initiation and 
Run-in Phases.......................................................................................... 26
Table 2
Schedule of Activities During the Maintenance Phase and Follow-up ...... 28
Table 3
Risk Assessment of SZC and the Use of SZC with Lisinopril or 
Valsartan as Background Interventions .................................................... 35
Table 4
Objectives and Endpoints......................................................................... 37
Table 5
Investigational Products........................................................................... 52
Table 6
Restricted Medications............................................................................. 57
Table 7
Examples of Drugs that Should be Taken 2 hours Before or After 
SZC/Placebo to Avoid Possible Raised Gastric pH Drug Interactions ...... 58
Table 8
Lisinopril and Valsartan Dose Titration Steps.......................................... 61
Table 9
Laboratory Efficacy Variables ................................................................. 70
Table 10
Central Laboratory Safety Variables ........................................................ 74
Table 11
Local Laboratory Safety Variables........................................................... 75
Table 12
Populations for Analysis .......................................................................... 84
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 89

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
15 of 125
Appendix B
RAASi Therapy Considerations for Inclusion into the Study and Dosing 
of Lisinopril and Valsartan....................................................................... 94
Appendix C
Instructions for Use of SZC/Placebo for Management of Serum 
Potassium During the Run-in and Maintenance Phases ............................ 98
Appendix D
Drug Interactions for Lisinopril and Valsartan ....................................... 101
Appendix E
Temporary Irbesartan Use in the Event of a Local Valsartan Shortage ... 104
Appendix F
Management of Study Procedures During the COVID-19 Pandemic...... 110
Appendix G
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 113
Appendix H
Handling of Human Biological Samples ................................................ 117
Appendix I
Abbreviations ........................................................................................ 119

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
16 of 125
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Phase 3, International, Randomised, Double-blind, Placebo-controlled Study to Evaluate the 
Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in 
Participants with CKD and Hyperkalaemia or at Risk of Hyperkalaemia
Short Title:
Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in 
Participants with CKD and Hyperkalaemia or at Risk of Hyperkalaemia
Rationale:
Current clinical practice guidelines for patients with CKD recommend renin-angiotensin-
aldosterone system inhibitor (RAASi) therapy, eg, angiotensin converting enzyme inhibitor 
(ACEi)/angiotensin II receptor blocker (ARB) therapy, as standard of care (SoC) to preserve 
kidney function and slow disease progression (KDIGO 2013, KDIGO 2020, NICE 2021, NKF 
2012). However, hyperkalaemia limits the use of adequate ACEi/ARB therapy. The efficacy 
of sodium zirconium cyclosilicate (SZC) in correcting hyperkalaemia and maintaining 
normokalaemia long-term, irrespective of underlying morbidity (including CKD), and its 
favourable safety profile have been well demonstrated in the clinical programme. It is 
proposed that an efficacious and safe potassium binder such as SZC could facilitate the use of 
ACEi/ARB medications at doses that confer kidney outcomes benefit. Unlike other available 
treatments that bind potassium in the gastrointestinal tract (sodium polystyrene sulfonate, 
calcium polystyrene sulfonate, and patiromer), SZC has a high specificity for binding 
potassium ions and it possesses clinically important advantages over the currently available 
treatment options for hyperkalaemia. It is reasonable to assume that enabling the use of 
optimal ACEi/ARB therapy by SZC would confer renal benefit in treated patients. Further, the 
known effects of SZC on serum potassium (S-K), bicarbonate, and aldosterone levels would 
contribute to renoprotection.
This study will investigate whether SZC, as adjunct to ACEi/ARB therapy (lisinopril or 
valsartan), is superior to placebo in slowing CKD progression (assessed as the reduction in 
participant’s expected estimated glomerular filtration rate [eGFR] decline over time) in 
participants with hyperkalaemia or at high risk of hyperkalaemia.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
17 of 125
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in slowing CKD progression, 
assessed as the reduction in participant’s expected 
eGFR decline over time
Co-primary b
•
Total slope: eGFR measurements starting at 
randomisation
•
Chronic slope: eGFR measurements starting at 
12 weeks after randomisation
Secondary
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing the incidence of the 
composite of kidney failure outcomes comprising: 
sustained ≥40% decline in eGFR, onset of ESKD, 
and death from kidney failure
•
Time from randomisation to the first occurrence 
of any component in the composite of
∀
Sustained ≥ 40% decline in eGFR c
∀
Onset of ESKD (kidney transplantation, 
maintenance dialysis, or sustained low 
eGFR) c
∀
Death from kidney failure c
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing the incidence of 
lisinopril/valsartan dose decrease, in participants on 
lisinopril/valsartan at randomisation
•
Time from randomisation to first 
lisinopril/valsartan dose decrease
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing albuminuria
•
UACR measurements at scheduled visits after 
randomisation
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in increasing serum bicarbonate 
levels
•
Serum bicarbonate measurements at scheduled 
visits after randomisation
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo on maintenance of 
normokalaemia
•
S-K level classification; normal 
(3.5-5.0 mmol/L) or non-normal (< 3.5 or 
> 5.0 mmol/L) at scheduled visits after 
randomisation

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
18 of 125
Objectives
Endpoints
Safety
To assess the safety and tolerability of treatment with 
SZC, as adjunct to ACEi/ARB therapy (lisinopril or 
valsartan a) as compared to placebo
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical laboratory variables, 
and ECGs
Assessments related to AEs cover:
•
Occurrence/frequency
•
Relationship to study intervention as assessed 
by the investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of study 
intervention
a
In case of a local market valsartan shortage, irbesartan will be temporarily used instead.
b
Both of the primary endpoints must be met in order for the study to be declared successful, ie, co-primary 
endpoints.
c
Levin et al 2020; see Section 8.1.2.
ACEi, angiotensin converting enzyme inhibitor; AE, adverse event; ARB, angiotensin II receptor blocker; 
CKD, chronic kidney disease; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ESKD, end 
stage kidney disease; SAE, serious adverse event; S-K, Serum potassium; SZC, Sodium zirconium cyclosilicate; 
UACR, urine albumin-to-creatinine ratio.
Overall Design
This is a Phase 3, international, randomised withdrawal, double-blind, parallel-group, 
placebo-controlled study, to evaluate the effect of SZC as adjunct to RAASi therapy (lisinopril 
or valsartan) in slowing CKD progression in participants with CKD and hyperkalaemia or at 
risk of hyperkalaemia.
Specifically, the study will include participants with hyperkalaemia (S-K > 5.0 to 
≤6.5 mmol/L by central laboratory) who are on adequate or limited RAASi therapy due to 
hyperkalaemia, and participants with normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L by central 
laboratory) who are on limited RAASi therapy due to high risk of hyperkalaemia. High risk of 
hyperkalaemia is defined as (1) participants with a previous medical history or record of 
hyperkalaemia within the prior 24 months who are on limited RAASi therapy despite 
indication in CKD; (2) participants in whom RAASi therapy is indicated in CKD but are on 
limited RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L; and (3) participants in whom 
RAASi therapy has been discontinued or reduced to suboptimal doses because of 
hyperkalaemia.
The study will be conducted at up to 250 study sites in up to 16 countries.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
19 of 125
Screening Period (Up to 13 days)
During the screening period, after signed informed consent is obtained, data required for 
determination of eligibility for the study will be collected and inclusion/exclusion criteria 
evaluated. Participants who fulfil the study eligibility criteria may proceed to the initiation 
phase. Participants who do not fulfil the study eligibility criteria are screen failures and may 
be rescreened once.
Initiation Phase (Up to 72 hours)
No changes will be made to the ACEi/ARB therapy during the initiation phase. The initial 
dosing of SZC will be based on the participant’s S-K as measured by local laboratory on the 
same day as, or within 24 hours prior to, Day 1 (Visit 2); the S-K results MUST be available 
before any other Visit 2 procedures/assessments are performed.
Participants who are hyperkalaemic (S-K > 5.0 to ≤ 6.5 mmol/L [local laboratory]) will 
receive 10 g SZC three times daily (TID) starting on Day 1 (Visit 2). S-K will be measured by 
local laboratory at 48 hours (Day 3; Visit 3b) and subsequently at 72 hours (Day 4; Visit 3c) if 
normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L) has not been previously achieved.
In case the S-K result is not available for up to 24 hours after sample collection, the 
participant will be notified by phone as soon as possible after the S-K results are available, 
and the following instructions should be followed for SZC:
!
Day 3 (Visit 3b): if the 48-hour S-K result is not available, the participant will take SZC 
10 g TID for one additional day.
!
Day 4 (Visit 3c): if the 48-hour S-K is > 5 to ≤ 6.5 mmol/L and the 72-hour S-K is not
available, the participant will take SZC 10 g once daily (QD) for one day.
If normokalaemia is achieved after 48 or 72 hours of treatment with SZC, the participant will 
proceed to the run-in phase, during which SZC dosing will be initiated at 10 g QD. 
Participants who do not achieve normokalaemia after 72 hours of treatment will undergo a 
follow-up visit at 7 (± 2) days after the participant’s last dose and exit the study.
Participants who are normokalaemic (S-K ≥ 3.5 to ≤ 5.0 mmol/L [local laboratory]) will 
receive SZC 5 g QD starting on Day 1 (Visit 2) for 48 hours. S-K will be measured by local 
laboratory at 48 hours (Day 3; Visit 3b). In case the S-K result is not available for up to 
24 hours after sample collection, the participant will continue with a third day of SZC 5 g QD 
and will be notified by phone as soon as possible after the 48-hour S-K results are available.
If normokalaemia is maintained after 48 hours of treatment with SZC, the participant will 
proceed to the run-in phase, continuing to receive 5 g QD. Participants who do not maintain 
normokalaemia after 48 hours of treatment will undergo a follow-up visit at 7 (± 2) days after 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
20 of 125
the participant’s last dose and exit the study. NOTE: Visit 3c is not applicable for participants 
who are normokalaemic at Visit 2.
Run-in Phase (3 months/up to Day 90)
As soon as possible after the participant is confirmed to be normokalaemic at the end of the 
initiation phase (based on local laboratory S-K results from Visits 3b or 3c), the participant 
will enter the run-in phase (Visit 3d).
Participants will receive open-label SZC and lisinopril or valsartan during the run-in phase.
Upon entering the run-in phase:
!
Participants who are not on ACEi or ARB therapy will be started on lisinopril or valsartan 
on the first day of the run-in phase. The choice of drug class is per investigator judgment. 
One of the following starting doses will be used: lisinopril 10 mg QD (or 5 mg QD if 
eGFR ≥10 to ≤30 mL/min/1.73m2 or if the participant is taking diuretics), or valsartan 
80 mg QD.
!
Participants who are on other ACEi or ARB therapy will be changed to lisinopril or 
valsartan on the first day of the run-in phase, keeping the corresponding drug class, ie, the 
ACEi will be changed to lisinopril and the ARB to valsartan. See Appendix B 1 and 
Appendix B 2 for guidance on the dosing equivalences among RAASi drugs and 
lisinopril/valsartan.
!
Participants who are on lisinopril or valsartan will continue treatment at the same dose.
A participant cannot receive both lisinopril and valsartan simultaneously and should not take 
any other ACEi or ARB concomitantly with lisinopril or valsartan.
The aim of the run-in phase is to increase ACEi or ARB therapy stepwise to their maximum 
doses using lisinopril or valsartan as per local labels (see Sections 6.6.2 and 6.6.3).
At the end of the run-in phase (Day 90 [±3 days], Visit 6a), S-K will be measured by local 
laboratory. The participant will continue to receive the current prescribed dose of SZC until 
the S-K result is available. If normokalaemic (S-K ≥3.5 to ≤5.0 mmol/L), the participant will 
proceed to the maintenance phase of the study. If not normokalaemic, the participant will 
undergo a follow-up visit at 7 (± 2) days after the participant’s last dose and exit the study.
NOTE: The study is designed to use valsartan as the ARB adjunct to SZC. However, if an 
actual shortage of valsartan in a local market jeopardises the ability of participants to enter or 
continue in the study, valsartan can be temporarily substituted with irbesartan until the 
shortage is resolved. See Appendix E for information on the use of irbesartan.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
21 of 125
Maintenance Phase, Double-blind, Parallel Groups (24 months/104 weeks)
As soon as possible after the participant is confirmed to be normokalaemic at the end of the 
run-in phase (based on local laboratory S-K results from Visit 6a), the participant will enter 
the maintenance phase. The date of randomisation is Day 1 of the maintenance phase 
(Visit 6b).
Participants will be randomised in a 1:1 ratio to receive either SZC or matching placebo. The 
starting dose of SZC/placebo will be the same dose as the last dose of SZC during the run-in 
phase. Lisinopril and valsartan will be continued at the same doses assigned at the end of the 
run-in phase.
Two safety visits will occur 2 and 7 (±1) days after randomisation and will include evaluation 
of S-K by local laboratory. The investigator must ensure that the choice of date for 
randomisation will allow for these 2 safety visits to occur 2 and 7 (±1) days after 
randomisation, respectively. Participants will then be monitored for approximately 24 months 
(through Week 104) for efficacy and safety assessments. A final safety follow-up visit will be 
conducted at Week 105, one week after the participant’s last dose, after which the participant 
will exit the study.
Disclosure Statement:
This is a treatment study with single arm open-label initiation and run-in phases followed by a 
randomised withdrawal maintenance phase with two parallel arms that is blinded to the 
participant, investigator, and Sponsor.
Number of Participants:
Approximately 3000 participants will be enrolled (screened) to achieve approximately 
1500 participants receiving at least one dose of SZC during the initiation phase, consequently 
leading to a target of 1360 participants randomly assigned to SZC or placebo.
Note that “Enrolled” refers to a participant’s, or their legally acceptable representative’s, 
agreement to participate in the study following completion of the informed consent process.
Intervention Groups and Duration:
A participant is expected to be in the study for approximately 28 months, which includes up to 
13 days for the screening period, 27 months for the intervention period, and 1 week for 
follow-up. The 27-month intervention period of the study consists of 3 phases, an initiation 
phase (up to 72 hours), a run-in phase (3 months/up to Day 90), and a maintenance phase 
(24 months/104 weeks).
The dose levels for SZC/placebo and lisinopril/valsartan that will be used in the study are:
!
SZC: 5 g SZC every other day (QOD) by mouth (PO) or 5, 10, or 15 g SZC QD PO

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
22 of 125
!
Placebo: 5 g placebo QOD PO or 5, 10, or 15 g placebo QD PO
!
Lisinopril: 5, 10, 20, or 40 mg QD PO
!
Valsartan: 40, 80, 160, 320 mg QD PO
See Section 6.6 for instructions on dose modification, including monitoring 
lisinopril/valsartan titration (Section 6.6.1) and management of abnormalities of S-K 
(Appendix C), lisinopril/valsartan dosing upon entry to and during the run-in phase 
(Section 6.6.2), strategy for lisinopril/valsartan up-titration during run-in phase visits 
(Section 6.6.3), use of SZC/placebo for management of S-K immediately after randomised 
withdrawal, ie, up to Week 6 of maintenance phase (Section 6.6.4), and additional 
unscheduled visits for titration of lisinopril/valsartan (Section 6.6.5).
Data Monitoring Committee:
An independent Data Monitoring Committee that is unblinded to treatment allocation will be 
responsible for safeguarding the interests of the participants throughout the study.
Statistical Methods
Statistical Hypotheses
Statistical testing will be performed for all primary and secondary hypotheses. In all cases, the 
null hypothesis will be that of no difference between the treatment arms (SZC vs placebo). 
The family-wise Type I error rate will be controlled in the strong sense over the families of the 
primary and the secondary hypotheses.
Two co-primary hypotheses (corresponding to the evaluation of the difference in total and 
chronic eGFR slope, respectively) are defined in the study. Provided both of the primary 
hypotheses are rejected, the testing will proceed to the secondary hypotheses. A fixed 
sequence MTP will be applied to the family of all secondary hypotheses, with the order in the 
sequence following the order specified in the Objectives and Endpoints table above.
Both of the co-primary hypotheses will be tested at a two-sided significance level of 0.05. In 
accordance with the fixed sequence MTP, significance for a hypothesis corresponding to a 
secondary endpoint will be declared if the corresponding two-sided p-value is smaller than 
0.05, provided that all other preceding hypotheses in the sequence have been rejected.
Sample Size Determination
To allow for up to 20% missing eGFR data, it is planned to randomise 1360 participants to 
SZC or placebo. Assuming a two-sided test of a difference in slopes based on a linear mixed 
model, with a two-sided significance level of 0.05, is performed, approximately 
1220 participants with complete eGFR data will provide a power of 91% for the evaluation of 
total slope. The power for the chronic slope will be approximately 85%. The evaluation of the 
chronic slope is assumed to start at 12 weeks. See Section 9.2 for further details including 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
23 of 125
assumptions for variability of eGFR measurements and missing data that form the basis of the 
sample size calculations.
Populations for analyses
Population/analysis set
Description
Enrolled
All participants who sign the ICF.
Safety analysis set, initiation 
phase (SAS-IP)
All participants receiving at least one dose of SZC during the initiation 
phase.
Safety analysis set, run-in 
phase (SAS-RIP)
All participants receiving at least one dose of SZC during the run-in phase.
Safety analysis set, 
maintenance phase (SAS-MP)
All randomised participants receiving at least one dose of SZC or placebo 
during the maintenance phase. Participants erroneously receiving incorrect 
SZC or placebo will be analysed according to the treatment arm they were 
randomised to.
Full analysis set (FAS)
All randomised participants.
ICF, informed consent form; SZC, Sodium zirconium cyclosilicate.
Efficacy:
The analysis of both primary and secondary efficacy endpoints will be performed according to 
the intention-to-treat principle and will be based on all randomised participants, regardless of 
whether they did or did not receive treatment or had any protocol deviations.
To evaluate both primary objectives, a linear mixed effects model will be used, with the eGFR 
values obtained at and after randomisation (total slope) and at and after 12-week visit (chronic 
slope) for a participant at a particular visit as the dependent variable. The following covariates 
will be included in the fixed effects part of the model:
!
Time since randomisation
!
Treatment
!
Time and treatment interaction
Other covariates, as appropriate, might also be included and will be specified in the Statistical 
Analysis Plan. In addition, 2 random effects, intercept and time since randomisation, will be 
incorporated within a participant, with an underlying assumption of an unstructured 
covariance matrix between the two. A covariance matrix that assumes independence for the 
distribution of the residuals within each participant, but allows for different variability for 
different time points, will be applied, with a more general structure (eg, unstructured) used if 
issues with the model fit are encountered. An unstructured covariance matrix will also be 
assumed for the distribution of the residuals within each participant. The null hypothesis of no 
difference between SZC and placebo will be tested by considering the fixed effect of time and 
treatment interaction term in the model above (ie, the difference in slopes between the 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
24 of 125
2 treatment arms). The estimates of the slopes obtained from the model, as well as the 
difference between the two, and the corresponding SD estimates, will be presented. For the 
difference, the two-sided 95% confidence intervals and p-values will also be provided.
A number of sensitivity analyses of the primary endpoints will be performed. These will 
include, but might not be limited to, the following:
!
A two-slope model (acute and chronic) with knot at 12 weeks post-randomisation (ie, 
using the same interval for the chronic slope as is utilised in the primary analysis). From 
this, estimates of the total and the chronic slope will be obtained. The purpose of this 
analysis is to evaluate the sensitivity of the results to the choice of approaching the 
primary objective via two separate models rather than a single combined one.
!
A series of two-slope models (acute and chronic) with varying position of knots (the 
times of connection between acute and chronic slopes) other than 12 weeks. The purpose 
of this analysis is to evaluate the impact of the choice of 12 weeks as the start of the 
chronic eGFR profile on the estimate of the treatment effect.
!
A shared parameter model that jointly models the eGFR profiles and time to ESKD or 
death. The purpose of this analysis is to evaluate the potential impact that the possibly 
informative drop-out caused by these 2 events has on the estimate of the effect of SZC.
!
A tipping point analysis to explore the potential impact of data that are missing due to 
participant being lost to follow-up or entering a modified follow-up that precludes 
collection of eGFR measurements.
!
A repeated measures model that includes the same covariates as the main analysis and 
utilises an unstructured (marginal) covariance matrix to reflect the dependence between 
observations obtained at different timepoints for the same participant.
!
Same model as the one utilised for the main analysis, where missing eGFR values will be 
imputed as follows: if a participant is considered to enter ESKD through initiation of 
dialysis or kidney transplant, but no corresponding eGFR value is available, this will be 
imputed to a value that is less than 15 mL/min/1.73m2.
In addition, graphical illustrations of eGFR profiles over time, eg, a scatter plot of eGFR 
values with a non-parametric smoothing curve in the respective treatment arm, will be 
provided to illustrate the plausibility of the assumption of a linear eGFR decline and the 
potential presence of acute effects.
The consistency of effect across subgroups defined by inclusion criterion 5 (Section 5.1) will 
be evaluated for the primary endpoint by obtaining effect estimates in each of these, along 
with the p-values for the test of the corresponding interaction. In addition, if the size of the 
subgroups allows, the subgroups in which the consistency of the main results will be evaluated 
will include, but might not be limited to the following: geographic region; diabetes at 
randomisation (yes/no); eGFR classification at randomisation; UACR classification at 
randomisation; adequate RAASi dose at screening (yes/no); adequate RAASi dose at 
randomisation (yes/no); CKD aetiology; SGLT2 inhibitor and/or finerenone use at 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
25 of 125
randomisation (yes/no). Further details of the subgroup analyses plan, including full 
specification of the groupings, will be provided in the SAP.
The eGFR will be calculated according to the race agnostic CKD-EPI formula (Delgado et al 
2022, Inker et al 2021) for the main analysis of the primary endpoint. The eGFR will also be 
calculated according to the original race adjusted CKD-EPI formula (Levey et al 2009) and 
may be used for sensitivity or supportive analyses.
Safety
Safety analyses will be performed separately for the different phases of the study using the 
3 safety sets defined above, as appropriate. Safety data will be presented primarily using 
descriptive statistics, by treatment arm and study phase.
1.2
Schema
The study design is presented in Figure 1.
Figure 1
Study Design
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; E, eligibility criteria met; 
n, number of participants; QD, once daily; QOD, every other day; R, randomisation; SZC, Sodium zirconium 
cyclosilicate; TID, three times daily.
1.3
Schedule of Activities
The schedule of activities (SoA) during the screening period and initiation and run-in phases 
of the study is presented in Table 1. The SoA during the maintenance phase and at the final 
follow-up visit is presented in Table 2.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
26 of 125
Table 1
Schedule of Activities During the Screening Period and Initiation and Run-in Phases
Study period/phase
Screening
Initiation a
Run-in b
Details in 
CSP section 
or appendix
Visit
1
2
3b
3c f
3d
4
5
6a
FU c
ED d
ESD e
Study day
-13 to -1
1
3
48h
4
72h
2, 3, 4, 
or 5
13
51
90
Window (days)
± 3
± 3
± 3
Informed consent prior to any study-specific 
procedures
X
5.1, A 3
Enrolment in IRT/RTSM
X
6.3
SZC accountability g
X h
X
X
X
X i
X i
X i
X i
6, 6.2, 6.3, 
6.4
Change to lisinopril/valsartan and assign dose
X
4.1.3, 6.6.2
B 1, B 2
Lisinopril/valsartan accountabilityg
X h
X
X
X
X i
X i
X i
6, 6.2, 6.3, 
6.4
Participant population
Inclusion/exclusion criteria
X
5.1, 5.2
Demography
X
8.9.2
Medical history
X
8.9.2
Height
X
8.2.1
Weight
X
X
X
X
8.2.1
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
6.5
AEs and other safety evaluations
AEs/SAEs
X j
X
X
X
X
X
X
X
X
X
X
8.3
12-lead ECG
X
8.2.3
Vital signs (pulse and BP)
X
X
X
X
X
X
X
X
X
X
8.2.2
Complete physical examination
X
8.2.1
Brief physical examination
X
X
X
X
8.2.1

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
27 of 125
Table 1
Schedule of Activities During the Screening Period and Initiation and Run-in Phases
Study period/phase
Screening
Initiation a
Run-in b
Details in 
CSP section 
or appendix
Visit
1
2
3b
3c f
3d
4
5
6a
FU c
ED d
ESD e
Study day
-13 to -1
1
3
48h
4
72h
2, 3, 4, 
or 5
13
51
90
Window (days)
± 3
± 3
± 3
Laboratory assessments
Clinical chemistry, including eGFR (C-lab)
X
8.1.1, 8.2.4.1
Haemotology (C-lab)
X
8.2.4.1
S-K and S-Cr (L-lab) k
X l
X
X
X
X
X
X
X
X
8.9.1
UACR (C-lab)
X
8.1.1
Serum pregnancy test (POCBP only) (C-Lab)
X
8.2.4.1
a
See Section 4.1.2 for details on the initiation phase.
b
See Section 4.1.3 for details on the run-in phase.
c
For participants who discontinue treatment during the initiation or run-in phases, the FU visit will be done 7 (± 2) days after the last dose of SZC during the initiation or 
run-in phases.
d
For details regarding early treatment discontinuation, see Section 7.1.
e
For details regarding ESD, see Section 7.2.
f
Participants who are normokalaemic at Visit 2 (Day 1) will not attend Visit 3c.
g
Accountability refers to collection/dispensation/re-dispensation of study intervention (SZC and lisinopril/valsartan).
h
Dispensation only.
i
Collection only.
j
Only SAEs will be collected during screening.
k
S-K and S-Cr samples collected and analysed by local laboratory at study visits and as part of routine clinical practice can also be used to adjust doses of SZC and 
lisinopril/valsartan.
l
The S-K (L-lab) result must be available prior to performing any other assessments/procedures on Day 1. If necessary, the sample can be drawn 24 hours prior to Day 1 to 
ensure result is available on Day 1. If S-K is > 6.5 mmol/L or < 3.5 mmol/L, the participant is not eligible for the study (ie, screen failure) and must not be dosed (see 
Section 5.2, exclusion criterion 18 and Section 5.4).
AE, adverse event; BP, blood pressure; C-lab, central laboratory; CSP, clinical study protocol; ECG, electrocardiogram; ED, early discontinuation; ESD, early study 
discontinuation; eGFR, estimated glomerular filtration rate; FU, follow-up; h, hours; IRT/RTSM, interactive response technology/randomisation and trial supply management;
L-lab, local laboratory; POCBP, participants of childbearing potential; SAE, serious adverse event; S-Cr, serum creatinine; S-K, serum potassium; SZC, Sodium zirconium 
cyclosilicate; UACR, urine albumin-to-creatinine ratio.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
28 of 125
Table 2
Schedule of Activities During the Maintenance Phase and Follow-up
Study phase
Maintenance phase a
Details
in CSP 
section 
or 
append
ix
Visit
6b b
7 c
8 c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
FU
EDd
ESDe
Maintenance 
phase day/week
Day
Week f
1(R)
3
8
6
12
16
20
24
34
46
57
69
80
92
96
100
104
105
Window (days)
± 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 2
Randomisation in 
IRT/RTSM
X b
6.3
SZC/placebo 
accountability g
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
X i
X i
X i
6, 6.2, 
6.3, 6.4
Lisinopril/ 
valsartan 
accountability g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X i
X i
X i
6, 6.2, 
6.3, 6.4
Participant population
Weight
X
X
X
X
8.2.1
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
AEs and other safety evaluations
Complete 
physical 
examination
X
8.2.1
Brief physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.1
12-lead ECG
X
8.2.3
Vital signs (pulse 
and BP)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.2
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
29 of 125
Table 2
Schedule of Activities During the Maintenance Phase and Follow-up
Study phase
Maintenance phase a
Details
in CSP 
section 
or 
append
ix
Visit
6b b
7 c
8 c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
FU
EDd
ESDe
Maintenance 
phase day/week
Day
Week f
1(R)
3
8
6
12
16
20
24
34
46
57
69
80
92
96
100
104
105
Window (days)
± 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 2
Laboratory assessments
Clinical 
chemistry, 
including eGFR 
(C-lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1, 
8.2.4.1
Haematology 
(C-lab)
X
X
8.2.4.1
Clinical 
chemistry 
(L-lab) j
X
X
X
X
X
X
X
X
X
X
8.2.4.2, 
8.9.1
UACR (C-lab)
X
X
X
8.1.1
a
See Section 4.1.4 for details on the maintenance phase.
b
The participant must be confirmed normokalaemic (L-lab S-K) at the end of the run-in phase (Visit 6a) prior to randomisation. The date of randomisation is Day 1 of the 
maintenance phase. All assessments/procedures designated at this visit should be performed prior to randomising the subject, except for SZC/placebo and lisinopril/valsartan 
accountability.
c
The investigator must ensure that Visits 7 and 8 occur 2 and 7 (±1) days after randomisation, respectively.
d
For details regarding early treatment discontinuation, see Section 7.1.
e
For details regarding ESD, see Section 7.2.
f
Week refers to the end of the week, eg: Week 6 is the end of the sixth week (ie, Day 43 [6 weeks × 7 days + 1 = 43]); Week 12 is the end of the twelfth week (ie, Day 85 
[12 weeks × 7 days + 1 = 85]), etc.
g
Accountability refers to collection/dispensation/re-dispensation of study intervention (SZC/placebo and lisinopril/valsartan).
h
Dispensation only.
i
Collection only.
j
The minimum local laboratory clinical chemistry tests for safety monitoring will include sodium, potassium, bicarbonate, chloride (electrolytes) and urea nitrogen and 
creatinine (kidney). The S-K and S-Cr samples collected and analysed by local laboratory at study visits and as part of routine clinical practice can also be used to adjust 
doses of SZC/placebo and lisinopril/valsartan.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
30 of 125
AE, adverse event; BP, blood pressure; C-lab, central laboratory; CSP, clinical study protocol; ECG, electrocardiogram; ED, early discontinuation; ESD, early study 
discontinuation; eGFR, estimated glomerular filtration rate; FU, follow-up; IRT/RTSM, interactive response technology/randomisation and trial supply management; L-lab, local 
laboratory; POCBP, participants of childbearing potential; R, randomisation; SAE, serious adverse event; S-Cr, serum creatinine; S-K, serum potassium; SZC, Sodium zirconium 
cyclosilicate; UACR, urine albumin-to-creatinine ratio.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
31 of 125
2
INTRODUCTION
Sodium zirconium cyclosilicate, hereafter abbreviated as SZC, is an oral, non-polymer 
inorganic cation-exchanger that represents a novel therapy for the treatment of hyperkalaemia. 
SZC selectively captures potassium ions in exchange for sodium and hydrogen ions in the 
gastrointestinal tract, thereby reducing S-K concentration and removing potassium from the 
body through increased faecal excretion. SZC exerts its effect locally and it is not absorbed 
systemically. Clinical use is therefore not associated with systemic toxicity. The formulation 
developed for therapeutic use is an insoluble, free-flowing, odourless, tasteless, white powder 
for oral suspension.
2.1
Study Rationale
Current clinical practice guidelines for patients with CKD recommend RAASi therapy, eg, 
ACEi/ARB therapy, as SoC to preserve kidney function and slow disease progression 
(KDIGO 2013, KDIGO 2020, NICE 2021, NKF 2012). However, hyperkalaemia limits the 
use of adequate ACEi/ARB therapy. The efficacy of SZC in correcting hyperkalaemia and 
maintaining normokalaemia long-term, irrespective of underlying morbidity (including CKD),
and its favourable safety profile have been well demonstrated in the clinical programme. It is 
proposed that an efficacious and safe potassium binder such as SZC could facilitate the use of 
ACEi/ARB medications at doses that confer kidney outcomes benefit. Unlike other available 
treatments that bind potassium in the gastrointestinal tract (SPS, CPS, and patiromer), SZC 
has a high specificity for binding potassium ions and it possesses clinically important 
advantages over the currently available treatment options for hyperkalaemia. It is reasonable 
to assume that enabling the use of optimal ACEi/ARB therapy by SZC would confer renal 
benefit in treated patients. Further, the known effects of SZC on S-K, bicarbonate, and 
aldosterone levels would contribute to renoprotection.
This study will investigate whether SZC, as adjunct to ACEi/ARB therapy (lisinopril or 
valsartan), is superior to placebo in slowing CKD progression (assessed as the reduction in 
participant’s expected eGFR decline over time) in participants with hyperkalaemia or at high 
risk of hyperkalaemia.
2.2
Background
2.2.1
Background Information on CKD
Chronic kidney disease is highly prevalent and an important contributor to morbidity and 
mortality around the world (GBD Chronic Kidney Disease Collaboration 2020). 
Approximately 850 million people have kidney disease worldwide and 1.2 million people died 
from it in 2017 (Jager et al 2019). The number of people receiving kidney replacement 
therapy exceeds 2.5 million globally and is projected to double to 5.4 million by 2030. 
However, in many countries, there is a shortage of kidney replacement services. In the US, 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
32 of 125
37 million people (15% of the adult population) are estimated to have CKD and over 
726 thousand people are living with ESKD (CDC 2019).
People with CKD are at high risk for CV disease, and the presence of CKD often complicates 
treatment and worsens prognosis of CV disease. The SoC for slowing the progression of CKD 
includes treatment with ACEi/ARB therapy (KDIGO 2013, KDIGO 2020, NICE 2021, NKF 
2012).
2.2.2
Background Information on SZC
The efficacy of SZC in correcting hyperkalaemia and maintaining normokalaemia long term, 
irrespective of underlying morbidity, and its favourable safety profile have been well 
documented in the clinical programme.
SZC has a rapid onset of effect and maintains normokalaemia for up to 12 months. SZC is 
highly selective for potassium ions and its use is not associated with any clinically significant 
changes in the concentrations of other electrolytes such as calcium or magnesium. Clinical 
studies in participants with hyperkalaemia consistently demonstrated that initial treatment 
with SZC 10 g TID for 24 hours up to 72 hours resulted in clinically meaningful S-K 
reduction with a majority of participants achieving normokalaemia within 24 to 48 hours. 
Moreover, participants with higher baseline S-K levels had greater reductions in S-K levels. 
Onset of efficacy was rapid with S-K reduction observed as early as 1 hour after dose intake. 
After correction of hyperkalaemia, continued maintenance treatment for 28 days with SZC 
5 g, 10 g, or 15 g QD resulted in continued effective control of S-K within the normokalaemic 
range. The proportion of participants who remained normokalaemic at the end of treatment 
with SZC 5 g, 10 g, and 15 g QD increased dose-dependently (range: 71% to 85%) and was 
superior to placebo. In addition, long-term maintenance treatment of up to 12 months with 
SZC utilising a dose titration scheme with the starting dose of 5 g QD or 10 g QD, titrated to a 
maximum of 15 g QD or a minimum of 5 g QOD was effective in maintaining normokalaemia 
in the majority of participants.
The clinical studies included a broad population of participants with hyperkalaemia with a 
wide range of concomitant diseases and treatments including CKD, hypertension, heart 
failure, and/or diabetes, as well as concomitant RAASi treatment, recognizing that many 
patients with hyperkalaemia have a variety of underlying conditions; approximately 78% of 
participants in Study D9480C00002 (HARMONIZE Global; NCT02875834) and 66% of 
participants in Study ZS-004 (NCT02088073) had CKD and hyperkalaemia (Zannad et al 
2020, Kosiborod et al 2014). Overall, SZC reduced S-K and maintained normokalaemia 
independently of the underlying conditions associated with hyperkalaemia, demonstrating 
similar efficacy in participants with CKD, heart failure, and diabetes mellitus, as well as in 
participants receiving concomitant RAASi treatment. In addition, SZC demonstrated similar 
efficacy across demographic subgroups, including age, sex, race, and geographic region.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
33 of 125
Overall, the SZC clinical programme showed treatment with SZC to be safe and well 
tolerated. The overall rate of AEs and laboratory abnormalities were low and generally similar 
to those observed with placebo. Identified adverse drug reactions for SZC are oedema-related 
events (oedema, oedema peripheral, generalised oedema, fluid overload, fluid retention, 
hypervolaemia, localised oedema, and peripheral swelling) and hypokalaemia (see 
Section 2.3.1).
A detailed description of the chemistry, pharmacology, efficacy, and safety of SZC is 
provided in the Investigator’s Brochure.
2.2.3
Rationale for the Use of SZC in Patients with CKD
2.2.3.1
Facilitation of RAASi Treatment Optimisation
Blockade of the RAAS with an ACEi or ARB remains the first-line therapy for both kidney 
and CV protection in patients with CKD (KDIGO 2013, KDIGO 2020, NICE 2021, NKF 
2012). Optimal ACEi/ARB doses in CKD patients conferred further kidney outcomes benefit 
as compared to suboptimal doses (ROAD trial; Hou et al 2007).
However, RAASi treatment often leads to hyperkalaemia, and down-titration or 
discontinuation of ACEi/ARB therapy is common following an episode of hyperkalaemia and 
occurs in 38% and 47% of patients with mild and moderate hyperkalaemia (Epstein 2016). 
Down-titration or discontinuation of ACEi/ARB treatment in CKD patients are both similarly 
associated with an approximately doubling of mortality compared with patients maintained on 
maximum dose ACEi/ARB treatment (Epstein 2016). The number of patients not attaining 
optimal ACEi/ARB therapy or an optimal dosing regimen is significant, as shown in studies of 
patients with moderate to severe CKD in which approximately 30% of patients were not 
prescribed ACEi/ARB treatment (Shirazian et al 2015, Yildirim et al 2012). A study of CKD 
and heart failure patients receiving ACEi/ARB therapy also showed that 73.2% were on a 
suboptimal ACEi/ARB dose (Polson et al 2017).
2.2.3.2
Increased Serum Bicarbonate
SZC has also been found to consistently raise serum bicarbonate and this effect is likely to be 
due to ammonium binding and elimination in the gut by SZC (Ash et al 2015, Roger et al 
2020). The observed increase in bicarbonate is a potential mechanism for nephroprotection by 
ameliorating acidosis, which is common in patients with CKD. Metabolic acidosis has been 
shown to be linked to CKD progression (Shah et al 2009) and bicarbonate therapy may slow 
its progression (Di Iorio et al 2019). Bicarbonate therapy has been suggested to provide 
kidney benefit to patients without overt acidosis (Mahajan et al 2010).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
34 of 125
2.2.3.3
Correction of Hyperkalaemia with Maintenance of Normokalaemia and 
Reduction in Aldosterone
Hyperkalaemia may offset some of the renoprotective ACEi/ARB effect. In a post-hoc 
analysis of the RENAAL study data (Miao et al 2011), hyperkalaemia was associated with an 
increased risk for kidney events (hazard ratio of 1.22). Adjustment of the overall treatment 
effect for S-K level augmented the renoprotective effect of losartan from 21% to 35%, 
suggesting that the renoprotective effects of losartan are offset by its effect on S-K. 
Furthermore, mild to moderate hyperkalaemia may independently increase the risk of ESKD 
regardless of ACEi/ARB treatment (Provenzo et al 2018). The risk of ESKD also increased by 
57% in patients with new-onset or persistent hyperkalaemia when there was non-use or 
discontinuation of ACEi/ARB treatment.
The adverse effects of hyperkalaemia on kidney function might be aldosterone mediated. 
Hyperkalaemia is known to increase aldosterone secretion (Himathongkam et al 1975). 
Furthermore, there is increasing evidence suggesting that aldosterone induces oxidative stress, 
inflammation, and fibrosis, resulting in CV and kidney injury (reviewed in Rüster et al 2006). 
Several SZC studies (ZS-005, ZS-004E, D9482C00001 [Japan long-term safety study] and 
D9480C00002 [HARMONIZE global]) have shown that serum aldosterone levels were 
reduced in response to SZC treatment. Treatment with finerenone, a selective MRA, resulted 
in lower risks of CKD progression and CV events than placebo in patients with type 2 
diabetes and CKD (Bakris et al 2020). Thus, correction of hyperkalaemia and maintenance of 
normokalaemia together with reduction of aldosterone would potentially confer 
renoprotection.
2.2.3.4
Estimated GFR in Long-term Studies of SZC
In previous long-term studies (ZS-005 and D9482C00001 [Japan Long-Term Safety Study]), 
the effects of SZC were studied in patients with hyperkalaemia and comorbid conditions 
(73.5% and 93.3%, respectively) including CKD (defined as eGFR < 60 mL/min/1.73m2) and 
followed up for one year. In patients with CKD at baseline, eGFR at the end of the one-year 
follow-up period was similar to the values observed at baseline. To a large degree, this was 
due to an acute improvement in eGFR following study initiation, followed by a decline that 
appeared to be slower than what would be expected in this population. However, as none of 
the studies were placebo-controlled, firm conclusions on causality cannot be made.
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
This study has been designed with appropriate measures in place to monitor and minimise any 
potential health risks to participants. A DMC that is unblinded to treatment allocation will be 
responsible for safeguarding the interests of the participants throughout the study 
(Appendix A 5.2). To ensure the safety of all participants in AstraZeneca-sponsored studies, 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
35 of 125
reviews of all safety information from all ongoing clinical SZC studies are conducted as they 
become available.
Details of the risk assessment in this study are presented in Table 3. Refer to the Investigator’s 
Brochure for detailed information on the risks of SZC. Refer to the applicable SmPC for 
lisinopril and valsartan for detailed information on the risks of these agents.
Table 3
Risk Assessment of SZC and the Use of SZC with Lisinopril or 
Valsartan as Background Interventions
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Hypokalaemia 
(S-K < 3.5 mmol/L)
Common for SZC (≥1/100 to 
< 1/10).
In clinical trials, 4.1% of 
participants treated with SZC 
developed hypokalaemia.
Periodic monitoring of S-K and 
dose adjustment as necessary.
Oedema-related events (includes 
fluid overload, fluid retention, 
generalised oedema, 
hypervolaemia, localised oedema, 
oedema, oedema peripheral, 
peripheral swelling)
Common for SZC (≥1/100 to 
< 1/10).
In clinical trials with SZC, the 
most commonly reported adverse 
reaction was oedema-related 
events which were reported by 
5.7% of participants treated with 
SZC; 1.7%, 2.7%, 5.2%, and 
14.3% of participants randomised 
to placebo, SZC 5 g, 10 g, or 15 g 
once daily up to one month, 
respectively.
Oedema management as per 
investigator’s medical judgment 
and standard clinical practice.
Hyperkalaemia 
(S-K > 5.0 mmol/L)
Lisinopril/valsartan can cause 
hyperkalaemia (especially in 
patients with impaired renal 
function) because they inhibit the 
release of aldosterone.
For participants randomised to 
placebo, there is risk of 
hyperkalaemia from lisinopril and 
valsartan.
Close monitoring of S-K after 
randomisation, including 
scheduled safety visits 2 and 
7 days after randomisation.
Down-titration/withdrawal of 
lisinopril/valsartan if significant 
hyperkalaemia persists.
Rescue therapy available per 
standard of care/clinical practice.
SZC/placebo dosing based on 
local laboratory S-K and 
instructions in Section 6.6 and 
Appendix C.
S-Cr, serum creatinine; S-K, serum potassium; SZC, Sodium zirconium cyclosilicate.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
36 of 125
2.3.2 Benefit Assessment
Participants in this clinical study will potentially derive benefit from having their RAASi 
doses up-titrated although more participants receiving SZC are likely to maintain the higher 
beneficial doses compared to those on placebo. Further, patients receiving SZC may benefit 
from the other mechanisms (bicarbonate rise, control of hyperkalaemia, and aldosterone 
reduction). Should the study hypothesis prove true, participants treated with SZC may have 
delayed progression of CKD. All participants in this clinical study, irrespective of whether 
treated with SZC or placebo, will be receiving SoC and closer medical attention compared to 
ordinary medical practice.
2.3.3 Overall Benefit: Risk Conclusion
Considering the potential benefit implied and the measures implemented to minimise risk to 
participants in this study, the benefit-risk of the study is deemed favourable.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
37 of 125
3
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for the study are detailed in Table 4.
Table 4
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in slowing CKD progression, 
assessed as the reduction in participant’s expected 
eGFR decline over time
Co-primary b
•
Total slope: eGFR measurements starting at 
randomisation
•
Chronic slope: eGFR measurements, starting at 
12 weeks after randomisation
Secondary
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing the incidence of the 
composite of kidney failure outcomes comprising: 
sustained ≥40% decline in eGFR, onset of ESKD, 
and death from kidney failure
•
Time from randomisation to the first occurrence 
of any component in the composite of
∀
Sustained ≥ 40% decline in eGFR c
∀
Onset of ESKD (kidney transplantation, 
maintenance dialysis, or sustained low 
eGFR) c
∀
Death from kidney failure c
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing the incidence of 
lisinopril/valsartan dose decrease, in participants on 
lisinopril/valsartan at randomisation
•
Time from randomisation to first 
lisinopril/valsartan dose decrease
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in reducing albuminuria
•
UACR measurements at scheduled visits after 
randomisation
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo in increasing serum bicarbonate 
levels
•
Serum bicarbonate measurements at scheduled 
visits after randomisation
To determine if treatment with SZC, as adjunct to 
ACEi/ARB therapy (lisinopril or valsartan a), is 
superior to placebo on maintenance of 
normokalaemia
•
S-K level classification; normal 
(3.5-5.0 mmol/L) or non-normal (< 3.5 or 
> 5.0 mmol/L) at scheduled visits after 
randomisation

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
38 of 125
Table 4
Objectives and Endpoints
Objectives
Endpoints
Safety
To assess the safety and tolerability of treatment with 
SZC, as adjunct to ACEi/ARB therapy (lisinopril or 
valsartan a), as compared to placebo
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical laboratory variables, 
and ECGs
Assessments related to AEs cover:
•
Occurrence/frequency
•
Relationship to study intervention as assessed 
by investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of study 
intervention
a
In case of a local market valsartan shortage, irbesartan will be temporarily used instead.
b
Both of the primary endpoints must be met in order for the study to be declared successful, ie, co-primary 
endpoints.
c
Levin et al 2020; see Section 8.1.2.
ACEi, angiotensin converting enzyme inhibitor; AE, adverse event; ARB, angiotensin II receptor blocker; 
CKD, chronic kidney disease; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ESKD, end 
stage kidney disease; SAE, serious adverse event; S-K, Serum potassium; SZC, Sodium zirconium cyclosilicate; 
UACR, urine albumin-to-creatinine ratio.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, international, randomised withdrawal, double-blind, parallel-group, 
placebo-controlled study, to evaluate the effect of SZC as adjunct to RAASi therapy (lisinopril 
or valsartan) in slowing CKD progression in participants with CKD and hyperkalaemia or at 
risk of hyperkalaemia.
Specifically, the study will include participants with hyperkalaemia (S-K > 5.0 to 
≤6.5 mmol/L by central laboratory) who are on adequate or limited RAASi therapy due to 
hyperkalaemia, and participants with normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L by central 
laboratory) who are on limited RAASi therapy due to high risk of hyperkalaemia. High risk of 
hyperkalaemia is defined as (1) participants with a previous medical history or record of 
hyperkalaemia within the prior 24 months who are on limited RAASi therapy despite 
indication in CKD; (2) participants in whom RAASi therapy is indicated in CKD but are on 
limited RAASi therapy and have S-K ≥4.7 to ≤5.0 mmol/L; and (3) participants in whom 
RAASi therapy has been discontinued or reduced to suboptimal doses because of 
hyperkalaemia (see Section 5.1, inclusion criterion 5).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
39 of 125
It is estimated that approximately 3000 participants at up to 250 study sites in up to 
16 countries will be enrolled (screened) to reach the target of approximately 1360 randomised 
participants (see Section 9.2).
A participant is expected to be in the study for approximately 28 months, which includes up to 
13 days for the screening period, 27 months for the intervention period, and 1 week for 
follow-up. The 27-month intervention period of the study consists of 3 phases, an initiation 
phase (up to 72 hours), a run-in phase (3 months/up to Day 90), and a maintenance phase 
(24 months/104 weeks).
An independent DMC that is unblinded to treatment allocation will be responsible for 
safeguarding the interests of the participants throughout the study (see Appendix A 5).
The overall study design is presented in Figure 1.
4.1.1
Screening Period (Up to 13 Days)
During the screening period, after signed informed consent is obtained, data required for 
determination of eligibility for the study will be collected and inclusion/exclusion criteria 
evaluated (Sections 5.1 and 5.2). Participants who fulfil the study eligibility criteria may 
proceed to the initiation phase. Participants who do not fulfil the study eligibility criteria are 
screen failures (see Section 5.4 for details on screen failures and rescreening).
4.1.2
Initiation Phase (Up to 72 hours)
No changes will be made to the ACEi or ARB therapy during the initiation phase. The initial 
dosing of SZC will be based on the participant’s S-K as measured by local laboratory on the 
same day as, or within 24 hours prior to, Day 1 (Visit 2); the S-K results MUST be available 
before any other Visit 2 procedures/assessments are performed. If S-K < 3.5 or > 6.5 mmol/L, 
the participant is not eligible for the study (see exclusion criterion 18, Section 5.2).
Hyperkalaemic (S-K > 5.0 to ≤ 6.5 mmol/L [local laboratory]) at Visit 2
Participants will receive 10 g SZC TID starting on Day 1 (Visit 2). S-K will be measured by 
local laboratory at 48 hours (Day 3; Visit 3b) and subsequently at 72 hours (Day 4; Visit 3c) if 
normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L) has not been previously achieved.
In case the S-K result is not available for up to 24 hours after sample collection, the 
participant will be notified by phone as soon as possible after the S-K results are available, 
and the following instructions should be followed for SZC:
!
Day 3 (Visit 3b): if the 48-hour S-K result is not available, the participant will take SZC 
10 g TID for one additional day.
!
Day 4 (Visit 3c): if the 48-hour S-K is > 5 to ≤ 6.5 mmol/L and the 72-hour S-K is not 
available, the participant will take SZC 10 g QD for one day.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
40 of 125
If normokalaemia is achieved after 48 or 72 hours of treatment with SZC, the participant will 
proceed to the run-in phase, during which SZC dosing will be initiated at 10 g QD. 
Participants who do not achieve normokalaemia after 72 hours of treatment will undergo a 
follow-up visit at 7 (± 2) days after the participant’s last dose per the SoA (Section 1.3) and 
exit the study.
Normokalaemic (S-K ≥3.5 to ≤5.0 mmol/L [local laboratory]) at Visit 2
Participants will receive SZC 5 g QD starting on Day 1 (Visit 2) for 48 hours. S-K will be 
measured by local laboratory at 48 hours (Day 3; Visit 3b). In case the S-K result is not 
available for up to 24 hours after sample collection, the participant will continue with a third 
day of SZC 5 g QD and will be notified by phone as soon as possible after the 48-hour S-K 
results are available.
If normokalaemia is maintained after 48 hours of treatment with SZC, the participant will 
proceed to the run-in phase, continuing to receive 5 g QD. Participants who do not maintain 
normokalaemia after 48 hours of treatment will undergo a follow-up visit at 7 (± 2) days after 
the participant’s last dose per the SoA (Section 1.3) and exit the study.
NOTE: Visit 3c is not applicable for participants who are normokalaemic at Visit 2.
4.1.3
Run-in Phase (3 months/up to Day 90)
As soon as possible after the participant is confirmed to be normokalaemic at the end of the 
initiation phase (based on local laboratory S-K results from Visits 3b or 3c), the participant 
will enter the run-in phase (Visit 3d).
Participants will receive open-label SZC and either lisinopril or valsartan. See Section 6.6.2
for instructions on lisinopril/valsartan starting doses. A participant cannot receive both 
lisinopril and valsartan simultaneously and should not take any other ACEi or ARB 
concomitantly with lisinopril or valsartan.
The aim of the run-in phase is to increase ACEi or ARB therapy stepwise to their maximum 
doses using lisinopril or valsartan as per local labels. See Section 6.6 for instructions on dose 
modification, including monitoring lisinopril/valsartan titration (Section 6.6.1) and 
management of abnormalities of S-K (Appendix C), lisinopril/valsartan dosing upon entry to 
and during the run-in phase (Section 6.6.2), strategy for lisinopril/valsartan up-titration during 
run-in phase visits (Section 6.6.3), and additional unscheduled visits for titration of 
lisinopril/valsartan (Section 6.6.5).
At the end of the run-in phase (Day 90 [±3 days], Visit 6a), S-K will be measured by local 
laboratory. The participant will continue to receive the current prescribed dose of SZC until 
the S-K result is available. If normokalaemic (S-K ≥3.5 to ≤5.0 mmol/L), the participant will 
proceed to the maintenance phase of the study. If not normokalaemic, the participant will 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
41 of 125
undergo a follow-up visit at 7 (± 2) days after the participant’s last dose per the SoA 
(Section 1.3) and exit the study.
NOTE: The study is designed to use valsartan as the ARB adjunct to SZC. However, if an 
actual shortage of valsartan in a local market jeopardises the ability of participants to enter or 
continue in the study, valsartan can be temporarily substituted with irbesartan until the 
shortage of valsartan is resolved.
Appendix E provides conversion information for changing from other ARBs or valsartan to 
irbesartan, dose equivalence ranges, irbesartan dose modification strategy, and other 
prescribing information about irbesartan.
During temporary treatment with irbesartan, the same procedures indicated for valsartan 
discontinuation (Section 7) and efficacy, safety, and other assessments (Section 8) must be 
followed.
As soon as the shortage is resolved, valsartan should be restarted at a dose determined by 
using the conversion table in Appendix B 1 unless in the investigator’s judgment a change in 
dose is required. Every effort should be made to maximise the doses of valsartan and of 
irbesartan if the latter needs to be used because of a valsartan shortage.
4.1.4
Maintenance Phase, Double-blind, Parallel Groups 
(24 months)/104 weeks)
As soon as possible after the participant is confirmed to be normokalaemic at the end of the 
run-in phase (based on local laboratory S-K results from Visit 6a), the participant will enter 
the maintenance phase. The date of randomisation is Day 1 of the maintenance phase 
(Visit 6b).
Participants will be randomised in a 1:1 ratio to receive either SZC or matching placebo. The 
starting dose of SZC/placebo will be the same dose as the last dose of SZC during the run-in 
phase. Lisinopril and valsartan will be continued at the same doses assigned at the end of the 
run-in phase. As described in the run-in phase, if there is a shortage of valsartan in a local 
market, valsartan can be temporarily substituted with irbesartan until the shortage of valsartan
is resolved (see Section 4.1.3 and Appendix E).
Two safety visits will occur 2 and 7 (±1) days after randomisation and will include evaluation 
of S-K by local laboratory. The investigator must ensure that the choice of date for 
randomisation will allow for these 2 safety visits to occur 2 and 7 (±1) days after 
randomisation, respectively. Participants will then be monitored for approximately 24 months 
(through Week 104) for efficacy and safety assessments. A final safety follow-up visit will be 
conducted at Week 105, one week after the participant’s last dose, after which the participant 
will exit the study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
42 of 125
See Section 6.6 for instructions on dose modification, including monitoring 
lisinopril/valsartan titration (Section 6.6.1) and management of abnormalities of S-K 
(Appendix C), use of SZC/placebo for management of S-K immediately after randomised 
withdrawal, ie, up to Week 6 of maintenance phase (Section 6.6.4), and additional 
unscheduled visits for titration of lisinopril/valsartan (Section 6.6.5).
4.1.5
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following:
!
Obtaining consent for the mitigation procedures and document this in the source data.
!
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
see Appendix F.
4.2
Scientific Rationale for Study Design
This is a randomised withdrawal, double-blind, placebo-controlled parallel-group study. 
Randomisation and double-blinding will minimise potential bias. The rationale for the 
randomised withdrawal design is to ensure that investigators up-titrate lisinopril/valsartan to 
their maximum doses during the run-in phase while participants are being treated with SZC to 
control S-K.
4.2.1
Rationale for the Study Population
The population included in this study comprises patients with moderate to severe CKD (eGFR 
≥25 to ≤59 mL/min/1.73m2) and albuminuria (UACR ≥200 and ≤5000 mg/g) with 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
43 of 125
hyperkalaemia or at risk of hyperkalaemia. The presence of a reduced eGFR together with 
significant albuminuria ensures that the selected population is at risk of progression of CKD 
and can potentially benefit from the proposed mechanisms of action of SZC. RAASi therapy, 
eg, ACEi/ARB treatment, is renoprotective and slows progression in early and advanced CKD 
patients. The low eGFR cut-off value is set at 25 mL/min/1.73m2 to avoid enrolling patients 
with more advanced CKD who are at risk for rapid progression to ESKD, and who commonly 
cannot tolerate maximal ACEi/ARB doses because of the risk of further haemodynamic 
kidney impairment. In addition, including patients with very advanced kidney disease would 
detract from the ability to obtain meaningful long term eGFR slope data. Hyperkalaemia is a 
common reason for down-titration or discontinuation of ACEi/ARB therapy and constitutes 
the main barrier to attaining optimal therapy. SZC is likely to benefit this population by 
enabling optimisation of ACEi/ARB therapy in hyperkalaemic patients, and in patients at high 
risk of hyperkalaemia upon ACEi/ARB up-titration.
As indicated in Section 2.2.3, SZC may exert renoprotective effects in the proposed study 
population independently of ACEi/ARB optimisation (bicarbonate rise and 
potassium/aldosterone reduction). To study the effects of all potential SZC mechanisms of 
action, the proposed study patient population will include 2 subgroups of approximately equal 
size, based on S-K and RAASi therapy criteria, as follows:
!
Hyperkalaemia and on adequate or limited RAASi therapy due to hyperkalaemia
!
Normokalaemia and on limited RAASi therapy due to high risk of hyperkalaemia
The mechanisms underlying the potential benefit of SZC are relevant in all 2 subgroups 
(RAASi optimisation, acidosis correction, hyperkalaemia amelioration, and aldosterone 
reduction). The study population defined by the above eligibility criteria and study subgroups 
is considered well representative of a CKD population at risk of progression that is likely to 
benefit from treatment with SZC.
4.2.2
Rationale for the Endpoints
4.2.2.1
Rationale for the Primary Endpoints
The co-primary endpoints (ie, eGFR at and after randomisation and eGFR at and after 
12-week visit) are appropriate for the objective of the study. These endpoints should reflect 
the combined results of the proposed SZC renoprotective mechanisms that include enabling 
the use of optimal ACEi/ARB therapy, and the anticipated effects on S-K, bicarbonate, and 
aldosterone levels as described in Section 2.2.3.
Data from observational cohorts as well as from randomised clinical studies support the 
validity of eGFR slope as a surrogate measure for kidney function decline (Astor et al 2011, 
Coresh et al 2014, Gansevoort et al 2011, Matsushita et al 2015, Turin et al 2013, Van der 
Velde et al 2011).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
44 of 125
Furthermore, large observational and clinical studies have shown that an improvement in total 
eGFR slope predicts/translates into benefit on clinical kidney outcomes, for instance:
!
In a patient-level meta-analysis of observational data from 122664 CKD participants with 
eGFR < 60 mL/min/1.73m2, a reduction in eGFR slope decline by 
0.75 mL/min/1.73m2/year over 2 years was associated with a 30% lower risk of 
subsequent ESKD (Grams et al 2019).
!
In a patient-level Bayesian meta-analysis including 47 clinical studies and 
60620 participants (2018 NKF/FDA/EMA Workshop), a treatment effect of 
0.75 mL/min/1.73m2/year in the total eGFR slope predicts an average 27% lower hazard 
for the treatment benefit on the clinical endpoint (Inker et al 2019, Levey et al 2020).
It is the Sponsor’s view that eGFR slope is a clinically relevant surrogate for CKD progression 
and use of eGFR slope allows faster and more efficient clinical trials in CKD. Due to the 
observed acute haemodynamic effects of RAASi and SZC on eGFR measures, both total 
eGFR slope and chronic eGFR slope are used in this study to mitigate the potential impact on 
kidney function assessment and minimise the risk of a type 1 error. Accordingly, this is 
expected to show a clinically relevant difference favouring SZC and will reflect a true effect 
on irreversible loss of kidney function.
4.2.2.2
Rationale for the Secondary Endpoints
The effect of SZC compared with placebo in reducing the incidence of the composite of 
kidney failure outcomes, comprising of ≥ 40% sustained decline in eGFR, onset of ESKD 
(kidney transplantation, maintenance dialysis, or sustained low eGFR), and death from kidney 
failure, will be evaluated to support analysis of the primary outcome measure. The 
components of the composite endpoint are based on international consensus definitions of 
clinical trial outcomes for kidney failure (Levin et al 2020). Additional secondary endpoints 
include time to lisinopril/valsartan dose decrease after randomisation, UACR, serum 
bicarbonate, and S-K levels, at scheduled visits after randomisation to further characterise the 
treatment effect of SZC/placebo and lisinopril/valsartan as well as the mechanisms of action 
of any renoprotective effects.
Standard safety parameters such as AEs/SAEs, vital signs, laboratory evaluations, and ECG 
will be evaluated to assess the safety profile of SZC compared to placebo as adjunct to 
lisinopril or valsartan.
4.2.3
Rationale for Placebo Control During the Maintenance Phase
It is hypothesised in this study that treatment of hyperkalaemia with SZC slows CKD 
progression. To date, no potassium binder has shown such a benefit in a randomised clinical 
study of patients with CKD. Therefore, other agents that treat hyperkalaemia in other clinical 
settings are not appropriate to use as controls in the proposed study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
45 of 125
The study protocol includes close monitoring of participant’s status with frequent recording of 
AEs and SAEs, specific safety visits to monitor S-K, and the use of short-term rescue therapy 
for managing severe hyperkalaemia. During the randomised withdrawal of the maintenance 
phase, protocol-mandated safety visits will be required for all participants 2 and 7 (± 1) days 
after randomisation. Instructions for strict monitoring of S-K during this time and the use of 
SZC/placebo for management of S-K are provided in Section 6.6.4. Thus, participant safety 
and ethical considerations are preserved while the scientific hypothesis is being adequately 
and robustly tested.
Additionally, the randomised withdrawal design with placebo control has been safely used in 
previous RAASi and hyperkalaemia studies (eg, OPAL-HK) and is used in an ongoing global 
heart failure outcomes trial (DIAMOND, N = 2388). To mitigate the potential rebound 
hyperkalaemia risk in placebo participants, there will be rigorous monitoring of S-K during 
the randomised withdrawal and throughout the maintenance phase.
Treatment with SZC or placebo will be administered as adjunct to RAASi therapy (lisinopril 
or valsartan) in the study population. Participation in the study will not deprive participants 
from receiving therapies considered as necessary by the investigator. Participants will receive 
SoC for any underlying medical conditions during the study. Potentially beneficial 
renoprotective treatments, including SGLT2 inhibitors (ie, dapagliflozin and canagliflozin), 
finerenone, or any other medications in these 2 classes that are approved for CKD, will not be 
withheld in the study. Participants who require restricted medications that may interfere with 
the objectives of the study (eg, chronic treatment with a potassium binder) will be 
discontinued from study interventions.
4.3
Justification for Dose
4.3.1
Justification for Dose of SZC
The SZC doses selected for this study have been studied in the clinical development 
programme and are in line with the approved label(s). SZC 5, 10, and 15 g QD have been 
proven to be tolerable and efficacious doses during long-term therapy in prior SZC studies 
(see data on the maintenance phase for Studies ZS-004 and ZS-005 in the Investigator’s 
Brochure). The SZC doses to be used in normokalaemic participants were also studied in a 
Phase 2 clinical trial (PRIORITIZE HF [Study D9484C00001; NCT03532009]) with no new 
safety concerns raised.
4.3.2
Justification for Dose of Lisinopril and Valsartan
Equivalence calculations for dosing lisinopril/valsartan during the run-in phase are based on 
the label recommendations for control of blood pressure as the primary indication. 
Appendix B 1 and Appendix B 2 detail the dosing equivalences among RAASi drugs that 
form the basis for determining the doses of lisinopril/valsartan to be used in the study and are 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
46 of 125
based on KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD 
(KDIGO 2020).
If participants are not already on maximum doses of lisinopril and valsartan upon entry into 
the run-in phase, stepwise dose adjustments to maximum doses as per local label will be done 
with close monitoring of S-K and S-Cr following clinical guidelines for RAASi therapy 
recommended by KDIGO guidelines (KDIGO 2020; see Section 6.6).
Any further dose increases of lisinopril/valsartan deemed clinically advisable after achieving 
the maximum tolerated dose during the early run-in phase should also follow KDIGO 
guidelines (KDIGO 2020). If necessary, dose reductions or discontinuation of 
lisinopril/valsartan are allowed as judged by the investigator, eg, because of hyperkalaemia, 
excessive (≥30%) rise in S-Cr, symptomatic hypotension, or other compelling medical 
reasons (KDIGO 2020).
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 scheduled follow-up visit after the maintenance phase, as indicated in 
the SoA (Section 1.3).
The end of the study globally is defined as the date of the last visit of the last participant.
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:
Informed Consent
1
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
Age
2
Must be ≥18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
3
Must have eGFR ≥25 and ≤59 mL/min/1.73m2 as calculated by central laboratory 
(CKD-EPI formula; Delgado et al 2022, Inker et al 2021) at screening (Visit 1).
4
Must have UACR ≥200 and ≤5000 mg/g as calculated by central laboratory at screening 
(Visit 1). If the first sample does not fulfil eligibility criteria, a second sample can be 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
47 of 125
obtained during the screening period; if so, the UACR measurement from the second 
sample must be within the eligibility range.
5
Any of the following criteria, a or b, at screening (Visit 1):
(a) Cohort A: Hyperkalaemia (S-K > 5.0 to ≤6.5 mmol/L) as measured by the central 
laboratory, and on adequate* or limited** RAASi therapy due to hyperkalaemia.
(b) Cohort B: Normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L) as measured by the central 
laboratory and on limited** RAASi therapy due to high risk of hyperkalaemia. High 
risk of hyperkalaemia is defined as:
(i)
Participants with a previous medical history or record of hyperkalaemia within 
the prior 24 months, who are on limited** RAASi therapy despite indication in 
CKD.
(ii) Participants in whom RAASi therapy is indicated in CKD, who are on limited** 
RAASi therapy and have S-K ≥4.7 to ≤5.0 mmol/L.
(iii) Participants in whom RAASi therapy has been discontinued or reduced to 
suboptimal* doses because of hyperkalaemia.
*Adequate RAASi dose levels are defined in Appendix B 3; doses lower than these are 
considered as suboptimal.
**Limited RAASi therapy is defined as no or suboptimal RAASi therapy according to 
dosing guidance provided in Appendix B 3.
6
If on thiazide or loop diuretics, the dose must have been stable for 2 weeks prior to 
screening (Visit 1).
7
If on RAASi therapy, the dose must have been stable for one month prior to screening 
(Visit 1) and remain stable during screening.
8
If on an SGLT2 inhibitor (ie, dapagliflozin and canagliflozin), finerenone, or any other 
medications in these 2 classes that are approved for CKD, the dose must have been stable 
for 3 months prior to screening (Visit 1).
Reproduction and Contraception
Contraceptive use by participants of childbearing potential should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical studies.
9
Participants must be one-year postmenopausal, surgically sterile, or using one highly 
effective form of birth control (defined as one that can achieve a failure rate of less than 
1% per year when used consistently and correctly). They should have been stable on their 
chosen method of birth control for a minimum of one month prior to screening (Visit 1) 
and willing to remain on the birth control until one month after the last dose of study 
intervention. See Section 5.3.3.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
48 of 125
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
New York Heart Association class III to IV congestive heart failure at the time of 
screening (Visit 1) or previous history of severe or symptomatic heart failure.
2
Myocardial infarction, unstable angina, stroke, or transient ischaemic attack within 
3 months prior to screening (Visit 1).
3
Participants with a known history of systolic blood pressure ≥160 mmHg or diastolic 
blood pressure ≥95 mmHg within 2 weeks prior to screening (Visit 1) are excluded. In 
addition, any participant with systolic blood pressure ≥160 mmHg or diastolic blood 
pressure ≥95 mmHg as measured at screening (Visit 1) and confirmed by repeated 
measurement is excluded. Participants may be rescreened once blood pressure is 
controlled.
4
QTcF > 550 msec at screening (Visit 1).
5
History of QT prolongation associated with other medications that required 
discontinuation of that medication.
6
Congenital long QT syndrome.
7
Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Participants with atrial fibrillation and heart rate 
controlled by medication are permitted.
9
Lupus nephritis or anti-neutrophil cytoplasmic antibody-associated vasculitis.
10 Change in renal function requiring hospitalisation or dialysis within 3 months prior to 
screening (Visit 1).
11 History of renal transplant (or anticipated need for renal transplant during the study).
12 Severe hepatic impairment, biliary cirrhosis, or cholestasis.
13 History of hereditary or idiopathic angioedema.
14 Any prior hypersensitivity to ACEi or ARB that in the investigator’s judgment precludes 
use of lisinopril and valsartan/irbesartan. Prior hypersensitivity reactions to consider 
include, but are not limited to, development of angioedema, icterus, hepatitis, or 
neutropaenia or thrombocytopaenia requiring treatment modification.
15 Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
16 Any condition outside the CV and renal disease area such as, but not limited to, 
malignancy, with a life expectancy of less than 2 years based on investigator´s clinical 
judgment.
17 Active malignancy requiring treatment at the time of screening (Visit 1), except for 
successfully treated basal cell or treated squamous cell carcinoma.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
49 of 125
18 S-K > 6.5 or < 3.5 mmol/L by local laboratory within 1 day prior to the scheduled first 
dose of SZC in the initiation phase.
19 Evidence of COVID-19 infection within 2 weeks prior to screening (Visit 1).
Prior/Concomitant Therapy
20 Treated with dual blockade of RAAS (combined use of an ACEi and ARB) within 
3 months prior to screening (Visit 1).
21 Treated with an angiotensin receptor neprilysin inhibitor (ARNI; sacubitril/valsartan 
[Entresto®]) within 3 months prior to screening (Visit 1).
22 Treated with an MRA not approved for CKD within 3 months prior to screening (Visit 1).
23 Treated with aliskiren-containing products with 3 months prior to screening (Visit 1).
24 Treated with SPS (eg, Kayexalate, Resonium), CPS (Resonium Calcium), patiromer 
(Veltassa®), or SZC (Lokelma®) within 7 days prior to screening (Visit 1).
Prior/Concurrent Clinical Study Experience
25 Participation in another clinical study with an investigational product administered within 
one month prior to screening (Visit 1).
Other Exclusions
26 Not willing or not able to change to lisinopril or valsartan/irbesartan, the 
protocol-mandated RAASi study intervention. Note: For participants taking a fixed 
combination of an ACEi or ARB with another agent (eg, calcium blockers or diuretics) as 
SoC, the investigator must make a judgment that it will be safe and efficacious for such 
participants to change to the study ACEi or ARB and to the other drug as separate agents.
27 Previous dosing with SZC in the present study.
28 Currently pregnant (confirmed with positive pregnancy test at screening [Visit 1]) or 
breastfeeding.
29 Judgment by the investigator that the participant is unlikely to comply with study 
procedures, restrictions, and requirements.
30 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
No study-specific dietary restrictions are required. Study site personnel are encouraged to 
instruct participants to adhere to any dietary restrictions that apply for similar patients not 
participating in a study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
50 of 125
5.3.2
Caffeine, Alcohol, and Tobacco
No additional study-specific restrictions are required in the study, except restrictions 
applicable prior to a blood pressure measurement (see Section 8.2.2).
5.3.3
Contraception
Participants of childbearing potential must use one highly effective form of birth control. They 
should have been stable on their chosen method of birth control for a minimum of one month 
prior to screening (Visit 1) and remain on the birth control until one month after the last dose 
of study intervention. Cessation of contraception after this point should be discussed with a 
responsible physician. Participants who are surgically sterile or those who are postmenopausal 
are not considered to be of childbearing potential.
!
Surgical sterilisation includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy.
!
Participants will be considered postmenopausal if they have been amenorrhoeic for 
12 months prior to screening (Visit 1) without an alternative medical cause.
!
Highly effective birth control methods (defined as one that can achieve a failure rate of 
less than 1% per year when used consistently and correctly) include:
#
Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal).
#
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable).
#
Intrauterine device.
#
Intrauterine hormone-releasing system.
#
Bilateral tubal occlusion.
#
Vasectomised partner.
#
Heterosexual abstinence, true abstinence in line with the participant’s preferred and 
usual lifestyle; however, periodic abstinence (calendar, symptothermal, post-
ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method are not acceptable methods of contraception. Female condom 
and male condom should not be used together.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently dosed in the initiation phase due to one or more of the eligibility criteria 
detailed in Sections 5.1 and 5.2 not being satisfied. 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 publishing requirements and to respond to 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
51 of 125
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 will re-sign the ICF on the rescreening visit (ie, 
repeated Visit 1). All procedures from the screening period will be repeated.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to or medical device(s) utilised by a study participant 
according to the study protocol. For this study, the intervention refers to SZC or matching 
placebo and lisinopril/valsartan.
The intervention is expected to be dispensed during protocol specified visits (see SoA, 
Section 1.3), in the amount expected to account for its usage as per the investigator’s 
prescription, including possible dose modifications that might occur before the next 
protocolised dispensation visit. Study intervention may also be dispensed at unscheduled 
visits.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
The study intervention (investigational products) to be administered in this study are presented 
in Table 5.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
52 of 125
Table 5
Investigational Products
Intervention name/
Characteristic
SZC
Placebo
Lisinopril
Valsartan a
Type
Drug
Drug
Drug
Drug
Dose formulation
Powder for oral suspension in a 
sachet
Powder for oral 
suspension in a sachet
Tablet
Tablet or capsule
Unit dose strength(s)
5 or 10 g SZC
Placebo to match 5 or 
10 g
2.5, 5, 10, or 20 mg b
40, 80, or 160 mg b
Dosage level(s)
Single dose will consist of 1-3 
sachets c
Initiation Phase:
•
S-K > 5 to ≤6.5 mmol/L 
(measured by L-Lab): Single 
dose contains 10 g SZC that 
should be suspended in 45 mL 
of water. The 10 g SZC single 
dose should be administered 
TID for up to 72 hours until 
normokalaemic (S-K 
3.5-5.0 mmol/L); the total 
daily dose is 30 g SZC.
•
S-K ≥3.5 to ≤5 mmol/L 
(measured by L-Lab): Single 
dose contains 5 g SZC that 
should be suspended in 45 mL 
of water and administered QD 
for 48 hours
Run-in and Maintenance Phases:
•
Single dose contains 5 g SZC 
administered QOD or 5, 10, or 
15 g SZC administered QD 
that should be suspended in 
45 mL of water
Single dose will consist of 
1-3 sachets c
Maintenance Phase:
Single dose contains 5 g 
placebo administered 
QOD or 5, 10, or 15 g 
placebo administered QD 
that should be suspended 
in 45 mL of water
5, 10, 20, or 40 mg QD d
40, 80, 160, or 320 mg QD d
Route of administration
Oral
Oral
Oral
Oral

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
53 of 125
Table 5
Investigational Products
Intervention name/
Characteristic
SZC
Placebo
Lisinopril
Valsartan a
Use
Experimental
Placebo
Background intervention
Background intervention
IMP or NIMP
IMP 
IMP 
IMP
IMP
Provider
AstraZeneca
AstraZeneca
Local sourcing preferred. 
Under certain circumstances 
when local sourcing is not 
feasible, lisinopril may be 
supplied centrally through 
AstraZeneca.
Local sourcing preferred. 
Under certain circumstances 
when local sourcing is not 
feasible, valsartan may be 
supplied centrally through 
AstraZeneca.
Packaging and labelling
•
Provided in sachet and labelled in accordance with GMP 
Annex 13 and per country regulatory requirement. Label 
text will be translated into local language.
•
For Japan: Labels will be prepared in accordance with GCP 
Ordinance. Details are specified in the document explaining 
the reconstitution procedures and other handling procedures 
for the investigational products.
•
Provided in original package and labelled in accordance 
with GMP Annex 13 and per country regulatory 
requirement. Label text will be translated into local 
language.
a
If there is a shortage of valsartan in a local market, valsartan can be temporarily substituted with irbesartan until the shortage of valsartan is resolved. See 
Appendix E 4 for details on irbesartan.
b
In countries where lisinopril and valsartan will be supplied centrally through AstraZeneca, specific unit dose strengths will be confirmed to the countries.
c
Further guidance and information are provided in the Pharmacy Manual.
d
For lisinopril and valsartan, the QD dose can be divided as long as the total daily dose is the prescribed dose, eg, valsartan 320 mg QD is equivalent to 
valsartan 160 mg BID.
BID, twice daily; GCP, Good Clinical Practice; GMP, Good Manufacturing Practice; IMP, investigational medicinal product; L-Lab, local laboratory; 
NIMP, non-investigational medicinal product; QD, once daily; QOD, every other day; S-K, serum potassium; SZC, Sodium zirconium cyclosilicate; TID, three 
times daily.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
54 of 125
6.2
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only authorised site 
staff may supply/dispense study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the investigator and authorised site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
6.3.1
The Process of Enrolment and Randomisation
An IRT/RTSM will be used for the assignment of unique participant numbers and 
randomisation codes in the study. The participant numbers will be obtained during screening 
for all participants, after the signature of the ICF, while the randomisation codes will be 
assigned only to the participants proceeding to the maintenance phase of the study. Before the 
study is initiated, detailed instructions describing the process of IRT/RTSM usage, including 
the telephone number and call-in directions for the IRT and/or the log in information and 
directions for the RTSM, will be provided to each site in the IRT/RTSM user manual.
In case of rescreening, the rescreened participants should be assigned the same participant 
number as for the initial screening.
Study intervention will be dispensed at the study visits summarised in the SoA (Section 1.3) 
and can also be dispensed at unscheduled visits. Returned study intervention in unopened 
packets or sachets may be re-dispensed to the same participant. For study intervention that is 
sourced centrally, 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. As the dosing 
regimen in the initiation phase is dependent on the participant’s local S-K value obtained prior 
to the first SZC dose, this value will have to be provided to the system before any SZC is 
dispensed.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
55 of 125
Direct-to-participant delivery of study intervention may be implemented where local 
regulations allow; instructions will be provided to the applicable investigator site(s) regarding 
dispensation of study intervention (ie, specific visits and delivery methods).
The study will aim at recruiting a certain minimum number of participants in the 2 cohorts 
described in inclusion criterion 5 (Section 5.1) as follows:
(a) Cohort A: Hyperkalaemia (S-K > 5.0 to ≤6.5 mmol/L) and on adequate or limited 
RAASi treatment due to hyperkalaemia; one half of all enrolled participants.
(b) Cohort B: Normokalaemia (S-K ≥3.5 to ≤5.0 mmol/L) and on limited RAASi 
treatment due to high risk of hyperkalaemia; one third of all enrolled participants.
During the study, sites will be notified if the number of participants recruited in a particular 
cohort approaches a point where further recruitment in the cohort would hinder the 
achievement of the desired number of participants in the other cohort.
In this study, the randomisation will be stratified by 3 factors: country; inclusion criterion 5 
(Section 5.1) categorisation as given above; and SGLT2 inhibitor and/or finerenone use at 
randomisation.
6.3.2
Break of the Blind
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention (ie, 
SZC/placebo) will affect the immediate management of the participant’s condition, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first consideration 
in making such a determination.
If a participant’s intervention assignment is unblinded, the Sponsor must be notified within 
24 hours after breaking the blind. The investigator should document and report the action to 
AstraZeneca, without revealing the treatment given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the randomisation code for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. Randomisation codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from each 
individual participant have been made and documented.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
56 of 125
6.3.3
Potentially Treatment-revealing Data
The following information will be considered as potentially treatment revealing during the 
maintenance phase of the study: 
!
S-K (central laboratory)
!
Serum bicarbonate (central laboratory)
!
SZC/placebo dose
!
Lisinopril/valsartan/irbesartan dose
To minimise the risk of revealing the treatment, the AstraZeneca study team will be blinded to 
the above.
The investigator site will be blinded to the central laboratory results/values of S-K and serum 
bicarbonate. However, if the S-K or serum bicarbonate laboratory results/values fall outside of 
the reference range with potential critical implications for the participant, the investigator and 
a pre-identified Sponsor contact will be notified.
Additional information about preserving the blind and maintaining study integrity will be 
detailed in another document. The clinical management of an individual participant is 
considered to have minimal risk of bias.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date of dose administration in the 
clinic will be recorded in the source documents.
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed primarily by counting 
returned sachets/tablets/capsules during the site visits and documented in the source 
documents.
A record of the number and strength of SZC/placebo sachets (5 or 10 g) and the number and 
strength of lisinopril/valsartan/irbesartan tablets/capsules dispensed to and returned by each 
participant must be maintained and reconciled with study intervention and compliance 
records. This information will be recorded in the source documents, together with the dates of 
the dispensation and return. In addition, the prescribed SZC/placebo and 
lisinopril/valsartan/irbesartan treatment, in terms of dosing and time of titration, will be 
recorded.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
57 of 125
For the purpose of study reporting, compliance to SZC/placebo treatment regimen will then be 
evaluated by means of comparison between the number and type of sachets estimated to be 
taken by the participant, and the recorded prescription. 
6.5
Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of 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
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. Medication other than that described in the subsections below, which is 
considered necessary for the participant’s safety and wellbeing, may be given at the discretion 
of the investigator.
6.5.1
Restricted Concomitant Medication
Restricted medications are listed in Table 6. Restricted medications taken outside the 
conditions as specified in the “Instruction” column, due to, eg, compelling medical reasons 
that necessitate such an action, will be considered as disallowed medications, the use of which 
constitutes a protocol deviation.
Table 6
Restricted Medications
Type of medication/treatment
Instruction
Potassium binders including SPS, CPS, patiromer 
sorbitex calcium (Veltassa®)
Only permitted to be used as short-term rescue 
therapy to treat an AE of severe hyperkalaemia 
(recommended if S-K > 6.0 mmol/L)
ACEi/ARB other than the study ACEi/ARB
Not permitted concomitantly with any ACEi/ARB 
study drug after the initiation phase
ACEi, angiotensin converting enzyme inhibitor; AE, adverse event; ARB, angiotensin II receptor blocker; 
CPS, calcium polystyrene sulfonate; SPS, sodium polystyrene sulfonate; S-K, serum potassium.
Interaction with Other Medicinal Products and Other Forms of Interaction
Effect of Other Medicinal Products on SZC
As SZC is not absorbed or metabolised by the body, there are no expected effects of other 
medicinal products on the pharmacological action of SZC.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
58 of 125
Effect of SZC on Other Medicinal Products
As SZC is not absorbed or metabolised by the body and does not meaningfully bind other 
medicinal products, there are limited effects on other medicinal products. 
SZC can transiently increase gastric pH by absorbing hydrogen ions that can lead to changes 
in solubility and absorption kinetics for co-administrated drugs with pH-dependent 
bioavailability. Therefore, SZC should be administered at least 2 hours before or 2 hours after 
oral medications with clinically meaningful gastric pH dependent bioavailability.
Examples of drugs that should be taken 2 hours before or after SZC/placebo to avoid possible 
raised gastric pH drug interactions are listed in Table 7.
Table 7
Examples of Drugs that Should be Taken 2 hours Before or After 
SZC/Placebo to Avoid Possible Raised Gastric pH Drug Interactions
Class of Drug
Drugs
Azole antifungals
Ketoconazole, itraconazole, posaconazole
Anti-HIV drugs
Atazanavir, nelfinavir, indinavir, ritonavir, saquinavir, 
raltegravir, ledipasvir, rilpivirine
Tyrosine kinase inhibitors
Erlotinib, dasatinib, nilotinib
HIV, human immunodeficiency virus; SZC, Sodium zirconium cyclosilicate.
SZC/placebo can be co-administered without spacing of dosing times with oral medications 
that do not exhibit pH-dependent bioavailability.
In a clinical drug-drug interaction study conducted in healthy subjects, co-administration of 
SZC with amlodipine, dabigatran, clopidogrel, atorvastatin, furosemide, glipizide, warfarin, 
losartan, or levothyroxine did not result in clinically meaningful drug-drug interactions. No 
dose adjustments or separation of the time of dosing are required for these drugs.
In another drug-drug interaction study in healthy volunteers, co-administration of SZC 15 g 
with tacrolimus 5 mg resulted in a decreased tacrolimus area under the concentration-time 
curve and maximum observed concentration by 37% and 29%, respectively. Therefore, 
tacrolimus should be taken at least 2 hours before or after SZC/placebo. In the same study, co-
administration of SZC and cyclosporin did not show a clinically meaningful interaction.
See Appendix D for drug interactions for lisinopril and valsartan.
6.5.2
Rescue Medication
Rescue therapy for controlling hyperkalaemia is defined as any short-term (24 to 48 hours) 
therapeutic intervention during the run-in and maintenance phases, that is considered 
necessary as per the investigator’s judgment and in accordance with local practice patterns to 
reduce S-K in the setting of an AE of severe hyperkalaemia. Rescue therapy is recommended 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
59 of 125
in general if S-K > 6.0 mmol/L unless otherwise specified in the protocol (see Section 6.6.4). 
Rescue therapy may include, but is not limited to, insulin/glucose, beta adrenergic agonists, 
sodium bicarbonate as well as dialysis, or other forms of renal replacement treatments, and 
other potassium binders including SPS, CPS, patiromer sorbitex calcium (Veltassa®) given 
for short-term control of severe hyperkalaemia. SZC/placebo must be temporarily 
discontinued while rescue therapy is administered.
All potassium binders other than SZC are considered restricted medications and can be used 
only for short-term rescue. They must not be used for chronic treatment during the study. Any 
participant who receives chronic treatment with potassium binders other than SZC/placebo 
must be discontinued from SZC/placebo study intervention.
Rescue medication for hyperkalaemia will not be provided as part of study medications.
6.5.3
COVID-19 Vaccination
COVID-19 vaccination of participants during the study is permitted as per national/local 
guidelines and provided the vaccine is licensed by country health authorities including 
emergency use authorisation by the FDA or similar authorisation by other regulatory agencies. 
The specific vaccine used (brand name) and each dose administered after enrolment should be 
recorded as concomitant medication. Adverse events suspected of being related to 
vaccinations should be reported as for any other AEs. Vaccines which are still in 
development, ie, in study, not yet approved, are not permitted.
6.6
Dose Modification
The investigator should rely primarily on local laboratories to make rapid or urgent decisions 
regarding clinical management. This includes monitoring of electrolytes (eg, S-K), renal 
function (eg, S-Cr), and other parameters that may be needed for appropriate CKD clinical 
management as per investigator's discretion.
The S-K and S-Cr samples collected and analysed by local laboratory as per the SoA 
(Section 1.3) or as part of routine clinical practice can also be used to adjust doses of 
SZC/placebo and lisinopril/valsartan.
During the run-in and maintenance phases, SZC/placebo can be titrated in the range 5 g QOD 
to 15 g QD. Lisinopril overall dose range/titration steps for this study are 5, 10, 20, or 40 mg 
QD; valsartan dose range/titration steps are 40, 80, 160, or 320 mg QD (see Table 8). In case 
of valsartan shortage, see Appendix E for irbesartan information. Temporary discontinuations 
of SZC/placebo or lisinopril/valsartan are permitted as part of the dosing regimen.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
60 of 125
If at any point in the study lisinopril/valsartan treatment is reduced or temporarily 
discontinued, the investigator should make every effort to restart and maximise the dose of 
these agents once the cause of the reduction or discontinuation has resolved.
Instructions for dose modification and monitoring and management of S-K during the study 
are provided in the subsections below.
6.6.1
Monitoring Lisinopril/Valsartan Titration During the Run-in and 
Maintenance Phases
Anytime during the run-in and maintenance phases, if lisinopril/valsartan doses are increased 
(or decreased or discontinued because of hyperkalaemia), participants will be called for 
additional local laboratory S-K sampling after 2 weeks, or earlier, as per investigator’s 
judgment. This includes dose changes that occur during scheduled study visits and during 
unscheduled visits corresponding to usual clinical care. This aligns with KDIGO 2020 Clinical 
Practice Guideline for Diabetes Management in CKD (KDIGO 2020, Practice Point 1.2.2), 
which indicates that changes in S-K, S-Cr, and blood pressure should be monitored within 2 to 
4 weeks of initiation or increase in the dose of an ACEi or ARB, and earlier laboratory 
monitoring may be indicated for participants at high risk of hyperkalaemia due to low eGFR, 
history of hyperkalaemia, or borderline high S-K concentration. Appendix C provides 
instructions for the use of SZC/placebo to manage abnormalities in S-K levels found in such 
visits.
All local S-K values that trigger either an SZC/placebo or lisinopril/valsartan dose 
modification should be specified in the clinical record. If lisinopril or valsartan doses need to 
be reduced or discontinued for reasons other than abnormalities in S-K, the reason should also 
be recorded (eg, rise in S-Cr > 30%, low blood pressure, AE).
6.6.2
Lisinopril/Valsartan Dosing Upon Entry to and During the Run-in 
Phase
Upon entering the run-in phase:
!
Participants who are not on ACEi or ARB therapy will be started on lisinopril or valsartan 
on the first day of the run-in phase at the starting dose (STEP 1) indicated in Table 8. The 
choice of drug class is per investigator judgment.
!
Participants who are on other ACEi or ARB therapy at the starting daily dose will be 
changed to lisinopril or valsartan on the first day of the run-in phase at the starting dose 
(STEP 1) indicated in Table 8, keeping the same drug class.
!
Participants who are on other ACEi or ARB therapy with daily doses in the mid-range or 
at maximum will be changed to lisinopril or valsartan on the first day of the run-in phase, 
keeping the same drug class, following the RAASi dose equivalence guidance in 
Appendix B 1 and Appendix B 2.
!
Participants who are on lisinopril or valsartan will continue treatment at the same dose.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
61 of 125
The following dose steps in Table 8 should be used for up-titration of lisinopril and valsartan:
Table 8
Lisinopril and Valsartan Dose Titration Steps
Dose steps (daily dose)
Lisinopril (mg)a
Valsartan (mg) a
STEP 1 – Starting dose
10 (5) b
80
STEP 2
20
160
STEP 3
40
320
a
Starting dose and dose range may differ per local labels. For example, in Japan, where starting and/or 
maximum doses are lower than specified above, the following would apply:
∀
STEP 1: lisinopril 10 mg; valsartan 40 mg
∀
STEP 2: lisinopril 20 mg; valsartan 80 mg
∀
STEP 3: lisinopril 20 mg; valsartan 160 mg
b
If lisinopril starting dose is 5 mg (eg, if eGFR ≥10 to ≤30 mL/min/1.73m2, or participant is on diuretics, or 
per local label), stepwise increase in these cases may require an additional step: 5, 10, 20 and 40 mg.
eGFR, estimated glomerular filtration rate.
As per Section 4.1.3, if temporary use of irbesartan is necessary due to local market shortage, 
see Appendix E for further details, including conversion information for changing from 
valsartan or other ARBs to irbesartan, ARB dose equivalence ranges, dose modification 
strategy for irbesartan, and other prescribing information about irbesartan.
6.6.3
Strategy for Lisinopril/Valsartan Up-Titration During the Run-in 
Phase Visits
Review of concurrent drugs and dietary potassium intake should be performed in all cases of 
hyperkalaemia before a decision is made to reduce or withdraw lisinopril/valsartan therapy. 
Whenever lisinopril/valsartan is temporarily discontinued because of hyperkalaemia and these 
agents are already at the lowest possible dose, every effort should be made to reinitiate them 
as soon as possible at the investigator’s discretion and following a review of concurrent drugs 
and dietary potassium intake. In this case starting doses of lisinopril/valsartan should be used. 
Suitability of lisinopril/valsartan up-titration based on other clinical parameters, such as S-Cr 
and blood pressure, is left to the investigator’s clinical judgment (KDIGO 2020). At any step 
during the study if hypokalaemia (S-K < 3.5 mmol/L) occurs, see Appendix C for further 
actions.
Visit 4 (Day 13 ± 3 days)
!
If S-K is ≥3.5 and < 4.7 mmol/L, and if not already on maximum dose, increase 
lisinopril/valsartan one step; follow 2 weeks later with a local laboratory measurement of 
S-K.
!
If S-K is ≥4.7 and ≤5.5 mmol/L, increase SZC to 15 g QD, repeat S-K in 48 hours and 
follow instructions in Appendix C; if lisinopril/valsartan is increased one step based on 
these instructions, follow 2 weeks later with a local laboratory S-K measurement.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
62 of 125
!
If S-K is > 5.5 and ≤6.0 mmol/L, temporarily discontinue lisinopril/valsartan, increase 
SZC to 15 g QD, repeat S-K in 48 hours and follow instructions in Appendix C. After 
48 hours:
#
If S-K is ≥3.5 and < 4.7 mmol/L, restart lisinopril/valsartan at previous dose.
#
If S-K is ≥4.7 and ≤5.0 mmol/L, restart lisinopril/valsartan at lower dose if 
available. If lower dose is not available, consider reinitiating lisinopril/valsartan at 
starting dose 2 weeks after visit or permanently discontinue lisinopril/valsartan as per 
investigator judgment.
#
If S-K is > 5.0 and ≤6.0 mmol/L, reduce or permanently discontinue 
lisinopril/valsartan per investigator judgment.
#
If S-K is > 6.0 mmol/L, permanently discontinue lisinopril/valsartan, continue 
short-term rescue therapy as per SoC.
!
If S-K > 6.0, temporarily discontinue lisinopril/valsartan, increase SZC to 15 g QD, repeat 
S-K in 48 hours, consider short-term rescue therapy as per SoC. Per Appendix C, after 
48 hours:
#
If S-K is ≥3.5 and < 4.7 mmol/L, restart lisinopril/valsartan at previous dose.
#
If S-K is ≥4.7 and ≤5.0 mmol/L, restart lisinopril/valsartan at lower dose if 
available. If lower dose is not available, consider reinitiating lisinopril/valsartan at 
starting dose 2 weeks after visit or permanently discontinue lisinopril/valsartan as per 
investigator judgment.
#
If S-K is > 5.0 and ≤6.0 mmol/L, reduce or permanently discontinue 
lisinopril/valsartan per investigator judgment.
#
If S-K is > 6.0 mmol/L, permanently discontinue lisinopril/valsartan, continue 
short-term rescue as per SoC.
!
Follow 2 weeks after any dose adjustment with a local laboratory S-K measurement or 
earlier if clinically indicated.
Unscheduled visit for monitoring of lisinopril/valsartan up-titration 2 weeks after Visit 4 (or 
earlier if clinically indicated)
!
If S-K is ≥3.5 and < 4.7 mmol/L, increase lisinopril/valsartan one step (if not already 
maximal); follow 2 weeks later with a local laboratory measurement of S-K.
!
If S-K is ≥4.7 mmol/L, follow instructions in Appendix C; chosen path depending on 
whether SZC is at maximum dose or not.
Up-titration of lisinopril/valsartan should be continued following the above stepwise scheme 
until the maximum dose has been achieved.
It is generally expected to take up to 3 up-titration steps and up to 6 weeks (2 weeks for each 
step) for a participant to reach the maximum lisinopril/valsartan dose during the run-in phase.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
63 of 125
6.6.4
Use of SZC/Placebo for Management of Serum Potassium Immediately 
after Randomised Withdrawal (Up to Week 6 of Maintenance Phase)
At Visit 6b, the participant is randomised to SZC or placebo (ie, to withdraw SZC and receive 
placebo), at the same dose as the last dose of SZC during the run-in phase. Lisinopril/valsartan 
is continued at the same dose received at the end of the run-in phase. As the investigator and 
the participant are blinded to the SZC/placebo treatment assignment, specific instructions for 
management of S-K during the period immediately following randomisation are provided 
below. All participants must return for Visit 7 exactly 2 days after randomisation.
Note: Use Table 8 for STEP-wise dose adjustments and Section 6.5.2 for information 
about rescue therapy.
Visit 7 (2 days after Visit 6b/randomisation)
!
If S-K ≥3.5 and ≤5.0 mmol/L, continue lisinopril/valsartan at the same dose; the 
participant must return 5 (± 1) days later to Visit 8 for a local S-K laboratory 
measurement.
!
If S-K is > 5.0 and ≤5.5 mmol/L and SZC/placebo IS NOT at maximum of 15 g QD, 
increase SZC/placebo to 15 g QD AND reduce lisinopril/valsartan one step. If 
lisinopril/valsartan is at the lowest dose, pause dosing and assess re-initiation of these 
agents at starting doses (STEP 1) during the next visit. The participant must return 
5 (± 1) days later to Visit 8 for a local S-K laboratory measurement.
!
If S-K is > 5.0 and ≤5.5 mmol/L and SZC/placebo IS at maximum of 15 g QD, reduce 
lisinopril/valsartan one step. If lisinopril/valsartan is at the lowest dose (STEP 1), pause 
dosing and assess re-initiation of these agents at STEP 1 starting doses during the next 
visit. The participant must return 5 (± 1) days later to Visit 8 for a local S-K laboratory 
measurement.
!
If S-K is > 5.5 mmol/L and:
#
Lisinopril/valsartan is at the lowest dose, permanently discontinue lisinopril/valsartan 
and consider short-term rescue therapy and management of hyperkalaemia as per 
SoC at the investigator’s discretion and local practice. Follow up at Visit 8 for 
monitoring of local S-K laboratory value.
#
Lisinopril/valsartan is at mid-range (STEP 2) or maximum dose (STEP 3), pause 
lisinopril/valsartan and SZC/placebo, and give short-term rescue therapy as per SoC 
at the investigator’s discretion (24 to 48 hours rescue treatment); re-start 
SZC/placebo after rescue and increase to 15 g QD if not already at maximum. Follow 
up at Visit 8 for monitoring of local S-K laboratory value.
Visit 8 (5 [±1] days after Visit 7)
!
If S-K is ≥3.5 and ≤5.0 mmol/L and lisinopril/valsartan treatment has continued at any 
dose since Visit 7, the dose will remain unchanged, and the participant will follow the 
SoA (Section 1.3) to return for Visit 9.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
64 of 125
!
If S-K is ≥3.5 and ≤5.0 mmol/L and lisinopril/valsartan treatment was paused on Visit 7, 
but no rescue was given, re-initiate these agents at starting doses (STEP 1). Follow up 
5 (± 1) days later in an unscheduled visit for a local S-K laboratory measurement.
!
If S-K is ≥3.5 and ≤5.0 mmol/L WITH rescue given at Visit 7 (but not during past 
72 hours), consider re-initiating lisinopril/valsartan at starting dose (STEP 1). If rescue 
was continued during past 72 hours, permanently discontinue lisinopril/valsartan and 
return to SoC as per local practice. Follow up 5 (± 1) days later in an unscheduled visit for 
a local S-K laboratory measurement.
!
If S-K is > 5.0 WITH rescue given at Visit 7, permanently discontinue lisinopril/valsartan 
and return to SoC as per local practice.
!
If S-K is > 5.0 and ≤5.5 mmol/L and no rescue was given at Visit 7 and SZC/placebo IS 
NOT at maximum of 15 g QD, increase SZC/placebo to 15 g QD AND reduce 
lisinopril/valsartan one step. If lisinopril/valsartan is at the lowest dose (STEP 1), pause 
dosing and assess re-initiation of these agents at starting doses during the next visit. The 
participant must return 5 (± 1) days later to an unscheduled visit for a local S-K 
laboratory measurement.
!
If S-K is > 5.0 and ≤5.5 mmol/L and no rescue was given at Visit 7 and SZC/placebo IS
already at 15 g QD, reduce lisinopril/valsartan one step. If lisinopril/valsartan is at the 
lowest dose (STEP 1), pause dosing and assess re-initiation of these agents at STEP 1 
starting doses during the next visit. The participant must return 5 (± 1) days later to an 
unscheduled visit for a local S-K laboratory measurement.
!
If S-K is > 5.5 mmol/L and no rescue was given at Visit 7 and:
#
Lisinopril/valsartan is at the lowest dose (STEP 1), permanently discontinue 
lisinopril/valsartan and consider short-term rescue therapy and management of 
hyperkalaemia as per SoC at the investigator’s discretion and local practice. Follow 
up 5 (± 1) days later to an unscheduled visit for a local S-K laboratory measurement.
#
Lisinopril/valsartan is at mid-range (STEP 2) or maximum dose (STEP 3), pause 
lisinopril/valsartan and SZC/placebo, consider short-term rescue therapy as per SoC 
at the investigator’s discretion; re-start SZC/placebo after rescue and increase to 15 g 
QD if not already at maximum. Follow up 5 (± 1) days later to an unscheduled visit 
for a local S-K laboratory measurement.
Unscheduled Visit (5 [± 1] days after Visit 8)
!
If S-K is ≥3.5 and ≤5.0 mmol/L and lisinopril/valsartan was paused at Visit 8, restart 
lisinopril/valsartan at starting dose and schedule follow-up visits as per KDIGO 2020 
Clinical Practice Guideline for Diabetes Management in CKD (KDIGO 2020, Practice 
Point 1.2.2); the participant will in addition follow the SoA (Section 1.3) and return for 
Visit 9.
!
If S-K is > 5.0 mmol/L, permanently discontinue lisinopril/valsartan if on treatment, and 
consider short-term rescue therapy and management of hyperkalaemia as per SoC at the 
investigator’s discretion and local practice.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
65 of 125
6.6.5
Additional Unscheduled Visits for Titration of Lisinopril/Valsartan 
Doses During the Run-in and Maintenance Phases
If at any time the participant exhibits any evidence of poor RAASi tolerability, which may 
include, but is not limited to, local laboratory S-K > 5.0 mmol/L, hypotension, or clinically 
significant decline of eGFR (per investigator judgment), down-titration of lisinopril/valsartan 
may be considered per investigator judgment. Similarly, if eGFR is < 20 mL/min/1.73m2, 
down-titration of lisinopril/valsartan will be at the investigator's discretion.
If at any point in the study an unexpected intercurrent clinical event causes lisinopril/valsartan 
dose to be reduced or temporarily discontinued, the investigator should make every effort to 
restart and maximise the dose of these agents once the event has resolved. The stepwise 
approach described above beginning in Visit 4 should be used if the participant cannot be 
restarted immediately on the same dose given prior to the event.
6.7
Intervention After the End of the Study
Not applicable. Individual physicians may manage each of their study participants according 
to local laboratory values and the local SoC.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
At any time, participants are free to discontinue study intervention or withdraw from the 
study, without prejudice to further treatment.
7.1
Discontinuation of Study Intervention
7.1.1
Permanent Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
any or all study intervention (SZC, placebo, lisinopril, and valsartan).
Note that permanent discontinuation from study intervention is NOT the same as withdrawal 
from the study. If, upon discontinuation of study intervention, the participant choses to 
withdraw from the study entirely, procedures described in Section 7.2 should be followed.
Participants should be discontinued from study intervention in the following situations as 
detailed below:
!
Situations applicable to all study interventions
#
Participant decision. The participant is at any time free to discontinue treatment, 
without prejudice to further treatment.
#
Initiation of dialysis or kidney transplantation occurring prior to randomisation.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
66 of 125
#
Severe non-compliance with the CSP.
#
Pregnancy (See Section 8.3.7).
!
Additional situations applicable to SZC/placebo
#
An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing with SZC/placebo.
#
Local laboratory S-K < 3.5 or > 6.5 mmol/L at any time during the initiation phase 
(applicable only for initiation phase).
#
Local laboratory S-K < 3.0 mmol/L at any time during the study; the participant 
should immediately receive appropriate medical intervention.
#
Absolute QTc > 550 ms, or an increase in QTc interval > 60 ms from baseline to 
> 500 ms is reached; the participant should immediately receive appropriate medical 
intervention. The QTcF algorithm is recommended. All participants meeting the 
QTc > 500 msec criterion on study intervention should immediately have potassium 
assessed, if not already done within 1 hour of performing the ECG.
#
Chronic use of potassium binders other than SZC.
!
Additional situations applicable to lisinopril/valsartan
#
An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing with lisinopril/valsartan, including, but not limited to, angioedema, jaundice, 
or marked elevations of hepatic enzymes.
#
Severe hyperkalaemia as per titration algorithm (see Appendix C).
#
Advanced CKD with low eGFR (eg, sustained eGFR < 20 mL/min/1.73m2).
7.1.1.1
Procedures for Permanent Discontinuation of Study Intervention
The following general procedures should be followed when study intervention is discontinued.
!
The Investigator should instruct participants to contact the site before or at the time study 
intervention is stopped. A participant who decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs.
!
If at any time during the course of the study, discontinuation of lisinopril/valsartan or 
SZC/placebo is deemed advisable by the Sponsor for safety reasons, the study physician 
will promptly discuss with the principal investigator to agree on discontinuing these 
agents and further actions to take to ensure the participant’s safety.
!
With the exception of the initiation phase, the participant should attend an ED visit if any 
study intervention is discontinued. The ED visit should take place as soon as possible 
after discontinuation and can be combined with a scheduled visit, if appropriate. See the 
SoA (Section 1.3) for data to be collected at the time of the ED visit. It is possible for a 
participant to have more than one ED visit (ie, if SZC/placebo or lisinopril/valsartan are 
discontinued at different times).
!
The time and the reason for discontinuation of any study intervention will be recorded.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
67 of 125
!
Participants discontinuing study intervention should be given locally available SoC 
therapy, at the discretion of the investigator.
Additional procedures to be followed when a participant is discontinued from study 
intervention are described below for each phase of the study:
!
Initiation Phase
#
If SZC is discontinued, the participant should attend a follow-up Visit 7 (± 2) days 
after the last dose of SZC. This is the last visit in the study for the participant. See the 
SoA (Section 1.3) for data to be collected at the follow-up visit.
!
Run-in Phase
#
If any study intervention (SZC or lisinopril/valsartan) is discontinued, the other study 
intervention must be discontinued. See NOTE.
#
The participant should attend an ED visit.
#
The participant should attend a follow-up Visit 7 (± 2) days after the last dose of 
study intervention. This is the last visit in the study for the participant. See the SoA 
(Section 1.3) for data to be collected at the follow-up visit.
!
Maintenance Phase
#
If either SZC/placebo or lisinopril/valsartan is discontinued:
o
The participant may remain on the other study intervention. See NOTE.
o
The participant should attend an ED visit.
o
The participant must remain in the study and attend all subsequent visits as 
planned.
#
If both SZC/placebo and lisinopril/valsartan are discontinued:
o
The participant should attend an ED visit.
o
It is preferred that the participant remain in the study and attend all subsequent 
visits as planned.
o
If the participant is unwilling to remain in the study and attend all subsequent 
visits as planned, it is acceptable to offer modified follow-up. Modified 
follow-up options include, but are not limited to, modified visit schedule, 
telephone contact, or allowing the investigator to check medical records for 
information about the participant’s health status.
NOTE: Participants who are started on lisinopril and who subsequently develop any common 
nonserious side effects (eg, cough), can change to valsartan at a comparable dose range per 
Appendix B 1 at the investigator’s discretion. If this happens, the participant will complete an 
ED visit when lisinopril is permanently discontinued. The participant can continue to receive 
SZC/placebo (and valsartan) in the study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
68 of 125
7.1.2
Temporary Discontinuation
Temporary discontinuation (hold) of study intervention is allowed for the following situations:
!
Situations applicable to all study intervention
#
Participant decision. The participant is at any time free to discontinue treatment, 
without prejudice to further treatment.
#
An AE temporarily precluding further therapy with SZC/placebo or 
lisinopril/valsartan
!
Additional situations applicable to SZC/placebo
#
Hypokalaemia
!
Additional situations applicable to lisinopril/valsartan
#
Hyperkalaemia as described in Appendix C and Section 6.6.4
#
Symptomatic hypotension
#
Rise in S-Cr > 30% within 2 weeks from previous dose increase visit
#
eGFR < 20 mL/min/1.73m2
Temporary discontinuation of any study intervention should not be a reason for permanent 
discontinuation and the participant should be allowed to resume treatment as soon as, in the 
opinion of the investigator, the participant’s condition is stable, and the participant wishes to 
resume. The time and reason for temporary discontinuation, as well as the time of the 
re-initiation of treatment, will be recorded.
Temporary discontinuation of SZC or lisinopril/valsartan in the run-in phase does not preclude 
randomisation provided the participant meets the requirement to proceed to the maintenance 
phase (Section 4.1.3).
7.1.3
Procedures for Erroneously Dosed or Randomised Participants
Participants who fail to meet the eligibility criteria for the study (Sections 5.1 and 5.2) or fail 
to meet requirements for entering any phases of the study (Sections 4.1.2, 4.1.3, and 4.1.4) 
will not, under any circumstances, enter that phase. There can be no exceptions to this rule. If 
a participant does not meet all the study eligibility criteria or the requirements for entering a 
study phase but is dosed in error, or incorrectly randomised, then the investigator should 
inform the AstraZeneca Study Physician immediately. A discussion should then occur 
between the AstraZeneca Study Physician and the investigator regarding whether to continue 
or discontinue the participant from treatment (see Section 7.1.1). The AstraZeneca Study 
Physician must ensure all decisions are appropriately documented. If the participant initiates 
the first phase of the study on a higher dose than indicated by the CSP (ie, 10 g TID rather 
than 5 g QD) due to a mistake in the initial S-K evaluation, then this should be considered an 
overdose, and the procedures detailed in Section 8.4 should be followed.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
69 of 125
7.2
Participant Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request without 
prejudice to further treatment. In exceptional circumstances, the participant may be withdrawn 
at any time at the discretion of the investigator for safety, behavioural, compliance, or 
administrative reasons.
A participant who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or collecting information from medical records).
At the time of withdrawal from the study, if possible, an ESD visit should be conducted per 
SoA (Section 1.3). The participant will discontinue the study intervention, if applicable, and 
be withdrawn from the study at that time.
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulation. The investigator 
must document the decision on use of existing samples in the site study records and inform the 
Global Study Team. 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.
7.3
Lost to Follow up
A participant will be considered lost to follow up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for any of the 
required study visits:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three 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.
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix A.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
70 of 125
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the SoA, is essential and required for study conduct. 
Unscheduled visits may occur in-between scheduled visits for evaluation of a participant’s 
clinical status. Assessments and activities that may be performed at such visits may include, 
but are not limited to, local or central laboratory measurements, collection of AEs/SAEs, 
study intervention dose adjustment, dispensation of study intervention, or other assessments 
deemed clinically necessary by the investigator.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria (Sections 5.1 and 5.2). 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. Similarly, the evaluation of normokalaemia must 
be completed before the entry into the run-in and the maintenance phases, with the results 
recorded as appropriate (see Sections 4.1.2, 4.1.3, and 8.9.1).
The following efficacy, safety (including AEs and SAEs), and other assessments apply also 
for irbesartan if used instead of valsartan because of a shortage of the latter. See Appendix E 8
for irbesartan overdose information.
8.1
Efficacy Assessments
8.1.1
Assessments Based on Laboratory Analyses
Laboratory efficacy variables are shown in Table 9.
Table 9
Laboratory Efficacy Variables
Primary endpoint
Secondary endpoint
•
eGFR a (S-Creatinine)
•
eGFR a (S-Creatinine)
•
UACR b (U-Albumin and U-Creatinine)
•
S-Potassium
•
S-Bicarbonate
a
The eGFR will be derived by race agnostic CKD-EPI equation (Delgado et al 2022, Inker et al 2021) and 
calculated by central laboratory for the analysis of the primary endpoint. The race adjusted eGFR will also 
be calculated and may be used for sensitivity or supportive analyses (Levey et al 2009).
b
The UACR will be calculated by central laboratory.
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; 
S, serum; U, urine; UACR, urine albumin-to-creatinine ratio.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
71 of 125
Analyses will be performed at a central laboratory contracted by AstraZeneca; the timing of 
the samples is indicated in the SoA (Section 1.3). For instructions on the sampling process, 
see Section 8.2.4.1.
8.1.2
Other Efficacy Assessments
Composite Outcome
The components of the composite of kidney failure outcomes are defined below, based on 
Levin et al 2020:
!
Sustained percent decline in eGFR, defined as percent decline in eGFR of ≥40% from the 
point of randomisation over at least 4 weeks, as evidenced by 2 consecutive central 
laboratory measurements taken at least 4 weeks apart. The start date of the event is the 
date of the first central laboratory measurement.
!
Onset of ESKD:
#
Kidney transplantation, defined as receipt of a kidney transplant or
#
Maintenance dialysis, defined as dialysis performed for at least 4 weeks, or
#
Sustained low eGFR, defined as eGFR < 15 mL/min/1.73m2 over at least 4 weeks, as 
evidenced by 2 consecutive central laboratory measurements taken at least 4 weeks 
apart.
!
Death from kidney failure, defined as the participant dies, AND kidney replacement 
therapy was never started (irrespective of reason), AND advanced CKD is the underlying 
cause of death.
The central laboratory will notify the site if there is ≥40% decline in eGFR compared to the 
point of randomisation or if eGFR is < 15 mL/min/1.73m2. A central laboratory re-sampling 
should be done at an unscheduled visit after at least 4 weeks, and preferably no later than 
6 weeks, after the first sampling.
Whether an event of death qualifies as death from kidney failure will be determined by the 
investigator and indicated in the source documentation and eCRF. Similarly, the initiation of 
renal replacement therapy (kidney transplantation or maintenance dialysis) will be recorded by 
the investigator in the source documentation and eCRF.
Lisinopril/Valsartan Dosing Pattern
The prescribed dose, the start, and the stop dates, as well as the timing of the dose titration of 
lisinopril/valsartan will be recorded and used to determine the time to the first dose change to 
a dose that is smaller than that taken at the point of randomisation.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
72 of 125
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
8.2.1
Physical Examinations
A complete physical examination will include an assessment of general appearance, 
respiratory system, CV system, abdomen, skin, head, and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid gland, musculoskeletal system (including spine and extremities), 
and neurological system.
A brief physical examination will include an assessment of general appearance, respiratory 
system, CV system, and abdomen.
New or worsening abnormalities may qualify as AEs; see Section 8.3 for details.
Height will be assessed using locally available tools without the participant wearing shoes. 
Weight will be assessed using the same scale (properly maintained and calibrated), and with 
the participant wearing a similar amount of clothes (eg, underwear only or light indoor 
clothing only) at each time.
8.2.2
Vital Signs
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. 
For all participants, blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest in a supine or sitting position in a quiet setting without distractions (eg, 
television, cell phones) and should be taken before any blood sampling (unless otherwise 
noted in the SoA; Section 1.3). The participant should be relaxed with the arm outstretched 
and supported. Blood pressure should be measured in the upper arm in either the supine or 
sitting position. No shift from one position to another should be made during the study. The 
participant should also abstain from caffeine for at least one hour prior to the measurements.
Systolic and diastolic blood pressure will be measured by an adequately trained health care 
professional. Measurements with a calibrated sphygmomanometer are preferred. If not 
available, another device calibrated carefully in proportion to a mercury sphygmomanometer 
is preferred. The use of aneroid manometers should be avoided. An appropriate cuff size must 
be used to ensure accurate measurement.
8.2.3
Electrocardiograms
A 12-lead ECG will be performed with a properly maintained and calibrated machine. The 
recording should be done after the participant has been lying down to rest for at least 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
73 of 125
5 minutes. For participants with pacemakers, ECG variables should be read manually. ECG 
may also be performed according to clinical judgment and should be performed in connection 
with hypokalaemia (S-K < 3.0 mmol/L) or hyperkalaemia (S-K > 6 mmol/L), or as indicated 
based on any symptoms or clinical events (eg, cardiac arrhythmia).
The following ECG parameters should be collected: PR interval, RR interval, QRS duration, 
QT and QTcF intervals, and heart rate. An overall evaluation of the ECG results should also 
be performed.
8.2.4
Clinical Safety Laboratory Assessments
8.2.4.1
Clinical Safety Central Laboratory Assessments
Blood samples for determination of clinical chemistry, haematology, and pregnancy will be 
taken at the visits indicated in the SoA (Section 1.3).
Analyses will be performed at a central laboratory contracted by AstraZeneca. Sites will be 
provided with ready-to-use laboratory kits, as well as appropriate instructions/manuals, where 
procedures for collection, processing, and sending samples to the central laboratory will be 
described.
All serum samples should be examined, and any haemolysed samples must be re-drawn.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.
The laboratory variables listed in Table 10 will be measured.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
74 of 125
Table 10
Central Laboratory Safety Variables
Haematology/haemostasis (whole blood)
Haemoglobin (Hb)
Leucocyte count
Leucocyte differential count (absolute count)
Platelet count
Clinical chemistry (serum)
Bilirubin, total, direct and indirect
Alkaline phosphatase (ALP)
Alanine transaminase (ALT)
Aspartate transaminase (AST)
Gamma glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Urea nitrogen
Creatinine
Glucose
Uric acid
Calcium
Phosphorus
Total protein
Albumin
Globulin
Triglycerides
Cholesterol
Creatine kinase (CK)
Sodium
Potassium
Bicarbonate
Chloride
Magnaesium
Pregnancy test (serum)
Human chorionic gonadotropin (HCG)
8.2.4.2
Clinical Safety Local Laboratory Assessments
Blood samples for determination of clinical chemistry for local laboratory safety monitoring 
will be taken at the visits indicated in the SoA (Section 1.3).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
75 of 125
All serum samples should be examined, and any haemolysed samples must be re-drawn.
Additional safety samples may be collected, if clinically indicated at the discretion of the 
investigator.
The minimum laboratory variables listed in Table 11 will be measured for safety monitoring. 
Additional variables may be measured if clinically indicated at the discretion of the 
investigator.
Table 11
Local Laboratory Safety Variables
Clinical chemistry (serum)
Urea nitrogen
Creatinine
Sodium
Potassium
Bicarbonate
Chloride
8.3
AEs and SAEs
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix G.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorised representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from the start of first dose of study intervention (Visit 2 of 
initiation phase) throughout the treatment period and including the follow-up period.
Serious AEs will be recorded from the time of signing of the ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the Study 
intervention 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.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
76 of 125
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate 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 when the AE started and stopped
!
Maximum intensity (mild, moderate, or severe). For event of hypokalaemia, mild 
intensity refers to S-K ≥ 3.0 to < 3.5 mmol/L, moderate intensity ≥ 2.5 to < 3.0 mmol/L, 
and severe intensity < 2.5 mmol/L.
!
Whether the AE is serious or not
!
Whether the AE required rescue therapy for severe hyperkalaemia or not
!
Whether the AE fulfils the criteria of death from kidney failure or not
!
Investigator causality rating against each study intervention, SZC, SZC/placebo, and 
lisinopril/valsartan (yes or no)
!
Action taken with regard to each study intervention
!
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 each study intervention and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
77 of 125
possibility that the event may have been caused by the study intervention?’ for each study 
intervention (SZC, SZC/placebo, lisinopril/valsartan).
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 G.
8.3.4 AEs 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 AEs Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarised in the 
CSR.
Deterioration as compared to baseline in protocol-mandated laboratory values 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 intervention or are considered to be clinically 
relevant as judged by the investigator (which may include but is not limited to consideration 
as to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
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).
Hypokalaemia leading to a temporary or a permanent discontinuation of SZC or SZC/placebo 
should be reported as an AE.
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.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
78 of 125
8.3.6
Reporting of SAEs
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within 1 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 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix G.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for SZC and is the applicable SmPC for lisinopril and valsartan.
8.3.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
!
Pregnancy discovered before the study participant has received any study intervention
!
Pregnancies in the partner of male participants
8.3.7.1
Maternal Exposure
If a participant becomes pregnant during the study, all study intervention should be 
discontinued immediately.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
79 of 125
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study.
If any pregnancy occurs during the study, then the investigator or other site personnel informs 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.6) and within 30 days for all other pregnancies.
8.3.7.2
Paternal Exposure 
There is no restriction on fathering children or donating sperm during the study.
8.3.8
Medication Error
Medication error reporting is only required for SZC and SZC/placebo.
The definition of a medication error can be found in Appendix G 4.
If a medication error occurs during the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (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 8.3.6) and within 30 days for all other 
medication errors.
8.4
Overdose
8.4.1
SZC or SZC/Placebo
For participants entering the initiation phase being hyperkalaemic (based on local laboratory 
S-K), any dose of SZC > 30 g within 1 day or continuation of the correction dose (10 g TID) 
for more than 72 hours will be considered an overdose. For participants entering the initiation 
phase being normokalaemic (based on local laboratory S-K), any dose of SZC > 5 g within 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
80 of 125
1 day will be considered an overdose. If the overdose is discovered during the initiation phase, 
the dosing regimen should immediately be corrected to the one pre-specified by the CSP.
During the run-in and maintenance phases, any dose of SZC or SZC/placebo > 15 g within 
1 day will be considered an overdose.
!
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 SZC or SZC/placebo occurs during the study, the investigator or other site 
personnel inform appropriate AstraZeneca representatives immediately, but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see section 8.3.6) and within 30 days
for all other overdoses.
8.4.2
Lisinopril/Valsartan
During the run-in and maintenance phases, any dose of valsartan or lisinopril greater than the 
prescribed daily dose is considered an overdose with potential risks, and safety monitoring as 
per SoC shall take place.
An overdose with associated SAEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.6).
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 H.
8.5.1
Pharmacokinetics
Pharmacokinetic samples are not collected in this study.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
81 of 125
8.5.2
Immunogenicity
Immunogenicity samples are not collected in this study.
8.5.3
Pharmacodynamics
Pharmacokinetic samples are not collected in this study.
8.6
Human Biological Sample Biomarkers
Samples for biomarker analysis will not be collected in this study.
8.7
Optional Genomics Initiative Sample
Optional Genomics Initiative research is not applicable in this study.
8.8
Medical Resource Utilisation and Health Economics
Medical resource utilisation and health economics data are not collected in this study.
8.9
Other Assessments
8.9.1
Local Laboratory Measurements
The S-K will be measured by local laboratory to determine if a participant can proceed into 
the next phase of the study (see Section 4.1). The S-K and S-Cr measurements obtained from 
the local laboratories will also be used to determine the need for dose adjustments 
(SZC/placebo and lisinopril/valsartan; see Section 6.6). Finally, local laboratories will be used 
for safety purposes to evaluate S-K in the period following the randomisation and throughout 
the maintenance phase.
For determination of SZC starting dose at Visit 2/Day 1 of the initiation phase, the local 
laboratory sample can be taken on the same day as the visit, or the day before.
For dose titration during the run-in and maintenance phases, the local laboratory samples can 
be taken on the same day as a scheduled or unscheduled visit, or the day before (excluding 
Visits 7 and 8); for Visits 7 and 8, the samples must be taken on the same day as the scheduled 
visit and not the day before.
Data results from local S-K laboratory samples should be obtained as soon as possible after 
sample collection, but no later than 24 hours after the sample collection. If dose adjustments 
are required, the investigator will inform the participant either by phone or during a visit, 
depending on the time point when the laboratory results are available.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
82 of 125
8.9.2
Demography and Medical History
Demography will include basic background participant information such as age, sex, and race. 
Collection of medical history will include history of nicotine use (former, current, never 
smoker) and an overview of relevant medical conditions, including CKD etiology.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
Statistical testing will be performed for all primary and secondary hypotheses. In all cases, the 
null hypothesis will be that of no difference between the treatment arms (SZC vs placebo). 
The family-wise Type I error rate will be controlled in the strong sense over the families of the 
primary and the secondary hypotheses.
Two co-primary hypotheses (corresponding to the evaluation of the difference in total and 
chronic eGFR slope, respectively) are defined in the study. Provided both of the primary 
hypotheses are rejected, the testing will proceed to the secondary hypotheses. A fixed 
sequence MTP will be applied to the family of all secondary hypotheses, with the order in the 
sequence following the order specified in Table 4.
Both of the co-primary hypotheses will be tested at a two-sided significance level of 0.05. In 
accordance with the fixed sequence MTP, significance for a hypothesis corresponding to a 
secondary endpoint will be declared if the corresponding two-sided p-value is smaller than 
0.05, provided that all other preceding hypotheses in the sequence have been rejected.
9.2
Sample Size Determination
Approximately 3000 participants will be enrolled (screened) to achieve approximately 
1500 participants receiving at least one dose of SZC during the initiation phase, consequently 
leading to a target of 1360 participants randomly assigned to SZC or placebo.
Note that “enrolled” refers to a participant’s, or their legally acceptable representative’s, 
agreement to participate in the study following completion of the informed consent process.
The assumptions for variability of the eGFR measurements between and within participants 
used in the calculation below are taken from the DECLARE study (D1693C00001 
[NCT01730534]): between-participant SD (ie, SD of the random slopes) of 2.6 and within-
participant SD (ie, SD of the residuals) of 7.7. The difference in slopes in the 2 treatment arms 
is assumed to be 0.75, a magnitude that is deemed clinically relevant. For the purpose of 
sample size determination, it is also assumed that no acute effects are present, ie, that the 
decline in eGFR over time in both treatment arms is well-approximated by a single line with a 
particular slope.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
83 of 125
Given this, and assuming a two-sided test of a difference in slopes based on a linear mixed 
model, with a two-sided significance level of 0.05, is performed, then approximately 
1220 participants with complete eGFR data will provide a power of 91% for the evaluation of 
total slope. This is true provided the following time points for eGFR assessment, in terms of 
weeks since randomisation, are observed for each participant as a minimum: 0 
(randomisation), 6, 12, 16, 20, 24, 46, 69, 92, 96, 100, and 104.
Under the same assumptions (ie, a difference in slopes of 0.75, no acute effect), the power for 
the chronic slope will be approximately 85%. The evaluation of the chronic slope is assumed 
to start at 12 weeks.
It is expected that approximately 20% of the eGFR data will be missing. As the eGFR data is 
correlated within participant, it is assumed that the data points available for a participant will 
provide information on the missed evaluations, and 20% of missed data would roughly 
correspond to approximately 10% of randomised participants with no eGFR data available. 
Hence, 1360 participants will be randomised in the maintenance phase.
Possible Causes for Missing Data during the Randomised Treatment Phase
The initial expectation that approximately 20% of eGFR measurements during the randomised 
treatment phase will be missing, is largely inferred from DAPA-CKD (Heerspink et al 2020). 
Death from any cause and ESKD were identified as the 2 potential main contributors for 
missing eGFR data. Looking at the placebo group in the aforementioned publication, it is 
expected that approximately 7% of participants will reach ESKD during the 2 years of 
randomised treatment phase, and approximately 6% of participants will die; this is a 
conservative assumption as some participants will likely experience both of these events. It 
should be noted that the DAPA-CKD study had a somewhat healthier patient population that 
included patients with eGFR between 25 and 75 mmol/L (10% of the patient population in the 
study had an eGFR > 60 mmol/L). In addition, the hyperkalaemia requirement in the 
STABILIZE-CKD study might lead to a lower baseline eGFR in general, so a somewhat 
larger percentage of missing data due to the reasons mentioned above is expected. The 
expectation is that approximately 15% of the missing values will originate from ESKD or 
death.
In addition to these 2 major reasons, it is expected that data points will also be missing due to 
a number of smaller issues, such as participants not attending visits, blood samples not being 
analysable, and participants either discontinuing the study or discontinuing treatment and 
choosing an alternative follow-up option that precludes blood sampling. The magnitude of 
such smaller issues is difficult to predict, but it is expected that they might, cumulatively, lead 
to an additional 5% of the data points being missing, which would, together with ESKD and 
death, add up to approximately 20% of missing data.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
84 of 125
9.3
Populations for Analyses
The populations for analysis are defined in Table 12.
Table 12
Populations for Analysis
Population/analysis set
Description
Enrolled
All participants who sign the ICF.
Safety analysis set, initiation 
phase (SAS-IP)
All participants receiving at least one dose of SZC during the initiation 
phase.
Safety analysis set, run-in 
phase (SAS-RIP)
All participants receiving at least one dose of SZC during the run-in phase.
Safety analysis set, 
maintenance phase (SAS-MP)
All randomised participants receiving at least one dose of SZC or placebo 
during the maintenance phase. Participants erroneously receiving incorrect 
SZC or placebo will be analysed according to the treatment arm they were 
randomised to.
Full analysis set (FAS)
All randomised participants.
ICF, informed consent form; SZC, Sodium zirconium cyclosilicate.
9.4
Statistical Analyses
The SAP will be finalised prior to data base lock and will provide a complete description of all 
the planned statistical analyses, including the analyses of the secondary objectives, sensitivity 
and complementary analyses of the primary objective, descriptions of supportive data 
overviews, and procedures for handling of missing data. The complementary analyses will eg, 
include an exploration of the potential effect that temporarily switches from valsartan to 
irbesartan have on the efficacy evaluation. This section is primarily a summary of the planned 
statistical analysis of the primary objective(s).
Analyses will be performed by AstraZeneca or its representatives.
9.4.1
General Considerations
The Full Analysis Set will be used for the efficacy evaluations, while the different safety 
analysis sets will be used for the safety evaluation, performed for each study phase separately.
9.4.2
Efficacy
The analysis of both primary and secondary efficacy endpoints will be performed according to 
the intention-to-treat principle and will be based on all randomised participants, regardless of 
whether they did or did not receive treatment or had any protocol deviations.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
85 of 125
9.4.2.1
Co-primary Endpoint(s)
Estimand
Population: Participants satisfying the inclusion and the exclusion criteria of the study and 
achieving normokalaemia after a 3-month run-in period, while on SZC treatment regimen, 
during which lisinopril/valsartan dose optimisation has been attempted.
Intervention: SZC and placebo, while receiving lisinopril/valsartan, as guided by the CSP.
Population-level summary: Difference in population-level eGFR slopes between SZC and 
placebo.
Intercurrent events: In general, the intercurrent events that lead to a potential change in the 
measurements profile, but for which post-intercurrent event data are available (eg, treatment 
discontinuation, introduction of eGFR altering concomitant therapy), will be ignored, and all 
eGFR data obtained, both pre and post the intercurrent event will be used in the primary 
analysis. This would correspond to a treatment policy approach as per ICH E9 (R1) and align 
with the intention-to-treat principle. The exception to this rule will be the events for which it 
could be argued that, after experiencing these, a participant ceases to belong to the population 
of interest, namely onset of ESKD as defined in Section 8.1.2. For such an event, any data 
collected post event occurrence will be excluded from the analysis of the primary objective.
Analysis
To evaluate both primary objectives, a linear mixed effects model will be used, with the eGFR 
values obtained at and after randomisation (total slope) and at and after 12-week visit (chronic 
slope) for a participant at a particular visit as the dependent variable. The following covariates 
will be included in the fixed effects part of the model:
!
Time since randomisation
!
Treatment
!
Time and treatment interaction
Other covariates, as appropriate, might also be included and will be specified in the SAP. In 
addition, 2 random effects, intercept and time since randomisation, will be incorporated within 
a participant, with an underlying assumption of an unstructured covariance matrix between the 
two. A covariance matrix that assumes independence for the distribution of the residuals 
within each participant, but allows for different variability for different time points, will be 
applied, with a more general structure (eg, unstructured) used if issues with the model fit are 
encountered. An unstructured covariance matrix will also be assumed for the distribution of 
the residuals within each participant. The null hypothesis of no difference between SZC and 
placebo will be tested by considering the fixed effect of time and treatment interaction term in 
the model above (ie, the difference in slopes between the 2 treatment arms). The estimates of 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
86 of 125
the slopes obtained from the model, as well as the difference between the two, and the 
corresponding SD estimates, will be presented. For the difference, the two-sided 95% 
confidence intervals and p-values will also be provided.
A number of sensitivity analyses of the primary endpoints will be performed. These will 
include, but might not be limited to, the following:
!
A two-slope model (acute and chronic) with knot at 12 weeks post-randomisation (ie, 
using the same interval for the chronic slope as is utilised in the primary analysis). From 
this, estimates of the total and the chronic slope will be obtained. The purpose of this 
analysis is to evaluate the sensitivity of the results to the choice of approaching the 
primary objective via two separate models rather than a single combined one.
!
A series of two-slope models (acute and chronic) with varying position of knots (the 
times of connection between acute and chronic slopes) other than 12 weeks. The purpose 
of this analysis is to evaluate the impact of the choice of 12 weeks as the start of the 
chronic eGFR profile on the estimate of the treatment effect.
!
A shared parameter model that jointly models the eGFR profiles and time to ESKD or 
death. The purpose of this analysis is to evaluate the potential impact that the possibly 
informative drop-out caused by these 2 events has on the estimate of the effect of SZC.
!
A tipping point analysis to explore the potential impact of data that are missing due to 
participant being lost to follow-up or entering a modified follow-up that precludes 
collection of eGFR measurements.
!
A repeated measures model that includes the same covariates as the main analysis and 
utilises an unstructured (marginal) covariance matrix to reflect the dependence between 
observations obtained at different timepoints for the same participant.
!
Same model as the one utilised for the main analysis, where missing eGFR values will be 
imputed as follows: if a participant is considered to enter ESKD through initiation of 
dialysis or kidney transplant, but no corresponding eGFR value is available, this will be 
imputed to a value that is less than 15 mL/min/1.73m2.
In addition, graphical illustrations of eGFR profiles over time, eg, a scatter plot of eGFR 
values with a non-parametric smoothing curve in the respective treatment arm, will be 
provided to illustrate the plausibility of the assumption of a linear eGFR decline and the 
potential presence of acute effects.
The consistency of effect across subgroups defined by inclusion criterion 5 (Section 5.1) will 
be evaluated for the primary endpoint by obtaining effect estimates in each of these, along 
with the p-values for the test of the corresponding interaction. In addition, if the size of the 
subgroups allows, the subgroups in which the consistency of the main results will be evaluated 
will include, but might not be limited to the following: geographic region; diabetes at 
randomisation (yes/no); eGFR classification at randomisation; UACR classification at
randomisation; adequate RAASi dose at screening (yes/no); adequate RAASi dose at 
randomisation (yes/no); CKD aetiology; SGLT2 inhibitor and/or finerenone use at 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
87 of 125
randomisation (yes/no). Further details of the subgroup analyses plan, including full 
specification of the groupings, will be provided in the SAP.
The eGFR will be calculated according to the race agnostic CKD-EPI formula (Delgado et al 
2022, Inker et al 2021) for the main analysis of the primary endpoint. The eGFR will also be 
calculated according to the original race adjusted CKD-EPI formula (Levey et al 2009) and 
may be used for sensitivity or supportive analyses.
9.4.2.2
Secondary Endpoint(s)
The analysis of the secondary objectives will be presented in the SAP.
9.4.3
Safety
Safety analyses will be performed separately for the different phases of the study using the 
3 safety sets defined above, as appropriate. Safety data will be presented primarily using 
descriptive statistics, by treatment arm and study phase.
Adverse Events
Adverse events will be coded using the most recent version of the MedDRA that will have 
been released for execution at AstraZeneca.
A high-level overview of AEs will be presented for each treatment group and will include the 
number and percentage of participants with any AE, AEs with outcome of death, SAEs, and 
AEs leading to discontinuation of SZC/placebo or lisinopril/valsartan.
Adverse events will be presented for each treatment group by system organ class and/or 
preferred term, covering number and percentage of participants reporting at least one event 
and number of events where appropriate. Similar tables will be created for SAEs, 
discontinuations due to AE, and AEs with the outcome of death. Separate AE tables will be 
provided to illustrate AE pattern with respect to causal relationship as assessed by the 
investigator, as well as the intensity of AEs. Key information will be presented for participants 
with AEs with outcome of death, serious AEs, and AEs leading to discontinuation of 
SZC/placebo. Adverse events occurring during the screening period will be presented in a 
listing.
Vital Signs, Laboratory Evaluations, and ECG
The distribution of the measurements over time will be illustrated by presenting the summary 
statistics (mean, SD, median, minimum, maximum) of the values obtained at the study visits, 
as well as change from baseline to each of the respective visits. The occurrence of extreme 
measurements, eg, measurements falling outside pre-defined criteria at any point during a 
study phase, or measurements judged to be abnormal by the investigator, will be summarised 
by means of frequencies and percentages.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
88 of 125
Events of Hypokalaemia and Oedema
A tabulated overview of oedema-related AEs will be presented, with oedema-related AE 
defined through the following preferred terms: fluid overload, fluid retention, generalised 
oedema, hypervolaemia, localised oedema, oedema, oedema peripheral, peripheral swelling.
Instances of S-K < 3.5 mmol/L at particular visits, as well as the number and percentage of 
participants with S-K < 3.5 mmol/L at any point during a study phase, will be tabulated. 
Instances of S-K < 3.0 and < 2.5 mmol/L will be presented in a similar manner.
9.5
Interim Analyses 
There are no interim analyses planned in this study.
9.6
Data Monitoring Committee
An independent DMC that is unblinded to treatment allocation will be responsible for 
safeguarding the interests of the participants throughout the study. For details on the DMC, 
see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
89 of 125
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
#
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
#
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
#
Applicable laws and regulations
!
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated.
!
Any 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 
Contract Research Organisation (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 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European Regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to the Sponsor of a serious adverse event (SAE) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary.
#
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
90 of 125
review and then file it along with the Investigator’s Brochure 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 or study centre.
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
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.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
91 of 125
A 5
Committees Structure
A 5.1
Executive Committee
Together with AstraZeneca, the Executive Committee will be responsible for the final overall 
study design, including the development of the study protocol and any protocol amendments 
needed during the study, liaison with the Data Monitoring Committee (DMC), as needed, 
development of the charter, and supervision, interpretation, and reporting (presentations at 
international congresses and publications in peer reviewed journals) of the study. 
The Executive Committee will make recommendations to AstraZeneca with regard to early 
stopping or modifications of the study based on the information received from the DMC. The 
Executive Committee will be comprised of designated international academic leaders and 
non-voting members of the Sponsor and will operate under an Executive Committee charter.
A 5.2
Data Monitoring Committee
An independent DMC will be appointed. The DMC will be responsible for monitoring the 
progress of the study with respect to randomisation, compliance, and follow up, as well as for 
reviewing the unblinded data for evidence of benefit or harm. The DMC can make 
recommendations to the Sponsor and the Executive Committee to alter or terminate all or part 
of the trial. A DMC charter will be prepared to detail precise roles and responsibilities and 
procedures to ensure maintenance of the blinding and integrity of the study in the review of 
accumulating data and interactions with the Executive Committee.
A 6
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 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on electronic case report form 
(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.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
92 of 125
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the in the Monitoring Plan and Clinical Trial Agreement.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs).
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data 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 ICH GCP Section 1.52 Source 
Documents.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
93 of 125
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines.
!
Inadequate recruitment of participants by the investigator.
!
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
94 of 125
Appendix B
RAASi Therapy Considerations for Inclusion into the Study 
and Dosing of Lisinopril and Valsartan
B 1
Guide for Change of Other RAASi therapy into an Equivalent 
Dose Range for Lisinopril or Valsartan
Other ACEi or ARB SoC dose a
Lisinopril (mg) b
Valsartan (mg) b
None or starting daily dose
10 (5) c
80
Mid-range daily dose (doses between starting and 
maximum dose if applicable)
20 (10) c
160
Maximum daily dose
20 (20) c
160
a
See Appendix B 2 for starting, mid-range (if applicable), and maximum daily dose of each individual 
ACEi/ARB drug.
b
Starting dose may differ per local labels. For example, in Japan, where starting doses are lower than 
specified above, the following would apply:
∀
Starting: lisinopril 10 mg; valsartan 40 mg
∀
Mid-range: lisinopril 20 mg; valsartan 80 mg
∀
Maximum: lisinopril 20 mg; valsartan 160 mg
c
If eGFR ≥10 to ≤30 mL/min/1.73m2 or participant is on diuretics, or per local label, lisinopril starting, 
mid-range, and maximum are 5, 10, and 20 mg, respectively.
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated 
glomerular filtration rate; SoC, standard of care.
For subsequent up-titration of lisinopril or valsartan during the run-in phase, see 
Sections 6.6.2 and 6.6.3.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
95 of 125
B 2
RAASi Dose Equivalence Table
Drug
Starting daily dose
Mid-range daily dose
(if applicable)
Maximum daily dose
ARB
Valsartan a
80 mg
160 mg 
320 mg
Losartan a
50 mg 
-
100 mg
Olmesartan
20 mg 
-
40 mg
Azilsartan
20 – 80 mg
40 mg
80 mg
Candesartan
16 mg 
-
32 mg
Irbesartan a
150 mg
-
300 mg
Telmisartan
40 mg 
-
80 mg
ACEi
Lisinopril a
10 mg
20 mg
40 mg
Ramipril
CrCl < 40 mL/min: 25% 
of normal dose
2.5 mg
5 mg, 10 mg
20 mg
Perindopril b
CrCl < 30 mL/min: not 
recommended
2 mg
4 mg
8 mg
Benazepril
10 mg
CrCl < 30 mL/min: 5 mg 
20 mg, 40 mg
80 mg
Captopril
CrCl 10-50 mL/min: 
75% of normal dose
CrCl < 10 mL/min: 50% 
of normal dose
12.5 – 25 mg bid to tid
12.5 mg tid
25 mg, 37.5 mg bid to tid
50 mg bid
Usually 50 mg tid (may 
go up to 450 mg)
Enalapril
5 mg
CrCl ≤30 mL/min: 
2.5 mg 
10 mg, 20 mg
40 mg
Fosinopril
10 mg 
20 mg, 40 mg
80 mg
Quinapril
10 mg
CrCl 61-89 mL/min: 
10 mg
CrCl 30-60 mL/min: 
5 mg
CrCl 10-29 mL/min: 
2.5 mg
20 mg, 40 mg
80 mg
Trandolapril
1 mg
CrCl < 30 mL/min: 
0.5 mg 
2 mg
4 mg

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
96 of 125
NOTE: Dosage recommendations are based on KDIGO guidelines (KDIGO 2020)/information from package 
inserts registered in the United States and may differ across countries and regulatory authorities.
a
Doses may differ per local labels. For example, valsartan starting dose can be 40 mg; losartan starting dose 
can be 25 mg; irbesartan starting dose can be 50 or 75 mg; irbesartan maximum dose can be 200 mg (eg, 
Japan); lisinopril starting dose can be 2.5 or 5 mg.
b
Refers to perindopril erbumine (tablet strength may differ depending on perindopril salt).
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; bid, twice daily; 
CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving 
Global Outcomes; tid, three times daily.
B 3
Definitions of RAASi Adequate Dose
Renin-angiotensin-aldosterone system inhibitor (RAASi) adequate dose levels are defined 
below. Doses lower than the ones listed below are considered as suboptimal.
The definition of “limited RAASi therapy” for purposes of inclusion in the study 
(Section 5.1) = no or suboptimal RAASi.
ARB
Adequate daily dose a, b
ACEi
Adequate daily dose a, b
Valsartan
160 - 320 mg
Lisinopril
20 - 40 mg
Losartan
50 - 100 mg
Ramipril
CrCl < 40 mL/min: 25% 
of normal dose
10 - 20 mg
Olmesartan
40 mg
Perindopril c
CrCl < 30 mL/min: not 
recommended
8 mg
Azilsartan
40 - 80 mg
Benazepril
20 - 80 mg
Candesartan
32 mg
Captopril
CrCl 10-50 mL/min: 
75% of normal dose 
CrCl < 10 mL/min: 50% 
of normal dose 
37.5 bid - 50 mg tid
Irbesartan
300 mg
Enalapril
10 - 40 mg
Telmisartan
80 mg
Fosinopril
20 - 80 mg
Quinapril
20 - 80 mg
Trandolapril
2 - 4 mg 
NOTE: Adequate dose level definitions are based on KDIGO guidelines (KDIGO 2020)/information from 
package inserts registered in the United States and may differ across countries and regulatory authorities.
a
Normokalaemic participants with hypertension or primary glomerular diseases with nephrotic range 
proteinuria (> 3.5 g/24 hours) who are at high risk of hyperkalaemia, not taking maximal RAASi doses as 
per local label but currently receiving doses in the range considered adequate in this table can be included in 
the normokalaemic cohort if in the investigator’s judgment the current RAASi dose is not optimal for their 
condition. In these participants, it is expected that RAASi doses will be up-titrated to maximal during the 
run-in phase.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
97 of 125
b
Where a range is indicated, any daily dose within that range is considered an adequate daily dose.
c
Refers to perindopril erbumine (tablet strength may differ depending on perindopril salt).
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; bid, twice daily; 
CrCl, creatinine clearance; RAASi, renin-angiotensin-aldosterone system inhibitor; tid, three times daily.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
98 of 125
Appendix C
Instructions for Use of SZC/Placebo for Management of 
Serum Potassium During the Run-in and Maintenance Phases
Anytime during the run-in and maintenance phases, if lisinopril/valsartan doses are increased 
(or decreased or discontinued because of hyperkalaemia), participants will be called for 
additional local laboratory serum potassium (S-K) sampling after 2 weeks or earlier if in the 
investigator’s judgment this is indicated. This includes dose changes that occur during 
scheduled study visits and during unscheduled visits corresponding to usual clinical care. This 
aligns with KDIGO 2020 Clinical Practice Guideline for Diabetes Management in chronic 
kidney disease (CKD) (KDIGO 2020, Practice Point 1.2.2), which indicates that changes in 
S-K, serum creatinine (S-Cr), and blood pressure should be monitored within 2 to 4 weeks of 
initiation or increase in the dose of an angiotensin converting enzyme inhibitor (ACEi) or 
angiotensin II receptor blocker (ARB), and earlier laboratory monitoring may be indicated for 
participants at high risk of hyperkalaemia due to low estimated glomerular filtration rate, 
history of hyperkalaemia, or borderline high S K concentration. Instructions for the use of 
SZC/placebo for management of S-K at such visits during the run-in and maintenance phases 
are provided below.
In addition, other appropriate monitoring as per routine clinical practice during 
renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in CKD (eg, S-Cr) should be 
performed. Refer to KDIGO 2020, which states that, in regard to renal function, initiation or 
up-titration of RAASi therapy can be done as long as S-Cr does not rise > 30% from pre-
dosing value.
If at any point in the study lisinopril/valsartan treatment is reduced or temporarily 
discontinued, the investigator should make every effort to restart and maximise the dose of 
these agents once the cause of the reduction or discontinuation has resolved.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
99 of 125
Note: If a lower dose of a study intervention (SZC/placebo or lisinopril/valsartan) is not available, temporary or 
permanent discontinuation should follow at the investigator’s discretion depending on the participant’s clinical 
condition. Also note that similar actions as algorithm above should be followed for irbesartan in case of 
temporary valsartan shortage.
a
After actions in a panel are completed: recheck S-K within 2 weeks if RAASi therapy is restarted at any 
dose or increased (see KDIGO 2020); otherwise, recheck S-K at investigator’s discretion; and proceed as 
per Appendix C per new S-K values.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
100 of 125
b
KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD (KDIGO 2020).
c
SZC/placebo must be temporarily discontinued when rescue therapy is administered. Once rescue therapy is 
completed (typically within a few hours), SZC/placebo can be resumed at the maximum dose (if not already 
at maximum dose).
d
If S-K is ≥4.7 and ≤5.0 mmol/L, and the participant is on SZC 15 QD and a stable dose of 
lisinopril/valsartan, a S-K re-check at 48h and further actions may not be necessary. This decision is left to 
the investigator’s clinical judgment.
CKD, chronic kidney disease; KDIGO, Kidney Disease: Improving Global Outcomes; PBO, placebo; QD, once 
daily; S-K, serum potassium; SoC, standard of care; SZC, Sodium zirconium cyclosilicate.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
101 of 125
Appendix D
Drug Interactions for Lisinopril and Valsartan
D 1
Drug Interactions for Lisinopril
Drug Interactions for Lisinopril
Type of medication/treatment
Instruction
Antihypertensive agents
When combined with other antihypertensive agents (eg, glyceryl 
trinitrate and other nitrates, or other vasodilators), additive falls in BP 
may occur.
Concomitant use with aliskiren-containing products is contraindicated 
in participants with diabetes mellitus or renal impairment 
(eGFR < 60 mL/min/1.73m2).
Concomitant use of ACEi, ARB, or aliskiren is associated with a 
higher frequency of AEs and increases the risk of hypotension, 
hyperkalaemia and decreased renal function (including acute renal 
failure). Dual blockade of RAAS through the combined use of ACEi, 
ARB, or aliskiren is therefore not recommended.
Sacubitril/valsartan
Concomitant use with sacubitril/valsartan is contraindicated as this 
increases the risk of angioedema. Treatment with sacubitril/valsartan 
must not be initiated earlier than 36 hours after the last dose of 
lisinopril. Treatment with lisinopril must not be initiated earlier than 
36 hours after the last dose of sacubitril/valsartan.
mTOR inhibitors (eg, temsirolimus, 
sirolimus, everolimus), NEP inhibitors 
(eg, racecadotril), vildagliptin, or tissue 
plasminogen activator
Concomitant use may increase the risk of angioedema (eg, swelling of 
the airways or tongue, with or without respiratory impairment). 
Caution should be used when starting racecadotril, mTOR inhibitors 
and vildagliptin in a patient already taking lisinopril.
Diuretics
Antihypertensive effects are usually additive. Participants already on 
diuretics and especially those in whom diuretic therapy was recently 
instituted, may occasionally experience an excessive reduction of BP 
when lisinopril is added. The possibility of symptomatic hypotension 
with lisinopril can be minimised by discontinuing the diuretic prior to 
initiation of treatment with lisinopril.
In some patients with bilateral renal artery stenosis or with a stenosis 
of the artery to a solitary kidney, where renovascular hypertension is 
also present there is an increased risk of severe hypotension and renal 
insufficiency. Diuretics should be discontinued, and renal function 
should be monitored during the first weeks of lisinopril therapy.
Potassium-sparing diuretics (eg, 
spironolactone, triamterene or 
amiloride), potassium supplements, 
potassium-containing salt substitutes, 
and other drugs that may increase serum 
potassium levels, eg, trimethoprim and 
co-trimoxazole 
(trimethoprim/sulfamethoxazole)
Concomitant use is not recommended. If concomitant use is indicated, 
they should be used with caution and with frequent monitoring of 
S-K.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
102 of 125
Drug Interactions for Lisinopril
Type of medication/treatment
Instruction
Ciclosporin
Hyperkalaemia may occur during concomitant use. Monitoring of S-K 
is recommended.
Heparin
Hyperkalaemia may occur during concomitant use. Monitoring of S-K 
is recommended.
Lithium
Reversible increases in serum lithium concentrations and toxicity
have been reported during concomitant administration of lithium with 
ACEi. Concomitant use of thiazide diuretics may increase the risk of 
lithium toxicity and enhance the already increased lithium toxicity 
with ACEi. Concomitant use is not recommended, but if the 
combination proves necessary, careful monitoring of serum lithium 
levels is recommended.
NSAIDs including acetylsalicylic acid 
≥3 g/day
When administered simultaneously (ie, acetylsalicylic acid at anti-
inflammatory dosage regimens, COX-2 inhibitors and non-selective 
NSAIDs), attenuation of the antihypertensive effect may occur. 
Concomitant use may lead to an increased risk of worsening of renal 
function, including possible acute renal failure, and an increase in 
S-K, especially in participants with poor pre-existing renal function. 
These effects are usually reversible. The combination should be 
administered with caution, especially in the elderly. Participants 
should be adequately hydrated, and consideration should be given to 
monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter.
Gold
Nitritoid reactions (symptoms of vasodilatation including flushing, 
nausea, dizziness, and hypotension, which can be very severe) 
following injectable gold (eg, sodium aurothiomalate) have been 
reported more frequently in patients receiving ACEi.
Tricyclic antidepressants/antipsychotics/
anaesthetics
May result in further reduction of BP. In patients undergoing major 
surgery or during anaesthesia with agents that produce hypotension, 
Lisinopril may block angiotensin II formation secondary to 
compensatory renin release. If hypotension occurs and is considered 
to be due to this mechanism, it can be corrected by volume expansion.
Sympathomimetics
May reduce the antihypertensive effects of lisinopril.
Antidiabetics, eg, insulins, oral 
hypoglycaemic agents
Epidemiological studies have suggested that concomitant 
administration of ACEi and antidiabetic medicines (insulins, oral 
hypoglycaemic agents) may cause an increased blood glucose 
lowering effect with risk of hypoglycaemia. This phenomenon 
appeared to be more likely to occur during the first weeks of 
combined treatment and in patients with renal impairment. In diabetic 
patients treated with oral antidiabetic agents or insulin, glycaemic 
control should be closely monitored during the first month of 
treatment with lisinopril.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
103 of 125
Drug Interactions for Lisinopril
Type of medication/treatment
Instruction
Acetylsalicylic acid, thrombolytics, beta-
blockers, nitrates
May be used concomitantly with acetylsalicylic acid (at cardiologic 
doses), thrombolytics, beta-blockers, and/or nitrates.
ACEi, angiotensin converting enzyme inhibitor; AE, adverse event; ARB, angiotensin II receptor blocker; 
BP, blood pressure; COX-2, cyclooxygenase-2; eGFR, estimated glomerular filtration rate; mTOR, mammalian 
target of rapamycin; NEP, neutral endopeptidase; NSAID, Non-steroidal anti-inflammatory drugs; RAAS, renin-
angiotensin-aldosterone system; S-K, serum potassium.
D 2
Drug Interactions for Valsartan
Drug Interactions for Valsartan
Type of medication/treatment
Instruction
Dual blockade of RAAS with ARB, 
ACEi, or aliskiren
Concomitant use with aliskiren-containing products is contraindicated 
in participants with diabetes mellitus or renal impairment 
(eGFR < 60 mL/min/1.73m2).
Concomitant use of ACEi, ARB, or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including 
acute renal failure). Dual blockade of RAAS through the combined 
use of ACEi, ARB, or aliskiren is therefore not recommended.
Lithium
Concomitant use is not recommended. Reversible increases in serum 
lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with ACEi or ARB. If the 
combination proves necessary, careful monitoring of serum lithium 
levels is recommended. If a diuretic is also used, the risk of lithium 
toxicity may presumably be increased further.
Potassium-sparing diuretics, potassium 
supplements, salt substitutes containing 
potassium and other substances that may 
increase potassium levels
Concomitant use is not recommended. If considered necessary, 
monitoring of S-K is advised.
NSAIDs, including selective COX-2 
inhibitors, acetylsalicylic acid > 3 g/day, 
and non-selective NSAIDs
Caution required with concomitant use. Attenuation of the 
antihypertensive effect may occur. Concomitant use may lead to an 
increased risk of worsening of renal function and an increase in S-K. 
Therefore, monitoring of renal function at the beginning of the 
treatment is recommended, as well as adequate hydration of the 
participant.
Transporters
Caution required with concomitant use. Co-administration of 
inhibitors of the uptake transporter (eg, rifampin, ciclosporin) or 
efflux transporter (eg, ritonavir) may increase the systemic exposure 
to valsartan. Exercise appropriate care when initiating or ending 
concomitant treatment with such drugs.
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; COX-2, cyclooxygenase-
2; eGFR, estimated glomerular filtration rate; NSAID, Non-steroidal anti-inflammatory drugs; RAAS, renin-
angiotensin-aldosterone system; S-K, serum potassium.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
104 of 125
Appendix E
Temporary Irbesartan Use in the Event of a Local Valsartan 
Shortage
Refer to this Appendix only if valsartan needs to be temporarily substituted with 
irbesartan during valsartan shortage.
The study is designed to use valsartan as the selected ARB therapy adjunct to SZC. However, 
if an actual shortage of valsartan in a local market jeopardises the ability of participants to 
enter or continue in the study, valsartan can be temporarily substituted with irbesartan until the 
shortage of valsartan is resolved.
During treatment with irbesartan, the same procedures indicated for valsartan discontinuation 
(Section 7) and efficacy, safety, and other assessments (Section 8) must be followed.
As soon as the shortage is resolved, valsartan should be restarted at a dose determined by 
using the conversion table in Appendix B 1, unless in the investigator’s judgment a change in 
dose is required. Every effort should be made to maximise the doses of valsartan and of 
irbesartan if the latter needs to be used because of a valsartan shortage.
E 1
Benefit/Risk Assessment for Irbesartan
See Section 2.3 for the overall benefit/risk assessment of the study.
Details of the risk assessment for irbesartan in this study are presented below. The risk 
assessment is similar to valsartan. Refer to the applicable SmPC for irbesartan for detailed 
information on the risks of this agent.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
105 of 125
Risk Assessment of Irbesartan as Background Intervention
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Hyperkalaemia 
(S-K > 5.0 mmol/L)
Irbesartan can cause 
hyperkalaemia (especially in 
patients with impaired renal 
function) because it inhibits the 
release of aldosterone.
For participants randomised to 
placebo, there is risk of 
hyperkalaemia from irbesartan
Close monitoring of S-K after 
randomisation, including 
scheduled safety visits 2 and 
7 days after randomisation.
Down-titration/withdrawal of 
irbesartan if significant 
hyperkalaemia persists.
Rescue therapy available per 
standard of care/clinical practice.
SZC/placebo dosing based on 
local laboratory S-K and 
instructions in Section 6.6 and 
Appendix C.
S-Cr, serum creatinine; S-K, serum potassium; SZC, Sodium zirconium cyclosilicate.
E 2
Overall Benefit: Risk Conclusion of Use of Irbesartan
Irbesartan is an ARB with comparable RAASi effects to valsartan, and a similar therapeutic 
and safety profile. The use of irbesartan as temporary substitution for valsartan does not 
impact the favourable Benefit/Risk assessment of the study.
E 3
Justification for Dose of Irbesartan
Equivalence calculations for dosing irbesartan during the run-in phase is based on the label 
recommendations for control of blood pressure as the primary indication. Appendix B 2
details the dosing equivalences among RAASi drugs that form the basis for determining the 
doses of irbesartan to be used in the study and are based on KDIGO 2020 Clinical Practice 
Guideline for Diabetes Management in CKD (KDIGO 2020).
If participants are not already on maximum doses of irbesartan upon entry into the run-in 
phase, stepwise dose adjustments to maximum doses as per local label will be done with close 
monitoring of S-K and S-Cr following clinical guidelines for RAASi therapy recommended 
by KDIGO guidelines (KDIGO 2020; see Section 6.6).
Any further dose increases of irbesartan deemed clinically advisable after achieving the 
maximum dose during the early run-in phase should also follow KDIGO guidelines (KDIGO 
2020). If necessary, dose reductions or discontinuation of irbesartan are allowed as judged by 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
106 of 125
the investigator, eg, because of hyperkalaemia, excessive (≥30%) rise in S-Cr, symptomatic 
hypotension, or other compelling medical reasons (KDIGO 2020).
E 4
Investigational Medicinal Product (Irbesartan)
See Section 6.1 for the study interventions (investigational products) SZC/placebo, 
lisinopril/valsartan of the study.
The study intervention (investigational product) irbesartan to be administered in this study 
during valsartan shortage is presented below.
Intervention name/
Characteristic
Irbesartan
Type
Drug
Dose formulation
Tablet
Unit dose strength(s) a
75, 150, or 300 mg
Dosage level(s) a
75, 150, or 300 mg QD
Route of administration
Oral
Use
Background intervention
IMP or NIMP
IMP
Provider
Local sourcing preferred. Under certain circumstances when 
local sourcing is not feasible, irbesartan may be supplied 
centrally through AstraZeneca.
Packaging and labelling
Provided in original package and labelled in accordance with 
GMP Annex 13 and per country regulatory requirement. Label 
text will be translated into local language.
a
For Japan, dose levels are 50, 100, or 200 mg QD with unit dose strengths 50 or 100 mg.
GMP, Good Manufacturing Practice; IMP, investigational medicinal product; NIMP, non-investigational 
medicinal product; QD, once daily.
E 5
Guide for Change of Other RAASi therapy into an Equivalent 
Dose Range for Irbesartan
In the situation that valsartan is not available when a participant should enter the run-in phase, 
the following instructions will be followed.
!
Participants who are not on ACEi or ARB therapy upon entering the run-in phase, and per 
investigator’s judgement are to be initiated on an ARB will be started on irbesartan on the 
first day of the run-in phase (starting dose as per table below).
!
Participants who are on ARB therapy other than irbesartan at screening will have their 
therapy changed to irbesartan upon entering the run-in phase. See Appendix B 2 for 
guidance on the dosing equivalences among ARB drugs and irbesartan.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
107 of 125
!
Participants who are on irbesartan will continue treatment at the same dose.
A participant cannot receive both lisinopril and irbesartan simultaneously and should not take 
any other ACEi or ARB concomitantly with irbesartan.
The table below applies also for dose equivalent conversion of valsartan to irbesartan at any 
stage of the study beyond the run-in phase.
Other ARB SoC dose a
Irbesartan (mg) b
None or starting daily dose
75
Mid-range daily dose (doses between starting and maximum dose if 
applicable)
150
Maximum daily dose
150
a
See Appendix B 2 for starting, mid-range (if applicable), and maximum daily dose of each individual ARB 
drug including valsartan.
b
Starting dose may differ per local labels. For example, in Japan, the following would apply:
∀
Starting: Irbesartan 50 mg if applicable
∀
Mid-range: Irbesartan 100 mg if applicable
∀
Maximum: Irbesartan 100 mg if applicable
ARB, angiotensin II receptor blocker; SoC, standard of care.
For subsequent up-titration of irbesartan during the run-in phase, see Appendix E 6.
E 6
Irbesartan Dose Titration Steps
Upon entering the run-in phase:
Every effort should be made to increase irbesartan to its maximum dose during the run-in 
phase. The following dose steps should be used for up-titration:
Dose steps (daily dose)
Irbesartan (mg) a
STEP 1
75
STEP 2
150
STEP 3
300
a
Starting dose and dose range may differ per local labels. For example, in Japan, the following would apply:
∀
STEP 1: Irbesartan 50 mg if applicable
∀
STEP 2: Irbesartan 100 mg if applicable
∀
STEP 3: Irbesartan 200 mg if applicable
For up-titration and dose modification strategy of irbesartan during the run-in and 
maintenance phases, see Sections 6.6.3, 6.6.4, 6.6.5 and follow the same recommendations as 
for valsartan.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
108 of 125
E 7
Drug Interactions for Irbesartan
Drug Interactions for Irbesartan
Type of medication/treatment
Instruction
Diuretics and other antihypertensive 
agents
Other antihypertensive agents may increase the hypotensive effects of 
irbesartan. Prior treatment with high dose diuretics may result in 
volume depletion and a risk of hypotension when initiating therapy 
with irbesartan. Intravascular volume depletion/symptomatic 
hypotension should be corrected before the administration of 
irbesartan.
Dual blockade of RAAS with ARB, 
ACEi, or aliskiren
Concomitant use with aliskiren-containing products is contraindicated 
in participants with diabetes mellitus or renal impairment 
(eGFR < 60 mL/min/1.73m
2).
Concomitant use of ACEi, ARB, or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including 
acute renal failure). Dual blockade of RAAS through the combined 
use of ACEi, ARB, or aliskiren is therefore not recommended.
Potassium-sparing diuretics, potassium 
supplements, salt substitutes containing 
potassium and other medicinal products 
that may increase potassium levels (eg, 
heparin)
Concomitant use is not recommended.
Lithium
Concomitant use is not recommended. Reversible increases in serum 
lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with ACEi. Similar effects have 
been very rarely reported with irbesartan so far. If the combination 
proves necessary, careful monitoring of serum lithium levels is 
recommended.
NSAIDs (ie, selective COX-2 inhibitors, 
acetylsalicylic acid > 3 g/day, and 
non-selective NSAIDs)
Caution required with concomitant use, especially in the elderly. 
Attenuation of the antihypertensive effect may occur. Concomitant 
use may lead to an increased risk of worsening of renal function, 
including possible acute renal failure, and an increase in S-K, 
especially in patients with poor pre-existing renal function. Patients 
should be adequately hydrated, and consideration should be given to 
monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter.
Repaglinide
Irbesartan has the potential to inhibit OATP1B1. Dose adjustment of 
antidiabetic treatment such as repaglinide may be required.
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; COX-2, cyclooxygenase-
2; eGFR, estimated glomerular filtration rate; NSAID, Non-steroidal anti-inflammatory drugs; 
OATP1B1, organic anion transporting polypeptide 1B1; RAAS, renin-angiotensin-aldosterone system; S-K, 
serum potassium.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
109 of 125
E 8
Irbesartan Overdose
During the run-in and maintenance phases, any dose of irbesartan greater than the prescribed 
daily dose is considered an overdose with potential risks, and safety monitoring as per SoC 
shall take place.
An overdose with associated SAEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.6).

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
110 of 125
Appendix F
Management of Study Procedures During the COVID-19 
Pandemic
F 1
Introduction
Safeguarding the health and wellbeing of our participants and ensuring the continued supply 
of our medicines to participants remains of paramount importance for AstraZeneca through 
the ongoing coronavirus disease 2019 (COVID-19) outbreak.
F 2
Risk Assessment for COVID-19 Pandemic
Sodium Zirconium Cyclosilicate (SZC) is a potassium binder acting in the gastrointestinal 
tract and is not absorbed. No additional risk from COVID-19 is expected due to SZC.
Lisinopril (angiotensin‐converting enzyme inhibitor) and valsartan (angiotensin receptor 
blocker) are oral renin-angiotensin-aldosterone system inhibitors (RAASi) drugs indicated for 
the treatment of hypertension, heart failure, and post-myocardial infarction state. Because 
angiotensin converting enzyme 2 is the receptor that allows coronavirus entry into cells and 
this receptor may be upregulated during RAASi therapy, the use of these drugs has been 
extensively monitored and studied during the COVID-19 pandemic. A comprehensive 
systematic review of a 1.4 million patient nationwide registry that provides the best available 
information on RAASi therapy during the pandemic has shown that these drugs are not 
associated with a higher likelihood of a positive test for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection, greater disease severity, or increased hospitalisations 
and mortality (Savarese et al 2020). Therefore, no additional risk from COVID-19 is expected 
due to lisinopril or valsartan.
However, the risk of exposure to infected people cannot be completely excluded during study 
participation 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).
F 2.1
Measures to Mitigate the Risks Associated with COVID-19
National laws and local recommendations regarding the pandemic will be strictly adhered to.
F 3
COVID-19 at Screening
It is important that participants with possible ongoing or not completely resolved COVID-19 
infection are not to be started on treatment in the study. If the participant has evidence of 
COVID-19 within 2 weeks prior to screening (Visit 1) (eg, a positive COVID-19 test or a 
clinical risk that has not been satisfactorily excluded), the participant should not be enrolled.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
111 of 125
F 4
Suspected COVID-19 After Screening
F 4.1
Participant is Severely Ill or Hospitalised
If the participant becomes symptomatic after screening and has suspected COVID-19 
(regardless of any SARS-CoV-2 test results that may be available), and is severely ill and/or 
hospitalised, the participant may temporarily or permanently discontinue study intervention at 
the discretion of the site investigator.
F 4.2
Participant is NOT Severely Ill or Hospitalised
If the participant becomes symptomatic after enrolment and has suspected COVID-19 
(regardless of whether any SARS-CoV-2 test results are available or not) and is NOT severely 
ill and/or hospitalised, the investigator should determine if continuation of treatment with 
study intervention is in the best interest of the participant.
If feasible and where local regulations allow, remote visits (telemedicine, phone contact) may 
be considered for follow-up purposes.
F 5
Study Interruptions due to COVID-19
F 5.1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete on-site 
study visits and assessments and alternative means for carrying out the visits and assessments 
may be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section F 5.2. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note: in the case of verbal reconsent, the informed 
consent form should be signed at the participant’s next contact with the study site). Visiting 
the study sites for the sole purpose of obtaining reconsent should be avoided.
F 5.2
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the study participants
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, visits that are scheduled to be on-
site may be replaced by a telemedicine visit if allowed by local/regional guidelines. Having a 
telemedicine contact with the participants will allow adverse events and concomitant 
medication to be reported and documented.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
112 of 125
F 5.3
Data Capture During Telemedicine Visits
Data collected during telemedicine visits will be captured by a qualified healthcare 
professional from the study site.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
113 of 125
Appendix G
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
G 1
Definition of Adverse Events
An adverse event (AE) is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
G 2
Definition of Serious Adverse Events
A serious adverse event (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-patient hospitalisation or prolongation of existing hospitalisation.
!
Results in persistent or significant disability or incapacity.
!
Is a congenital anomaly or birth defect.
!
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse events for malignant tumours reported during a study should generally be assessed 
as SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgment on an individual event basis should 
be applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
114 of 125
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 judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring intravenous 
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, neutropaenia 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 
intensity whereas seriousness is defined by the criteria in Appendix G 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
115 of 125
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix G 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 an SAE when it satisfies the criteria 
shown in Appendix G 2.
G 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 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related.’
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
116 of 125
G 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 intervention that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:
!
Occurred
!
Was identified and intercepted before the participant received the drug
!
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet
!
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature
!
Wrong participant received the medication (excluding Interactive Response Technology 
[IRT]/Randomisation and Trial Supply Management [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)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or SoC medication in open-label 
studies, even if an AstraZeneca product
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
117 of 125
Appendix H
Handling of Human Biological Samples
H 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 the 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 lifecycle 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 lifecycle.
H 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented, and study site is notified.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
118 of 125
H 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 three categories: Category A, Category B, or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
them occurs, are 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.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
119 of 125
Appendix I
Abbreviations
Abbreviation or special 
term
Explanation
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
ARB
angiotensin II receptor blocker
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COVID-19
coronavirus disease 2019
CPS
calcium polystyrene sulfonate
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
cardiovascular
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
ED
early discontinuation
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ESD
early study discontinuation
ESKD
end stage kidney disease
FDA
Food and Drug Administration
ICF
informed consent form
ICH
International Council for Harmonisation
IRT
Interactive Response Technology
KDIGO
Kidney Disease: Improving Global Outcomes
MRA
mineralocorticoid receptor antagonist
MTP
multiple testing procedure
QD
once daily
QOD
once every other day
QTcF
QT interval corrected using Fridericia’s formula
RAAS
renin-angiotensin-aldosterone system
RAASi
renin-angiotensin-aldosterone system inhibitor
RTSM
Randomisation and Trial Supply Management
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
120 of 125
Abbreviation or special 
term
Explanation
S-Cr
serum creatinine
SD
standard deviation
SGLT2
sodium-glucose cotransporter-2
S-K
serum potassium
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SoC
standard of care
SPS
sodium polystyrene sulfonate
SZC
sodium zirconium cyclosilicate
TID
three times daily
UACR
urine albumin-to-creatinine ratio
US
United States

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
121 of 125
11
REFERENCES
Ash et al 2015
Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of 
hyperkalemia in patients with chronic kidney disease suggests that the selective potassium 
trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-11.
Astor et al 2011
Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, et al. 
Chronic Kidney Disease Prognosis Consortium: lower estimated glomerular filtration rate and 
higher albuminuria are associated with mortality and end-stage renal disease. A collaborative 
meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79(12):1331-40.
Bakris et al 2020
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone 
on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-29.
CDC 2019
Centers for Disease Control and Prevention. Chronic kidney disease in the United States, 
2019. Available from: https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-
Kidney-Disease-Fact-Sheet.pdf. Accessed 28 February 2022.
Coresh et al 2014
Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, et al. Decline in estimated 
glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 
2014;311(24):2518-31.
Delgado et al 2022
Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, et al. A unifying 
approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing 
the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2022;79(2):268-88.e1.
Di Iorio et al 2019
Di Iorio BR, Bellasi A, Raphael KL, Santoro D, Aucella F, Garofano L, et al. Treatment of 
metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the 
UBI Study. J Nephrol. 2019;32(6):989-1001.
Epstein 2016
Epstein M. Hyperkalemia constitutes a constraint for implementing renin-angiotensin-
aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-
world clinical arena. Kidney Int Suppl. 2016;6(1):20-8.
Gansevoort et al 2011
Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. 
Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A 
collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 
2011;80(1):93-104.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
122 of 125
GBD Chronic Kidney Disease Collaboration 2020
GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic 
kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 
2017. Lancet. 2020;395(10225):709-33.
Grams et al 2019
Grams ME, Sang Y, Ballew SH, Matsushita K, Astor BC, Carrero JJ, et al. Evaluating 
glomerular filtration rate slope as a surrogate end point for ESKD in clinical trials: an 
individual participant meta-analysis of observational data. J Am Soc Nephrol. 2019;30(9): 
1746–55.
Heerspink et al 2020
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al; 
DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic 
kidney disease. N Engl J Med. 2020;383(15):1436-46.
Himathongkam et al 1975
Himathongkam T, Dluhy RG, Williams GH. Potassium-aldosterone-renin interrelationships. J 
Clin Endocrinol Metab. 1975;41(1):153-9.
Hou et al 2007
Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, et al. Renoprotection of optimal 
antiproteinuric doses (ROAD) Study: a randomized controlled study of benazepril and 
losartan in chronic renal insufficiency. J Am Soc Nephrol. 2007;18(6):1889–98.
Inker et al 2019
Inker LA, Heerspink HJL, Tighiouart H, Levey AS, Coresh J, Gansevoort RT, et al. GFR 
slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis 
of treatment effects of randomized controlled trials. J Am Soc Nephrol. 2019;30(9):1735-45.
Inker et al 2021
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New creatinine- and 
cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737-
49.
Jager et al 2019
Jager KJ, Kovesdy C, Langham R, Rosenberg M, Jha V, Zoccali C. A single number for 
advocacy and communication - worldwide more than 850 million individuals have kidney 
diseases. Kidney Int. 2019;96(5), 1048–50.
KDIGO 2013
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
clinical practice guideline for the evaluation and management of chronic kidney disease. 
Kidney Int. 2013;3(1):1-150.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
123 of 125
KDIGO 2020
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 
clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 
2020;98(4S):S1-115.
Kosiborod et al 2014
Kosiborod M, Rasmussen HS, Lavin P, Qunibi WY, Spinowitz B, Packham D, et al. Effect of 
sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with 
hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-33.
Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-12.
Levey et al 2020
Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, Grams ME, et al. Change in 
albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific 
workshop sponsored by the National Kidney Foundation in collaboration with the US Food 
and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020;75(1):84-
104.
Levin et al 2020
Levin A, Agarwal R, Herrington WG, Heerspink HL, Mann JFE, Shahinfar S, et al; 
participant authors of the International Society of Nephrology’s 1st International Consensus 
Meeting on Defining Kidney Failure in Clinical Trials. International consensus definitions of 
clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020;98(4):849-59.
Mahajan et al 2010
Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE. Daily oral sodium 
bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive 
nephropathy. Kidney Int. 2010;78(3):303-9.
Matsushita et al 2015
Matsushita K, Coresh J, Sang Y, Chalmers J, Fox C, Guallar E, et al. Estimated glomerular 
filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative 
meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3(7):514-25.
Miao et al 2011
Miao Y, Dobre D, Heerspink HJL, Brenner BM, Cooper ME, Parving HH, et al. Increased 
serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in 
NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia. 
2011;54(1):44-50.
NICE 2021
NICE Guideline: Chronic kidney disease: assessment and management. Published 25 August 
2021; last updated 24 November 2021. Available from: 
https://www.nice.org.uk/guidance/ng203. Accessed 28 February 2022.

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
124 of 125
NKF 2012
National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 
update. Am J Kidney Dis. 2012;60(5):850-86.
Polson et al 2017
Polson M, Lord TC, Kangethe A, Speicher L, Farnum C, Brenner M, et al. Clinical and 
economic impact of hyperkalemia in patients with chronic kidney disease and heart failure. J 
Manag Care Spec Pharm. 2017;23(4-a Suppl):S2-9.
Provenzo et al 2018
Provenzano M, Minutolo R, Chiodini P, Bellizzi V, Nappi F, Russo D, et al. Competing-risk 
analysis of death and end stage kidney disease by hyperkalaemia status in non-dialysis chronic 
kidney disease patients receiving stable nephrology care. J. Clin. Med. 2018;7(12):499.
Roger et al 2020
Roger SD, Spinowitz BS, Lerma EV, Fishbane S, Ash SR, Martins JG, et al. Sodium 
zirconium cyclosilicate increases serum bicarbonate concentrations among patients with 
hyperkalaemia: exploratory analyses from three randomized, multi-dose, placebo-controlled 
trials. Nephrol Dial Transplant. 2021;36(5):871-83.
Rüster et al 2006
Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J 
Am Soc Nephrol. 2006;17(11):2985-91.
Savarese et al 2020
Savarese G, Benson L, Sundström J, Lund LH. Association between renin-angiotensin-
aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million 
patient nationwide registry analysis. Eur J Heart Fail. 2021;23(3):476-85.
Shah et al 2009
Shah SN, Abramowitz M, Hostetter TH, Melamed ML. Serum bicarbonate levels and the 
progression of kidney disease: a cohort study. Am J Kidney Dis. 2009;54(2):270-7.
Shirazian et al 2015
Shirazian S, Grant CD, Mujeeb S, Sharif S, Kumari P, Bhagat M, et al. Underprescription of 
renin angiotensin system blockers in moderate to severe chronic kidney disease. Am J Med 
Sci. 2015;349(6):510-5.
Turin et al 2013
Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, et al. Change in the 
estimated glomerular filtration rate over time and risk of all-cause mortality. Kidney Int. 
2013;83(4):684-91.
Van der Velde et al 2011
van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, et al. Lower 
estimated glomerular filtration rate and higher albuminuria are associated with all cause and 

Clinical Study Protocol - 2.0 (Amendment 1)
AstraZeneca
Sodium Zirconium Cyclosilicate (SZC), Lisinopril, and Valsartan - D9488C00001
CONFIDENTIAL AND PROPRIETARY
125 of 125
cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. 
Kidney Int. 2011;79(12):1341-52.
Yildirim et al 2012
Yildirim T, Arici M, Piskinpasa S, Aybal-Kutlugun A, Yilmaz R, Altun B, et al. Major 
barriers against renin angiotensin- aldosterone system blocker use in chronic kidney disease 
stages 3–5 in clinical practice: a safety concern? Ren Fail. 2012;34(9):1095-9.
Zannad et al 2020
Zannad F, Hsu BG., Maeda Y, Shin SK, Vishneva EM, Rensfeldt M, et al. Efficacy and safety 
of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo‐controlled 
HARMONIZE‐Global study. ESC Heart Failure 2020;7(1):54-64.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9488c00001-csp-v2-amendment-1
Document Title:
D9488C00001 Clinical Study Protocol version 2 Amendment
1
Document ID:
Doc ID-004539970
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
09-Jun-2022 15:21 UTC
Content Approval
09-Jun-2022 08:35 UTC
Content Approval
09-Jun-2022 07:22 UTC
Content Approval
13-Jun-2022 12:50 UTC
Content Approval
13-Jun-2022 12:23 UTC
Content Approval
14-Jun-2022 06:30 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD
PPD
PPD
PPD