Conditions: Hyperkalemia
Keywords: Hemodialysis Hyperkalemia Cardiovascular Events Atrial Fibrillation Ventricular Tachycardia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2690
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of Sodium Zirconium Cyclosilicate (SZC) on arrhythmia-related cardiovascular outcomes in participants on chronic hemodialysis with recurrent hyperkalemia.

Detailed description:
This is an international, multicenter, event-driven, randomized, double-blind, parallel group, placebo-controlled study, evaluating the utility of SZC versus placebo to reduce the incidence of sudden cardiac death (SCD), stroke, and arrhythmia-related hospitalizations, interventions, and emergency department (ED) visits in participants on chronic hemodialysis with recurrent hyperkalemia.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Sodium Zirconium Cyclosilicate (SZC) intervention 2: SZC Placebo
Intervention descriptions: intervention 1: Powder for oral suspension in a sachet. A dose is titrated in 5 g increments during a period of 4 weeks from 5 g up to 15 g qd on non-dialysis days. Afterward, the dose is adjusted monthly (or more frequent based on clinical judgment) depending on the current potassium value as measured after the long interdialytic interval (LIDI). intervention 2: Powder for oral suspension in a sachet. A dose is titrated in 5 g increments during a period of 4 weeks from 5 g up to 15 g qd on non-dialysis days. Afterward, the dose is adjusted monthly (or more frequent based on clinical judgment) depending on the current potassium value as measured after the LIDI.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
Sodium Zirconium 
Cyclosilicate (SZC)
Study Code
D9487C00001
Version
3.0
Date
04 April 2023
An International, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on 
Arrhythmia-Related Cardiovascular Outcomes in Participants on 
Chronic Hemodialysis with Recurrent Hyperkalemia 
(DIALIZE-Outcomes)
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden
(Japan) AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Numbers:
EudraCT 2020-005561-14
This clinical study protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D9487C00001
Amendment Number: 2
Study Intervention: Sodium Zirconium Cyclosilicate
Study Phase: Phase III
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Brief Title: Effect of Sodium Zirconium Cyclosilicate on Arrhythmia-Related Cardiovascular 
Outcomes in Participants on Chronic Hemodialysis with Recurrent Hyperkalemia
Acronym: DIALIZE-Outcomes
Study Physician Name and Contact Information Will Be Provided Separately
International Coordinating Investigator: 
North Shore University Hospital
True North Dialysis Center, LLC
100 Community Drive, second floor
Great Neck, New York 11021
United States
PPD




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!
Section 7.2
Clarification regarding use of coded data for future research.
!
Section 10 Appendix 7
Clarification regarding time records and documents need to be retained at sites.
!
Section 8.3.7.1 and Appendix B section B2
Wording for “congenital abnormality” was changed to “congenital anomaly”.
!
Section 9 Statistical Considerations
Clarification regarding the estimand for the primary analysis, as well as the type I error 
rate that is planned to use for the interim analysis.
!
Appendix
Primary endpoint reporting functionality deleted. Time of the digital support start 
corrected from screening to randomization.
Version 3, 04 April 2023
General changes throughout the protocol amendment are as follows:
!
Regulatory Agency Identification Number added to synopsis per new template.
!
Study being conducted in approximately 26 countries at approximately 330 study sites.
!
Sample size increased to 2800 patients throughout, thus participants to be enrolled 
increased to 5600 throughout.
!
The anticipated average treatment period updated throughout to approximately 
37 months.
!
DMC futility analysis and interim analysis text updated and clarified throughout.
!
Two-sided significance level changed to 4.46% throughout.
!
Change in study milestones and recruitment timelines throughout.
!
Clarity regarding K-binder chronic therapy timeframe added throughout.
!
Updates in line with the new CSP template throughout, including appendices.
!
Style, grammatical, and spelling corrections throughout.
Additional minor changes to Section 6.1.2, Section 6.5.2, and Section 11 in-line with text 
added to Section 4.2.1.


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Specific changes to sections throughout the protocol amendment are as follows:
!
Table 1 SoA – Screening Phase
Laboratory safety variables clarified and accompanying footnote updated.
!
Table 2 SoA – Randomized Study Intervention Phase
Laboratory safety variables clarified.
Study Events questionnaire administration added to IP dispensation visits and followed 
by an investigator phone visit, if needed.
Questions clarified.
!
Section 3
Per new template, added information regarding primary estimand details.
!
Section 4.2
For Hungary-specific Rationale for Study Design, see Appendix E.
!
Section 4.4
End of study definition new template text added.
!
Section 5.1
Updated inclusion criterion #3 per request of the Local Study Leader from Japan. See 
Appendix E.
Updated inclusion criterion #8 per Austrian requirements. See Appendix E.
!
Section 5.2
Clarified exclusion criterion #10 per Italy’s request. See Appendix E.
!
Section 5.4
Added cross reference to guidance for exclusion criterion #9 regarding screen failure 
patients who have received K-Binder therapy (due to high potassium) within the prior 
7 days.
!
Section 6.1.2
Added clarity regarding serum potassium measurement 1 week after the dose change.
Study Events questionnaire administration added to IP dispensation visits and followed 
by an investigator phone visit, if needed.
Questions clarified.
!
Section 6.3
Deletion of S-K results from local laboratories as a data item with potential to unblind 
study team members.
!
Section 6.4


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Added that compliance < 80% and > 120% between the scheduled investigational 
product dispensation visits are considered deviations.
!
Section 6.5, Table 5 Restricted Medications
Based on the drug-drug interaction study, tacrolimus and cyclosporin have been 
included as restricted medications.
Text added below Table 5 to clarify dosing of SZC and concomitant medications.
!
Section 6.5.2
Additional information added regarding recording of rescue medications.
Regarding rescue therapy for hyperkalemia, included information clarifying potassium 
binder use and additional rescue therapies included.
Hungary-specific information in Appendix E.
!
Section 7.1.1
To avoid a protocol deviation, clarify that restricted medications are a mandatory 
requirement for patients who permanently discontinue from investigational product and 
remain in the study.
Italy-specific information in Appendix E.
!
Section 7.2
Added Patient Follow-Up Checklist Form and Withdrawal of Consent Checklist should 
be used to document the process for participants withdrawing from the study.
Text added to clarify the process of participant withdrawal from the study.
!
Section 8.2.5.2
Adding text regarding potassium measurement 1 week after dosage change for local 
laboratory assessments.
!
Section 8.3.8
Medication error, drug abuse, and drug misuse sub-sections added per new template.
!
Section 8.3.6
Text updated regarding electronic data capture and reporting of SAEs.
!
Section 9.2
Sample size determination updates: 730 primary endpoint events will result in 
approximately 85% power to demonstrate a statistically significant difference at 
either interim analysis (two-sided significance level of 1.64%) or at final analysis
(two-sided significance level of 4.46%).


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!
Section 9.5 Interim Analysis
Updates regarding the non-binding futility testing to be performed by DMC when 40% 
of the total adjudicated events have accrued. The threshold for futility has also been 
updated. Updated interim efficacy analysis plan to occur at 70% accrual and 
adjudication of 730 total events. Necessary changes applied throughout relevant 
sections, including Appendix 2.
!
Appendix A6
Template text added.
!
Appendix B4
Drug abuse and drug misuse template text added.
!
Appendix B5
Study Events Questionnaire referred to in Table 1 included for reference.
!
Appendix E
Mobile software application will not be used during the study; thus, content is not 
required and removed from appendix. Reference to Appendix E in Section 8 also 
removed.
!
Appendix E
Local CSPs for Hungary, Japan, Austria, and Italy merged with global CSP per the EU 
CTR updated policy. All information and text provided in Appendix E.
∀
For Hungary, the Ethics Committee for Clinical Pharmacology of the Medical 
Research Council (ETT- KFEB) of Hungary expressed concern regarding the use 
of placebo in patients with hyperkalemia in study D9487C00001. Thus, the 
scientific rationale for study design (Section 4.2) and rescue medicine text 
(Section 6.5.2) were updated to clarify that investigators have the ability and 
discretion to use rescue therapy as needed, according to local practice, to treat all 
participants; plus, the justification for use of placebo added to emphasize safety of 
participants in both study arms. These updates can be found in Appendix E.
∀
For Japan, updated inclusion criterion #3, Section 5.1, by removing, “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.” Text no longer required due to civil code change.
∀
For Austria, change applies to inclusion criterion #8, Section 5.1.
∀
For Italy, changes apply to exclusion criterion #10, Section 5.2; and permanent 
discontinuation of study intervention in Section 7.1.1.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY AND SUMMARY OF CHANGES..................................................... 3
TABLE OF CONTENTS ...................................................................................................... 8
LIST OF FIGURES ............................................................................................................ 10
LIST OF TABLES .............................................................................................................. 10
LIST OF APPENDICES ..................................................................................................... 11
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......................................... 12
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 20
1.3
Schedule of Activities ....................................................................................... 20
2
INTRODUCTION............................................................................................ 25
2.1
Study Rationale ................................................................................................ 25
2.2
Background ...................................................................................................... 25
2.3
Benefit/Risk Assessment................................................................................... 27
3
OBJECTIVES, ENDPOINTS, AND ESTIMANDS .......................................... 28
4
STUDY DESIGN ............................................................................................. 30
4.1
Overall Design.................................................................................................. 30
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 32
4.2
Scientific Rationale for Study Design ............................................................... 32
4.3
Justification for Dose........................................................................................ 33
4.4
End of Study Definition.................................................................................... 33
5
STUDY POPULATION.................................................................................... 34
5.1
Inclusion Criteria .............................................................................................. 34
5.2
Exclusion Criteria ............................................................................................. 35
5.3
Lifestyle Considerations ................................................................................... 36
5.3.1
Meals and Dietary Restrictions ......................................................................... 36
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 37
5.3.3
Activity............................................................................................................. 37
5.3.4
Contraception ................................................................................................... 37
5.4
Screen Failures ................................................................................................. 38
6
STUDY INTERVENTION ............................................................................... 38
6.1
Study Intervention(s) Administered................................................................... 38
6.1.1
Investigational Products.................................................................................... 38
6.1.2
Dose and Treatment Regimens.......................................................................... 39


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6.2
Preparation/Handling/Storage/Accountability ................................................... 40
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 40
6.4
Study Intervention Compliance......................................................................... 42
6.5
Concomitant Therapy........................................................................................ 42
6.5.1
Other Concomitant Therapy.............................................................................. 44
6.5.2
Rescue Medicine............................................................................................... 44
6.6
Dose Modification ............................................................................................ 45
6.7
Intervention After the End of the Study............................................................. 46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 46
7.1
Discontinuation of Study Intervention............................................................... 46
7.1.1
Permanent Discontinuation of Study Intervention ............................................. 46
7.1.2
Temporary Discontinuation............................................................................... 47
7.1.3
Procedure for Erroneously Randomized Participants......................................... 47
7.1.4
Procedures for Premature Study Intervention Discontinuation Visit .................. 47
7.1.5
Procedures for End of Study Intervention Visit ................................................. 48
7.1.6
Procedures for Study Closure Visit.................................................................... 48
7.2
Participant Withdrawal from the Study.............................................................. 49
7.3
Lost to Follow-up ............................................................................................. 50
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 51
8.1
Efficacy Assessments........................................................................................ 51
8.1.1
Adjudicated Endpoint Reporting Overview....................................................... 51
8.1.1.1
Death................................................................................................................ 52
8.1.1.2
Stroke............................................................................................................... 52
8.1.1.3
Hospitalizations, Interventions, or Emergency Department Visits...................... 52
8.1.2
Serum Potassium Measurements....................................................................... 52
8.2
Safety Assessments........................................................................................... 52
8.2.1
Physical Examinations and Height .................................................................... 52
8.2.2
Weight and Interdialytic Weight Gain................................................................ 53
8.2.3
Vital Signs ........................................................................................................ 53
8.2.4
Electrocardiograms........................................................................................... 53
8.2.5
Clinical Safety Laboratory Assessments............................................................ 53
8.2.5.1
Central Laboratory Assessments ....................................................................... 53
8.2.5.2
Local Laboratory Assessments.......................................................................... 54
8.3
Adverse Events and Serious Adverse Events..................................................... 54
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 55
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 55
8.3.3
Causality Collection.......................................................................................... 56
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 56
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 56
8.3.6
Reporting of Serious Adverse Events................................................................ 57
8.3.7
Pregnancy......................................................................................................... 58


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8.3.7.1
Maternal Exposure............................................................................................ 58
8.3.7.2
Paternal Exposure............................................................................................. 59
8.3.8
Medication Error, Drug Abuse, and Drug Misuse.............................................. 59
8.3.8.1
Timelines.......................................................................................................... 59
8.3.8.2
Medication Error............................................................................................... 59
8.3.8.3
Drug Abuse....................................................................................................... 59
8.3.8.4
Drug Misuse ..................................................................................................... 59
8.4
Overdose .......................................................................................................... 59
8.5
Human Biological Samples............................................................................... 60
8.5.1
Pharmacokinetics.............................................................................................. 60
8.5.2
Immunogenicity Assessments ........................................................................... 60
8.5.3
Pharmacodynamics........................................................................................... 60
8.6
Human Biological Sample Biomarkers ............................................................. 60
8.7
Optional Genomics Initiative Sample................................................................ 60
8.8
Health Economics............................................................................................. 60
9
STATISTICAL CONSIDERATIONS................................................................ 61
9.1
Statistical Hypotheses....................................................................................... 61
9.2
Sample Size Determination............................................................................... 61
9.3
Populations for Analyses................................................................................... 62
9.4
Statistical Analyses ........................................................................................... 62
9.4.1
General Considerations..................................................................................... 62
9.4.2
Efficacy ............................................................................................................ 62
9.4.2.1
Primary Endpoint(s).......................................................................................... 62
9.4.2.2
Secondary Endpoint(s)...................................................................................... 63
9.4.2.3
Tertiary/Exploratory Endpoint(s) ...................................................................... 64
9.4.3
Safety ............................................................................................................... 64
9.4.4
Other Analyses.................................................................................................. 64
9.5
Interim Analysis................................................................................................ 64
9.6
Data Monitoring Committee ............................................................................. 65
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 66
11
REFERENCES................................................................................................. 86
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 20
LIST OF TABLES
Table 1
Schedule of Activities – Screening Phase................................................. 21


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Table 2
Schedule of Activities – Randomized Study Intervention Phase............... 23
Table 3
Objectives and Endpoints......................................................................... 28
Table 4
Investigational Products........................................................................... 39
Table 5
Restricted Medications............................................................................. 42
Table 6
Drug Interactions..................................................................................... 43
Table 7
Laboratory Safety Variables..................................................................... 53
Table 8
Populations for Analysis .......................................................................... 62
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 66
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 73
Appendix C
Handling of Human Biological Samples .................................................. 79
Appendix D
Management of Study Procedures During the COVID-19 Pandemic........ 81
Appendix E
Country-specific Changes........................................................................ 83


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or Special 
Term
Explanation
AE
adverse event
AF
atrial fibrillation
BP
blood pressure
CKD
chronic kidney disease
CPS
calcium polystyrene sulfonate
CSP
clinical study protocol
CSR
clinical study report
CV
cardiovascular
ECG
electrocardiogram
eCRF
electronic case report form
ED
emergency department
EDC
electronic data capture
DMC
Data Monitoring Committee
EOIV
end of study intervention visit
ESRD
end stage renal disease
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
Unless otherwise noted, ‘GCP’ shall mean ‘the International Conference on 
Harmonisation Tripartite Guideline for Good Clinical Practice’ (ICH GCP) and 
the Japanese ‘Good Clinical Practice for Trials on Drugs (Ministry of Health, 
Labor and Welfare [MHLW] Ordinance No. 28, 27 March 1997, partially 
revised by MHLW Ordinance and their related notifications’ (GCP Ordinance)
HR
hazard ratio
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
Kd
dialysate potassium concentration
LIDI
long interdialytic interval
PIDV
premature study intervention discontinuation visit
qd
once daily
QTcF
QT interval corrected by the Fridericia method


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Abbreviation or Special 
Term
Explanation
RTSM
Randomization and Trial Supply Management
S-K
serum potassium
SAE
serious adverse event 
SAP
statistical analysis plan
SCD
sudden cardiac death
SCV
study closure visit
SED
study end date
SoA
Schedule of Activities
SPS
sodium polystyrene sulfonate
SZC
sodium zirconium cyclosilicate
TIA
transient ischemic attack


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title
An International, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Effect of Sodium Zirconium Cyclosilicate on Arrhythmia-Related Cardiovascular Outcomes 
in Participants on Chronic Hemodialysis with Recurrent Hyperkalemia (DIALIZE-Outcomes)
Brief Title
Effect of Sodium Zirconium Cyclosilicate on Arrhythmia-Related Cardiovascular Outcomes 
in Participants on Chronic Hemodialysis with Recurrent Hyperkalemia
Acronym: DIALIZE-Outcomes
Regulatory Agency Identifier Numbers
EudraCT 2020-005561-14
Rationale
Patients with end stage renal disease (ESRD) on hemodialysis have an increased prevalence of 
cardiac arrhythmias that predisposes them to a higher risk of sudden cardiac death (SCD) and 
stroke. Pre-dialysis hyperkalemia and rapid serum potassium (S-K) shifts that occur during 
hemodialysis may aggravate or trigger these arrhythmias. Clinical studies in patients with 
hyperkalemia have demonstrated the efficacy of sodium zirconium cyclosilicate (SZC) in the 
correction of hyperkalemia and maintenance of normokalemia. Specifically, the efficacy of 
SZC for treatment of hyperkalemia in patients with ESRD on chronic hemodialysis was 
demonstrated in the DIALIZE study (randomized, placebo-controlled, double-blind study). 
The current study will evaluate the effect of treatment with SZC on arrhythmia-related 
cardiovascular (CV) outcomes in patients with ESRD on chronic hemodialysis with recurrent 
hyperkalemia.






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composite endpoint is approximately 11 per patient-year in the placebo group, it is expected 
that approximately 2800 participants will need to be randomized.
Assuming a screen failure rate of 50%, approximately 5600 participants will be enrolled to 
achieve approximately 2800 participants randomly assigned (1:1) to study intervention (SZC 
or placebo).
Note: “Enrolled” means a participant’s, or his/her legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. “Screen failures” are defined as participants who signed the informed consent form to 
participate in the clinical study (ie, “enrolled”) but did not fulfill the eligibility criteria and, as 
a consequence, were not subsequently randomized to a treatment group.
Intervention Groups and Duration
The study design will consist of the following planned phases:
!
Screening phase (2 to 6 weeks; no study intervention administered). Data required for 
determination of eligibility are collected and inclusion/exclusion criteria are evaluated.
!
Randomized (1:1 ratio) treatment phase (on study intervention until required number of 
events are accrued). The dose of study intervention will be up-titrated weekly in 5 g 
increments starting at 5 g once daily (qd) on non-dialysis days (4 doses per week) based 
on local laboratory pre-dialysis S-K values to achieve and maintain a pre-dialysis S-K 
between 4.0 and 5.0 mmol/L after the LIDI. The maximum dose of study intervention will 
be 15 g qd on non-dialysis days. After the initial up-titration, monthly (or more frequent 
based on clinical judgment) pre-dialysis S-K will be collected after the LIDI at the local 
laboratory to guide further dose adjustment at any time during the study to achieve and 
maintain a pre-dialysis S-K between 4.0 to 5.0 mmol/L.
The study is event-driven. The study closure procedures will be initiated when the 
predetermined number of primary endpoint events are expected to have occurred (730 events). 
The anticipated recruitment period is planned to be 32 months. The anticipated average 
treatment period is approximately 37 months, which in practice will be dependent on the 
actual event rate observed during the study, as the study duration is event-driven. The study 
duration may be changed if the number of participants enrolled, the event rate, or the 
randomization rate is different than anticipated. Any decision to increase or decrease 
participant numbers or extend or shorten the study duration will be based on blinded event rate 
data.
The Data Monitoring Committee (DMC) will be responsible for monitoring the progress of 
the study with respect to randomization, compliance, and follow-up, as well as for reviewing 
the unblinded data for evidence of benefit or harm. The DMC can make recommendations to 


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the sponsor and the Executive Committee to alter or terminate all or part of the trial. The 
DMC will conduct a non-binding futility analysis when 40% of the planned number of 
primary endpoint events have accrued and have been adjudicated. An interim analysis for 
efficacy when 70% of the planned number of primary endpoint events have accrued and have 
been adjudicated is also planned to take place. The DMC will notify the sponsor if the formal 
stopping criteria for superiority or futility are met.
Data Monitoring Committee: Yes
Statistical Methods
The efficacy analyses will be performed according to the intent-to-treat principle. The Full 
Analysis Set will be used, which will consist of all randomized participants, regardless of 
whether participants received study intervention.
The primary endpoint is time to the first occurrence of SCD, stroke, or 
hospitalization/intervention/ED visit due to arrhythmias (AF, bradycardia, asystole, ventricular 
fibrillation). The occurrence of intercurrent events (eg, termination of study intervention or 
initiation of an additional treatment that potentially affects the primary outcome) will be 
ignored. The only exception to this rule is death: participants who die during the study, for 
any cause that is not SCD, will be censored at that time point. This would reflect a 
“hypothetical strategy”, the results representing a hypothetical patient population in which a 
death that is not a SCD does not occur.
The primary hypothesis of no difference between study intervention arms will be evaluated by 
means of a Cox regression, with time to first event/censoring as response and study 
intervention arm and geographic region as covariates. Other covariates may also be included 
as appropriate as specified in the statistical analysis plan. The HR estimate, its standard 
deviation, 95% confidence interval, and p-value will also be provided. Kaplan-Meier 
estimates of time to the first occurrence of any event in the composite endpoint will be 
calculated and plotted.
The following secondary time to event endpoints will be analyzed similarly:
!
Time to first occurrence of hospitalization/intervention/ED visit due to arrhythmias (AF, 
bradycardia, asystole, ventricular tachyarrhythmia such as ventricular fibrillation, 
ventricular tachycardia, etc)
!
Time to first instance of rescue therapy use for hyperkalemia
!
Time to SCD
!
Time to first occurrence of stroke
!
Time to CV death


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!
Time to death of any cause
A logistic model with the binary variable (yes/no) as response and study intervention arm and 
geographic region as covariates will be used to evaluate the efficacy of SZC as compared with 
placebo in the following secondary endpoints. As for the primary endpoint analysis, other 
covariates may also be included as appropriate. The proportion of participants fulfilling each 
endpoint criteria will also be presented by study intervention arm. The estimated odds ratio, 
corresponding 95% confidence interval, and two-sided p-value will be presented.
!
S-K of 4.0 to 5.5 mmol/L (yes/no) after the LIDI at the 12-month visit
!
S-K > 6.5 mmol/L (yes/no) after the LIDI at the 12-month visit
A negative binomial model with number of events as response and study intervention arm and 
geographic region as covariates (other covariates included as appropriate) will be used to 
evaluate the efficacy of SZC as compared with placebo for the following secondary endpoint. 
The logarithm of the participant’s corresponding follow-up time will be used as an offset 
variable in the model to adjust for participants having different exposure times during which 
the events occur. Number of events will also be presented by study intervention arm. The 
estimated rate ratio, corresponding 95% confidence interval, and two-sided p-value will be 
presented.
!
Number of hospitalizations/interventions/ED visits due to arrhythmias (AF, bradycardia, 
asystole, and ventricular tachyarrhythmia such as ventricular fibrillation, ventricular 
tachycardia etc)
A non-binding futility analysis will be performed by the DMC when 40% of the planned 
number of primary endpoint events have accrued and have been adjudicated. The threshold for 
futility is defined as the estimated hazard ratio at the interim analysis, SZC versus placebo 
being equal to or larger than 1. This will correspond to a predictive power of < 5.1%.
Additionally, the DMC is also planning an interim analysis for efficacy when 70% of the 
primary endpoint events have accrued and have been adjudicated, using an O’Brian and 
Fleming rule (O’Brian P, Fleming T. Cytel Inc. Software Package East 6.5, Copyright 2018). 
The Type I error rate for the final analysis of the primary endpoint and subsequent secondary 
endpoints will be adjusted for the interim analysis performed by the DMC.
To control the familywise Type I error rate, a fixed sequence multiple testing procedure for 
primary and secondary endpoints will be performed. For the primary endpoint the hypothesis 
of no difference between study intervention arms will be tested at the 4.46% two-sided level 
(assuming one interim analysis for efficacy). Once the null hypothesis concerning the primary 
composite efficacy endpoint is rejected, the hypotheses for the secondary efficacy endpoints 


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will be tested separately in the order listed in the table above with the same alpha level as the 
primary endpoint. The testing procedure will continue down the hierarchy if the current 
endpoint is rejected at a two-sided 4.46% level and will stop if the current endpoint is not 
rejected at a two-sided 4.46% level.
Safety analyses will be performed using the Safety Analysis Set, defined as all participants 
who receive at least one dose of study intervention. Safety data will be presented using 
descriptive statistics unless otherwise specified.
1.2
Schema
The study design is presented in Figure 1.
Figure 1
Study Design
R randomization; SZC sodium zirconium cyclosilicate; w week.
1.3
Schedule of Activities
The SoA to be performed during the screening phase is presented in Table 1. The SoA to be 
performed during the randomized study intervention phase is presented in Table 2.


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Table 1
Schedule of Activities – Screening Phase
Visit
1
2
3
(if needed)a
Details in CSP 
Section or 
Appendix
Study Day (Window)
-21 (-7 days)
-14 (-7 days)
-7 (-7 days)
In case retest of lab sample is needed screening may last 
up to 42 days.
Each screening visit can be repeated once.
Type of Visit
LIDI
LIDI
LIDI
Informed consent prior to 
any study specific 
procedures
X
Section 5.1; 
Appendix A
Enrollment in IRT/RTSM
X
Inclusion/exclusion criteria
X
Sections 5.1 and 
5.2
Demographics
X
Medical/surgical history b, c
X
Dialysis prescription d
X
Concomitant Medications
X
X
X
Section 6.5
Pulse and BP e
X
Section 8.2.3
Physical examination
X
Section 8.2.1
Height
X
Section 8.2.1
12-lead ECG
X
Section 8.2.4
Pre-dialysis weight
X
Section 8.2.2
Serum HCG pregnancy test 
(FOCBP only) f
X
Section 8.2.5
Pre-dialysis central 
laboratory safety variables: 
clinical chemistry (serum) 
panel (including LIDI S-K)g
X
X
X
Section 8.2.5
SAEs
X
X
X
Section 8.3
a
If S-K measurement criteria are met at V1 and V2 participant should be randomized without performing 
V3. V3 in this Schedule of Event becomes V4 - the randomization visit because participant has met 
inclusion criteria. If S-K measurement criteria are not met at V1 and V2 participant should be screen failed 
without performing V3. 
b
Including dialysis history: (I) dialysis vintage (time since first dialysis in years); (II) type of access: AV 
fistula, AV graft, tunneled central venous catheter, other (specify).
c
Including cause of end stage renal disease.
d
The following parameters will be collected: date when dialysis was initiated; prescribed duration for 
dialysis; prescribed duration for dialysis unit; dialysate potassium concentration; dialysate potassium 
concentration unit; blood flow (Qb); blood flow unit; other blood flow unit; dialysate flow (Qd); dialysate 
flow unit; other dialysiate flow unit, specified; prescribed ultrafiltration; prescribed ultrafiltration unit; 
dialysis adequacy (spKt/V); and urea removal rate (%).


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e
Pulse and BP should be measured prior to the hemodialysis procedure. Pulse and BP should be measured in 
triplicate after the participant is comfortably at rest in either supine or seated position quietly for at least 
5 minutes.
f
A suspected pregnancy should be confirmed by increasing levels of serum beta HCG (repeated after one or 
2 weeks) or a uterine ultrasound if pregnancy test result is questionable. Repeated serum HCG pregnancy 
tests may be analyzed by the local laboratory.
g
If needed laboratory safety variables: clinical chemistry (serum) panel (including LIDI S-K) can be repeated 
(after LIDI) once for each screening visit. If there is a need to repeat screening visit more than once this 
needs to be consulted with the Study Physician.
AV arteriovenous; BP blood pressure; CSP clinical study protocol; ECG electrocardiogram; FOCBP females 
of childbearing potential; HCG human chorionic gonadotropin; IRT/RTSM interactive response 
technology/randomization and trial supply management; LIDI long interdialytic interval; S-K serum potassium; 
SAE serious adverse event.


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Table 2
Schedule of Activities – Randomized Study Intervention Phase
Visit Description
Randomization
On-site Visit
3 months
On-site 
Visit
6 months
On-site 
Visit
9 months
On-site 
Visit
12 months
On-site 
Visit
TC/Video/
On-site 
Visit a
EOIV or 
PIDV
On-site Visit
SCV 
TC/Video/
On-site Visit a
Details in 
CSP Section 
or Appendix
Visit
4
5
6
7
8
9, 10, 11, etc.
EOIV or 
PIDV b
SCV c
Study Day
1
92
± 7 days
183  
± 7 days
274
± 7 days
  365
± 7 days
Every 3rd
Month
± 7 days
Type of Visit
LIDI
LIDI
LIDI
LIDI
LIDI
LIDI
LIDI b
Pulse and BP d
X
X
Section 8.2.3
Physical examination
X
X
Section 8.2.1
12-lead ECG
X
Section 8.2.4
Pre-dialysis weight (measured 
at the dialysis clinic) g
X
X
X
X
X
X
X
Section 8.2.2
Post-dialysis weight after the 
prior dialysis session 
(measured at the dialysis 
clinic) e, g
X
X
X
X
X
X
X
Section 8.2.2
Pre-dialysis central 
laboratory safety variables: 
clinical chemistry (serum) 
panel (including LIDI S-K)
Hematology/hemostasis 
(whole blood) panel (only 
at randomization, Day 1)
X
X
Sections 
8.1.2, 8.2.5
Randomization in IRT/RTSM
X
Section 6.3
Study intervention 
dispensation, compliance 
reminder, and accountability
Study intervention will be dispensed to the participant at the time of the dose adjustment review: weekly for 
4 dispensations and every 4 weeks thereafter. Study intervention may be dispensed more frequently if 
needed (eg, if the participant’s dose is changed per dose adjustment review). Compliance reminder, and 
accountability check will be done at every dispensation.
Sections 
6.1.1, 6.1.2, 
6.2, 6.4


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Table 2
Schedule of Activities – Randomized Study Intervention Phase
Visit Description
Randomization
On-site Visit
3 months
On-site 
Visit
6 months
On-site 
Visit
9 months
On-site 
Visit
12 months
On-site 
Visit
TC/Video/
On-site 
Visit a
EOIV or 
PIDV
On-site Visit
SCV 
TC/Video/
On-site Visit a
Details in 
CSP Section 
or Appendix
Visit
4
5
6
7
8
9, 10, 11, etc.
EOIV or 
PIDV b
SCV c
Study Day
1
92
± 7 days
183  
± 7 days
274
± 7 days
  365
± 7 days
Every 3rd
Month
± 7 days
Type of Visit
LIDI
LIDI
LIDI
LIDI
LIDI
LIDI
LIDI b
Study Events evaluation/ 
Study Events Questionnaire h
X
X
X
X
X
X
X
Appendix 
B 5
Concomitant medication
X
X
X
X
X
X
X
X
Section 6.5
Endpoint collection f
X
X
X
X
X
X
X
X
Section 8.1
AEs and SAEs
X
X
X
X
X
X
X
X
Section 8.3
a
Visit can be done via TC, video call or on-site visit, if more convenient.
b
Refer to Section 7.1.5 for further details on the EOIV. Refer to Sections 7.1 and 7.1.4 for further details on the PIDV. The PIDV is not required to be performed at a LIDI 
visit.
c
Refer to Section 7.1.6 for further details on the SCV.
d
Pulse and BP should be measured prior to the hemodialysis procedure. Pulse and BP should be measured in triplicate after the participant is comfortably at rest in either 
supine or seated position quietly for at least 5 minutes.
e
The prior session post-dialysis weight measured at dialysis session immediately prior to the study visit will be used in the calculation of interdialytic weight gain.
f
Potential endpoints will be collected from randomization throughout the study until and including the participant’s last visit.
g
Pre and post-dialysis weight not to be collected if the visit is done via TC/ video.
h
Study Events evaluation to be done during study intervention dispensation visit. Study Events Questionnaire to be used to facilitate the evaluation. In case Study Events 
evaluation is not done by the Investigator/ Sub-investigator and there is positive answer to any of the question unscheduled follow up visit/ phone visit should be done by 
Investigator/ Sub-investigator within a week to complete Study Event evaluation and to report AEs. In case an SAE needs to be reported, timelines for SAE reporting apply. 
Refer to Appendix B 5 Study Events Questionnaire.
AE adverse event; BP blood pressure; CSP clinical study protocol; ECG electrocardiogram; EOIV end of study intervention visit; IP investigational product; 
IRT/RTSM interactive response technology/randomization and trial supply management; LIDI long interdialytic interval; PIDV premature study intervention discontinuation 
visit; S-K serum potassium; SAE serious adverse event; SCV study closure visit; TC telephone call.


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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 hyperkalemia. 
SZC selectively captures potassium ions in exchange for hydrogen and sodium ions in the 
gastrointestinal tract, thereby reducing S-K concentration and removing potassium from the 
body through increased fecal excretion. SZC exerts its effect locally and it is not absorbed 
systemically.
2.1
Study Rationale
Patients with ESRD on hemodialysis have an increased prevalence of cardiac arrhythmias that 
predisposes them to a higher risk of SCD and stroke (Foley et al 2011, Jadoul et al 2012, 
Seliger et al 2003). Pre-dialysis hyperkalemia and rapid S-K shifts that occur during 
hemodialysis may aggravate or trigger these arrhythmias. Clinical studies in patients with 
hyperkalemia have demonstrated the efficacy of SZC in the correction of hyperkalemia and 
maintenance of normokalemia. Specifically, the efficacy of SZC for treatment of 
hyperkalemia in patients with ESRD on chronic hemodialysis was demonstrated in the 
DIALIZE study (randomized, placebo-controlled, double-blind study; Fishbane et al 2019). 
The current study will evaluate the effect of treatment with SZC on arrhythmia-related CV 
outcomes in patients with ESRD on chronic hemodialysis with recurrent hyperkalemia.
2.2
Background
With the progression of CKD to ESRD the ability of the kidneys to eliminate potassium is 
eventually lost resulting in the need for renal replacement therapy to maintain a normal S-K. 
While kidney transplantation is the preferred treatment option for most patients with ESRD, 
dialysis remains the global standard of care for those awaiting, or not being eligible for, 
transplantation. Hemodialysis is the most common modality and is usually performed 3 times 
a week, with a Kd of 2.0 to 2.5 mmol/L being the most commonly used prescription 
(Karaboyas et al 2017). However, despite dialysis, hyperkalemia remains common in this 
population (62.9 per 100 patient-months at the end of the LIDI) (Yusuf et al 2016). These 
patients are therefore chronically exposed to the pro-arrhythmic effects of potassium, and at 
higher risk of SCD, which accounts for 26% of all deaths in the ESRD population (Jadoul et al 
2012). Recent studies have shown that S-K levels above 5.6 mmol/L are associated with 
increased CV and all-cause mortality (Kovesdy et al 2007, Yusuf et al 2016).
Further, cardiac conduction disorders and arrhythmias are common in hemodialysis patients. 
The reported annualized event rate for arrhythmias requiring hospitalization is 
13.6 per 100 person-years with 25.9% of hemodialysis patients having an admission for an 
arrhythmia event during a follow-up period of 2.2 years (Foley et al 2011).


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Atrial fibrillation is one of the strongest risk factors for ischemic stroke and an independent 
predictor of death in the general population (Benjamin et al 1998, Dries et al 1998, 
Sankaranarayanan et al 2015, Wolf et al 1998). The estimated prevalence of AF among 
patients with ESRD in observational studies has been reported to be as high as 27% (Genovesi 
et al 2005, Soliman et al 2010). Rates of hospitalized stroke are reportedly 5- to 10-fold higher 
in dialysis patients when compared to non-ESRD patients, with ischemic strokes being the 
most common (Seliger et al 2003, Sozio et al 2009).
Recent studies using continuous heart rhythm monitoring with implantable loop recorders for 
up to 21 months in patients with ESRD on hemodialysis have shown a prevalence of AF 
between 21% and 42% (Roy-Chaudhury et al 2018, Sacher et al 2018, Wong et al 2015). The 
highest rates of AF occur during the dialysis session, but a significantly increased AF event 
rate is also observed at the end of the LIDI and during the 12 hours following completion of a 
dialysis session (Roy-Chaudhury et al 2018, Wong et al 2015). The mechanisms for the 
increased frequency of AF surrounding dialysis sessions are unknown, but sudden shifts in 
S-K resulting from a large gradient between pre-dialysis S-K and Kd have been proposed to 
play a role (Roy-Chaudhury et al 2018). A decrease in S-K during hemodialysis is associated 
with modifications of atrial electrophysiology that can favor AF onset, namely a decrease in 
atrial conduction velocity and a decrease in atrial cell effective refractory period; decreased 
P-wave conductivity is a known risk factor for AF (Severi et al 2010). Therefore, reducing 
large, sudden shifts in S-K during dialysis by achieving pre-dialysis normokalemia and a 
smaller S-K-Kd gradient can potentially decrease abnormalities in atrial electrophysiology and 
reduce susceptibility to AF.
Another important finding in hemodialysis patients is the occurrence of high rates of atrio-
ventricular conduction disorders, bradycardia, and periods of asystole (Roy-Chaudhury et al 
2018, Sacher et al 2018, Wong et al 2015). The availability of implantable loop recorders for 
continuous heart monitoring has provided compelling evidence that bradyarrhythmias, rather 
than tachyarrhythmias, are the pre-eminent arrhythmic associations of SCD and fatal events 
(Kalra et al 2018). In one study, prolonged episodes of bradycardia leading to asystole and 
SCD were documented in several patients (Wong et al 2015).
The LIDI has been associated with the highest incidence of SCD (Foley et al 2011). In one 
study using implantable loop recorders, the LIDI was found to be the highest-risk period for 
all forms of arrhythmias and SCD (Wong et al 2015). In another study, the LIDI was the 
highest-risk period for bradyarrhythmias and asystole (Roy-Chaudhury et al 2018). A 
pre-dialysis S-K > 5.0 mmol/L was associated with a higher risk of conduction disorders, 
which may lead to bradyarrhythmias and asystole (Sacher et al 2018). A reduction in 
interdialytic hyperkalemia may therefore potentially decrease the susceptibility to conduction 
disorders, bradycardia, and asystole.


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Potassium-binding resins (SPS and CPS) are used in some instances to treat hyperkalemia in 
dialysis patients; however, these agents have not been extensively studied, are not universally 
used, and have no specific indications in this population. Moreover, even after dynamic 
management of Kd (more frequent prescription of 2.0 mmol/L) and potassium binder 
treatment (increasing the dose), only 6.3% of patients become normokalemic within 3 months 
after an S-K of > 5.5 mmol/L (Rossignol et al 2017). There is, therefore, a medical need for a 
pharmacological treatment that can effectively correct and maintain S-K levels within the 
normokalemic range during the interdialytic intervals in this segment of the hyperkalemia 
patient population.
The effect of SZC in reducing S-K has consistently been demonstrated in the clinical 
development program. In randomized, double-blind, placebo-controlled studies in non-dialysis 
patients, SZC rapidly, effectively, and safely reduced S-K into the normokalemic range across 
a broad population of patients with hyperkalemia and with various underlying comorbidities, 
concomitant treatments, and demographic characteristics. Furthermore, continued SZC 
administration effectively maintained normokalemia for up to 12 months. Importantly, the 
DIALIZE study demonstrated that SZC is effective in maintaining normokalemia during the 
LIDI in the segment of the hyperkalemia patient population on chronic hemodialysis. It is 
hypothesized in this study that treatment with SZC may reduce the occurrence of SCD, stroke, 
or hospitalizations, interventions, or ED visits due to arrhythmias and potentially reduce 
morbidity and mortality in patients on chronic hemodialysis with hyperkalemia.
A detailed description of the chemistry, pharmacology, efficacy, and safety of SZC is provided 
in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
The primary benefit for participants randomized to SZC treatment is expected to be the 
maintenance of normokalemia during the LIDI, in line with what was observed in the 
DIALIZE study. Further, should the study hypothesis prove true, this may bring a consequent 
improvement in arrhythmia-related CV outcomes and urgent ED/hospital visits for 
hyperkalemia-related arrhythmias. The likelihood of treatment with SZC raising safety 
concerns is deemed to be low, as no clinically relevant safety findings were observed in the 
DIALIZE study.
Participants treated with placebo may not obtain any benefit in terms of hyperkalemia 
correction and maintenance but may benefit from the closer follow-up. Participants will 
receive alternative therapies whenever clinically indicated.
An established dose adjustment algorithm will be used during the study to titrate SZC doses to 
enable participants to achieve and maintain pre-dialysis normokalemia (S-K between 4.0 to 
5.0 mmol/L) after the LIDI (Section 6.1.2). In accordance with the algorithm, the dose may be 






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PRIMARY ESTIMAND DETAILS
Primary clinical question: Can SZC, compared to placebo, reduce the incidence of 
SCD/stroke/arrhythmia-related hospitalizations/interventions/ED visits in participants 
receiving chronic hemodialysis with recurrent hyperkalemia?
The hazard ratio for SZC versus placebo will be estimated regardless of treatment 
discontinuation and additional therapy (treatment policy) for the time to the first event of 
SCD/stroke/arrhythmias in participants receiving chronic hemodialysis with recurrent 
hyperkalemia. 
Targeted population: All participants receiving chronic hemodialysis with recurrent 
hyperkalemia and satisfying other inclusion exclusion criteria. 
Endpoint: Time to the first occurrence of adjudicated events of SCD, stroke, or arrhythmia-
related hospitalizations/interventions/ED visits.
Treatment condition: Study intervention/placebo taken on non-dialysis days and titrated per 
protocol. 
Intercurrent events: The main intercurrent events are treatment discontinuation, introduction 
of rescue therapy or other potassium altering treatment and deaths that are not SCD. The main 
approach of handling intercurrent events in the study is treatment policy. In the primary 
analysis, event free participants will be censored at non-SCD if it occurs.
Population-level summary: Hazard ratio for SZC versus placebo.
Rationale for estimand: The rationale for the population and treatment condition is explained 
in Section 2.1. Hazard ratio is the target of estimation as per standard approach to time to 
event analysis. Treatment policy approach is in line with the standard intention to treat 
principle and corresponds to a conservative evaluation of treatment effect.
For secondary endpoints, a similar approach of adopting the treatment policy strategy will be 
applied.
4
STUDY DESIGN
4.1
Overall Design
This is an international, multicenter, event-driven, randomized, double-blind, parallel group, 
placebo-controlled study, evaluating the utility of SZC versus placebo to reduce the incidence 


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of SCD, stroke, and arrhythmia-related hospitalizations, interventions, and ED visits in 
participants on chronic hemodialysis with recurrent hyperkalemia.
It is estimated that approximately 5600 participants at about 330 study sites in about 
26 countries will be enrolled to reach the target of 2800 participants randomized (1:1) to study 
intervention (SZC or placebo).
The study design will consist of the following planned phases:
!
Screening phase (2 to 6 weeks; no study intervention administered). Data required for 
determination of eligibility are collected and inclusion/exclusion criteria are evaluated.
!
Randomized (1:1 ratio) treatment phase (on study intervention until required number of 
events are accrued). The dose of study intervention will be up-titrated weekly in 5 g 
increments starting at 5 g qd on non-dialysis days (4 doses per week) based on local 
laboratory pre-dialysis S-K values to achieve and maintain a pre-dialysis S-K between 
4.0 and 5.0 mmol/L after the LIDI. The maximum dose of study intervention will be 15 g 
qd on non-dialysis days. After the initial up-titration, monthly (or more frequent based on 
clinical judgment) pre-dialysis S-K will be collected after the LIDI at the local laboratory 
to guide further dose adjustment at any time during the study to achieve and maintain a 
pre-dialysis S-K between 4.0 to 5.0 mmol/L.
This study is event-driven. The study closure procedures will be initiated when the 
predetermined number of primary endpoint events are expected to have occurred (730 events). 
The anticipated recruitment period is planned to be 32 months. The anticipated average 
treatment period is approximately 37 months, which in practice will be dependent on the 
actual event rate observed during the study, as the study duration is event-driven. The study 
duration may be changed if the number of participants enrolled, the event rate, or the 
randomization rate is different than anticipated. Any decision to increase or decrease 
participant numbers or extend or shorten the study duration will be based on blinded event rate 
data.
The study is designed and will be directed and published by an Executive Committee. The 
following additional committees will be selected: a National Lead Investigator Committee, an 
Adjudication Committee, and an independent DMC (Appendix A 5). The DMC will be 
responsible for monitoring the progress of the study with respect to randomization, 
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 non-binding futility analysis will be undertaken when 40% 
of the planned number of primary endpoint events have accrued and have been adjudicated 


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(Section 9.5). The DMC will also conduct an interim analysis for efficacy when 70% of the 
planned number of primary endpoint events have accrued and have been adjudicated. The 
DMC will notify the sponsor if the formal stopping criteria for superiority or futility are met.
The overall study design is presented in Figure 1.
4.1.1
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 GCP, and minimize risks to study integrity.
Where permissible 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, 
refer to Appendix D.
4.2
Scientific Rationale for Study Design
This is a randomized, double-blind, placebo-controlled parallel-group event-driven study. 
Randomization and double-blinding will minimize potential bias.
The study includes hemodialysis participants who have been on dialysis for a minimum of 
4 months and receive treatment 3 times a week and who have at least 2 out of 2 or 2 out of 
3 pre-dialysis S-K values ≥5.5 mmol/L at the end of the LIDI during screening. No clinically 
justified therapy for severe acute hyperkalemia will be withheld from study participants. 
Choice of rescue therapy will be available according to local practice patterns. Furthermore, 


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since the hypothesis that reducing LIDI hyperkalemia will reduce patient-experienced 
outcomes, which is the purpose of this study, has not been proven, placebo is deemed to be the 
appropriate comparator in this study.
Sudden cardiac death, stroke, and increased hospitalizations, ED visits and therapeutic 
interventions can result from arrhythmias associated with interdialytic hyperkalemia (ie, 
bradyarrhythmias and asystole) and rapid S-K fluxes during hemodialysis (ie, AF) 
(Section 2.2). Therefore, a composite of SCD, stroke, and hospitalizations, interventions, and 
ED visits due to these arrhythmias is selected as the primary endpoint. Such interventions may 
be pharmacological or non-pharmacological. All of the components of the primary endpoint 
will be adjudicated.
While the key objective of the study is to demonstrate benefit on clinical outcomes, evidence 
of successful hyperkalemia management long-term is deemed clinically relevant. Additionally, 
hospitalizations due to arrhythmias as well as from any cause are important outcomes from a 
patient and health resource utilization perspective and help further describe the clinical benefit 
of SZC.
The Hungary-specific rationale is included in Appendix E.
4.3
Justification for Dose
The recommended starting dose in this study in participants on chronic hemodialysis is 5 g qd 
on non-dialysis days. To establish normokalemia, the dose should be titrated up or down 
weekly based on pre-dialysis S-K after the LIDI in increments of 5 g up to a maximum of 15 g 
qd on non-dialysis days. SZC will be dosed and titrated in this study according to the 
approved label in the dialysis population (US PI, SmPC).
For details regarding the dosing regimen, see Section 6.1.
4.4
End of Study Definition
For Clinical Trial Transparency (CTT) the definition of the end of the study differs under FDA 
and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last participant 
for any protocol related activity.
Food and Drug Administration requirements defines 2 completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 


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different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
The Executive Committee and AstraZeneca will monitor the accrual of endpoint events and 
when appropriate define the SED at which time at least the pre-defined target number of 
730 participants are anticipated to have had events for the primary composite endpoint. The 
study sites will be instructed to plan for EOIVs and SCVs.
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 (Appendix A 9).
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
In this protocol, “enrolled” means a participant’s, or his/her legally acceptable 
representative’s, agreement to participate in a clinical study following completion of the 
informed consent process. “Randomized” participants are defined as those who undergo 
randomization and receive a randomization number (Section 6.3). “Screen failures” are 
defined in Section 5.4.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all 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.
2
Provision of signed and dated, written ICF prior to any mandatory study-specific 
procedures, sampling, and analyses (Appendix A).
Age
3
Must be ≥18 years of age, at the time of signing the ICF (see Appendix E for 
Japan-specific update).
Type of Participant and Disease Characteristics
4
Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of ESRD for 
≥4 months before enrollment


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5
Must have hemodialysis access consisting of an arteriovenous fistula, arteriovenous graft, 
or tunneled (permanent) catheter which is expected to remain in place for the entire 
duration of the study
6
At least 2 out of 2 or 2 out of 3 pre-dialysis S-K values ≥5.5 mmol/L after the LIDI 
during screening
Contraception and Reproduction
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
7
Negative pregnancy test for female participants of childbearing potential
8
Female participants must be 1 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 3 months before entering the study and 
willing to remain on the birth control until 12 weeks after the last dose. See Section 5.3.4. 
See Appendix E for Austria-specific update.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not 
considered a screening failure: sampling or full screening can be postponed to a later time 
as applicable)
2
Presence of cardiac arrhythmias or conduction defects that require immediate treatment
3
Participants who have a pacemaker or implantable cardiac defibrillator
4
Any medical condition, including active, clinically significant infection or liver disease, 
that in the opinion of the investigator or sponsor may pose a safety risk to a participant in 
this study, confound safety or efficacy assessment and jeopardize the quality of the data, 
or interfere with study participation, or any other restrictions or contraindications in the 
local prescribing information for SZC
5
History of QT prolongation associated with other medications that required 
discontinuation of that medication
6
Congenital long QT syndrome
7
QTcF > 550 msec
8
Atrial fibrillation requiring immediate/urgent intervention at screening or randomizations.


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Prior/Concomitant Therapy
9
Treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium 
polystyrene sulfonate (CPS Resonium Calcium), patiromer (Veltassa), or SZC (Lokelma) 
within 7 days before screening or anticipated requiring chronic use of any of these agents 
during the study.  If a participant requires rescue therapy (potassium binder or dialysate 
S-K change during screening period, see Section 6.5.2), the participant will be screen 
failed.
Prior/Concurrent Clinical Study Experience
10 Participation in another clinical study with an investigational product, device, or 
non-standard hemodialysis procedure administered within one month before screening. 
See Appendix E for Italy-specific update.
Other Exclusions
11 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
12 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
13
Previous randomization in the present study
14
Females who are pregnant (confirmed with positive pregnancy test or a uterine 
ultrasound if pregnancy test result is questionable), breastfeeding, or planning to become
pregnant during the study.
15
Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
16 Scheduled date for living donor kidney transplant.
Medical Conditions continuation
17. Sustained Ventricular Tachycardia > 30 seconds requiring assessment / intervention.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Dialysis clinics included in the study should provide participants with dietary advice. 
Although details may vary across sites, the overall approach should be to give participants 
dietary advice targeted to maintain low potassium intake (limited amount of high-potassium 
food, restrictions on raw vegetables) while maintaining adequate nutrition in terms of protein 
and caloric intake. The use of print educational materials to educate participants is 
encouraged.


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5.3.2
Caffeine, Alcohol, and Tobacco
No restrictions regarding caffeine, alcohol, or tobacco intake, beyond those specified by 
dietary counselling as described above.
5.3.3
Activity
No physical activity restrictions.
5.3.4
Contraception
Female participants of childbearing potential must have a negative pregnancy test during 
screening (before first dose of study intervention).
Female 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 3 months before entering the study and willing to remain on the birth control until 12 weeks 
after the last dose. Women who are surgically sterile or those who are postmenopausal are not 
considered to be of childbearing potential.
!
Surgical sterilization includes: hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy.
!
Women will be considered postmenopausal if they have been amenorrhoeic for
12 months prior to the planned date of randomization 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 (estrogen 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
∀
Vasectomized partner
∀
Sexual abstinence (true abstinence in line with the participant’s preferred and usual
lifestyle; however, periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods], declaration of abstinence for the duration of exposure to the
study intervention, and withdrawal are not acceptable methods of contraception)


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Serum levels of beta HCG can be elevated in ESRD patients on dialysis in the absence of 
pregnancy. A suspected pregnancy should be confirmed by increasing levels of serum beta 
HCG (repeated after one or 2 weeks) or a uterine ultrasound. Repeated serum HCG pregnancy 
tests may be analyzed by the local laboratory.
5.4
Screen Failures
Screen failures are defined as participants who signed the ICF to participate in the clinical 
study (ie, “enrolled”) but did not fulfill the eligibility criteria and, as a consequence, were not 
subsequently randomized to a treatment group via the IRT/RTSM. 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 queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, any SAE, and information necessary to link laboratory 
assessments with central laboratory data.
Individuals who do not meet the S-K criteria for participation in this study during the 
screening period (screen failure) may be rescreened once, if the cause of the S-K ineligibility 
is thought to be transient in the opinion of the investigator; the participant must have the 2 or 
3 weekly S-K measurements repeated when the transient condition is resolved in the opinion 
of the investigator (refer to Section 5.2, exclusion criterion #9).
Rescreened participants will keep the originally assigned enrollment number and are not 
required to sign another ICF if the rescreening occurs within 60 days from the previous ICF 
signature date (Appendix A 3). Repeated assessments will be documented as rescreening visits 
in the eCRF.
Enrolled participants who are not randomized (eg, due to screen failure or participant decision) 
should have the reason for study withdrawal recorded in the eCRF.
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) utilized by a study participant 
according to the study protocol. Study intervention in this study refers to SZC or placebo.
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 4.


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Table 4
Investigational Products
Arm Name
Arm A
Arm B
Intervention Name
SZC
SZC Placebo
Type
Drug
Drug
Dose formulation
Powder for oral suspension in a sachet
Powder for oral suspension in a sachet
Unit dose strength(s)
5 g or 10 g SZC
5 g or 10 g SZC placebo
Dosage level(s)
Single dose contains 5 to 15 g SZC 
that should be suspended in 45 mL of 
water by participant and administered 
qd on non-dialysis days.
Single dose contains 5 to 15 g SZC 
placebo that should be suspended in 
45 mL of water by participant and 
administered qd on non-dialysis days.
Route of administration
Oral
Oral
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor
Packaging and labeling
Study intervention will be provided in sachet. Each sachet will be labeled in 
accordance with GMP Annex 13 and per country regulatory requirement. 
Labels will be prepared in accordance with GMP and local regulatory 
guidelines. The labels will fulfil1 GMP Annex 13 requirements for labeling. 
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.
GCP Good Clinical Practice; GMP Good Manufacturing Practice; IMP investigational medicinal product; 
NIMP non-investigational medicinal product; qd once daily; SZC sodium zirconium cyclosilicate.
6.1.2
Dose and Treatment Regimens
SZC or placebo will be suspended in 45 ml of water and administered orally on non-dialysis 
days.
For participants on dialysis, study intervention should only be dosed on non-dialysis days. The 
recommended starting dose is 5 g once daily. To establish normokalaemia (4.0 to 5.0 mmol/L
based on local laboratory pre-dialysis S-K values), the dose should be titrated weekly based on 
the pre-dialysis serum potassium value after the LIDI.
The dose should be adjusted at intervals of 1 week in increments of 5 g up to 15 g once daily 
on non-dialysis days. In case of dose adjustment serum potassium must be measured one week 
after the dosage change. After the initial titration and once normokalaemia is established, 
potassium should be monitored regularly (eg, monthly, or more frequently based on clinical 
judgment including changes in dietary potassium or medication affecting serum potassium).


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Once normokalaemia is established, pre-dialysis S-K will be collected after the LIDI at the 
local laboratory and the study intervention dose adjusted depending on the current potassium 
value to achieve and maintain a pre-dialysis S-K between 4.0 to 5.0 mmol/L. The maximum 
dose of study intervention will be 15 g qd on non-dialysis days.
Study intervention will be dispensed to the participant at the time of the dose adjustment 
review: weekly for 4 dispensations and every 4 weeks thereafter. Study intervention may be 
dispensed more frequently if needed (eg, if the participant’s dose is changed per dose 
adjustment review). The Study Events questionnaire will be administered at each dispensation 
visit and followed by an investigator follow-up/phone visit, if needed (refer to Table 2 and 
Appendix B 5). Compliance reminders and accountability checks will also be performed at 
every dispensation (Sections 6.2 and 6.4).
Rescue therapy should be guided by local clinical practice patterns. Rescue therapy should be 
followed by the appropriate dose adjustment if appropriate and proper documentation of the 
event (Section 6.5.2).
6.2
Preparation/Handling/Storage/Accountability
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. All study intervention should be kept in a secure 
place under appropriate storage conditions. The study intervention label specifies the 
appropriate storage.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
6.3
Measures to Minimize Bias: Randomization and Blinding
All participants who fulfill eligibility criteria will be centrally assigned to randomized study 
intervention using an IRT/RTSM. Before the study is initiated, the telephone number and 
call-in directions for the IRT and/or the log-in information and directions for the RTSM will 
be provided to each site.


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The randomization codes will be computer generated in blocks using the AstraZeneca Global 
Randomization System in a way that ensures approximate balance (1:1) between the 
2 intervention arms. 
The randomization will be stratified by country.
If a participant withdraws from the study, then his/her enrollment/randomization code cannot 
be reused. Withdrawn participants will not be replaced.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the intervention 
randomization. The IRT/RTSM programmed with blind-breaking instructions will be available 
at all times. In case of an emergency, in which the knowledge of the specific blinded study 
intervention will affect the immediate management of the participant’s condition, the 
investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If a participant’s intervention assignment is unblinded, the 
sponsor must be notified within 24 hours after breaking the blind. The investigator documents 
and reports the action to AstraZeneca, without revealing the study intervention given to the 
participant to the AstraZeneca staff. The actual result of the S-K sample taken at the 12-month 
visit will be blinded to the investigator site and the AstraZeneca study team. The S-K values 
that fall outside of the reference range at this visit with potential critical implications for the 
participant, will be notified to the principal investigator and a pre-identified sponsor contact.
Information on study drug dose adjustment has the potential to unblind study team members 
and therefore requires special handling (EX/DA modules and IRT reports are redacted). The 
local Study Team, AZ IRT Lead and IQVIA DM Team will be unblinded to that data. 
Information about dosing information must not be shared with the Global Study Team (not to 
be included in the MV reports, Follow up Letters, Q&A logs or other kind of communication 
with the Global Study Team).
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study intervention and that potentially require expedited 
reporting to regulatory authorities. Care should be taken to maintain the blinding to the 
Executive Committee and AstraZeneca Study Team conducting the trial. Randomization 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.
Routines for all measures listed in this section will be described in the IRT/RTSM user manual 
that will be provided to each center.


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6.4
Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed. Compliance will be assessed by counting returned sachets and 
documented in the source documents and eCRF. Deviation(s) from the prescribed dosage 
regimen should be recorded in the eCRF.
The rule to be followed regarding study intervention compliance is: < 80% and > 120% 
(including dose adjustments) between the study intervention dispensation visits should be 
considered deviations. For lost/unreturned study intervention < 80% of returned study 
intervention sachets are to be considered deviations.
A record of the number of study intervention sachets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment 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. The medications listed in Table 5 are restricted during the study.
Restricted medications taken outside the conditions as specified in the “Usage” 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 5
Restricted Medications
Restricted Medication/Class of Drug
Usage
Potassium Binders: SPS (Kayexalate, Resonium), 
CPS (Resonium Calcium), or patiromer (Veltassa)
These drugs should be avoided during the study and 
can only be used as rescue therapy (Section 6.5.2).


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Table 5
Restricted Medications
Restricted Medication/Class of Drug
Usage
Loop Diuretics: Bumex (bumetanide), Edecrin 
(ethacrynic acid), Lasix (furosemide), Demadex 
(torsemide)
Changes to loop diuretics (including adding a new 
changing the dose or discontinuation or switching of 
loop diuretics) during the study are discouraged. If 
changes in loop diuretics are clinically indicated this 
should be documented in the electronic case report 
form. 
SZC (Lokelma)
Once the participant has been enrolled in the study, 
SZC cannot be used for rescue therapy. 
CPS calcium polystyrene sulfonate; SPS Sodium polystyrene sulfonate.
Effect of Other Medicinal Products on SZC
As SZC is not absorbed or metabolized by the body, there are no clinically significant drug-
drug interactions with other medicinal products on the pharmacological action of SZC.
Effect of SZC on Other Medicinal Products
As SZC is not absorbed or metabolized 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, the study intervention should be administered at least 2 hours 
before or 2 hours after oral medications with gastric pH-dependent bioavailability to mitigate 
the risk of drug interactions. 
SZC can be co-administered with oral medications that do not exhibit pH-dependent 
bioavailability without spacing of dosing times.
Examples of drugs that should be taken 2 hours before or after SZC to avoid possible raised 
gastric pH drug interaction are listed in Table 6.
Table 6
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
Immunosuppressives
tacrolimus
HIV human immunodeficiency virus.


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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.
6.5.1
Other Concomitant Therapy
Medication other than that described above, which is considered necessary for the
participant’s safety and wellbeing, may be given at the discretion of the investigator, and 
recorded in the appropriate sections of the eCRF.
6.5.2
Rescue Medicine
Rescue therapy for controlling hyperkalemia is defined as any short-term (24 to 48 hours) 
therapeutic intervention during the study, that is considered necessary per the investigator’s 
judgment and in accordance with local practice patterns to reduce S-K in the setting of an AE 
of severe hyperkalemia. See Hungary-specific text in Appendix E.
Rescue Therapy Permissible in Dialize-Outcomes Study
Specifically, rescue therapy applies only to short-term (24 to 48 hours) therapy to treat an AE 
of severe hyperkalemia as defined in the CSP. Note that rescue medications indicated for 
treatment of severe hyperkalemia encompass primarily rapid-acting IV or inhalable drugs that 
reduce serum potassium within a few hours (eg, insulin/glucose, beta adrenergic agonists, 
sodium bicarbonate); these drugs must take precedence over oral potassium binders in such 
acute setting given that oral binders have delayed onset of action and lack approval for life-
threatening hyperkalemia. Potassium binders (other than SZC) should only be used for short 
periods of time (24 to 48 hours) to complement the action of rapid acting hyperkalemia rescue 
drugs. Potassium binders (other than SZC IP) are restricted medications and must not be used 
recurrently or for chronic treatment during the study.
The date and time of rescue medication administration, as well as the name and dosage 
regimen of the rescue medication, must be recorded. Rescue medication for hyperkalemia will 
not be provided as part of study medications (Table 5).


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Rescue therapy includes, but is not limited to, any of the following:
1
Insulin/glucose, beta-adrenergic agonist, sodium bicarbonate, etc.
2
Other potassium binders: SPS (eg, Kayexalate, Resonium), CPS (eg, Resonium Calcium) 
and patiromer (Veltassa) (Table 5). 
NOTE: All potassium binders other than SZC are considered restricted medications and 
can be used only for short-term rescue (24 to 48 hours). Once the participant has been 
enrolled in the study, SZC cannot be used for rescue therapy. SZC/placebo must be 
temporarily discontinued while rescue therapy is administered. Table 5 lists medications 
restricted during the study.
3
Any additional dialysis or other forms of renal replacement treatments when used 
specifically for the treatment of severe hyperkalemia.
4
Any reduction in the Kd that is prescribed for the treatment of severe hyperkalemia 
during the study.
Rescue therapy should be guided by local clinical practice patterns and limited to the setting 
of severe hyperkalemia. Rescue therapy is recommended for treatment of S-K > 6.0 mmol/L, 
if clinically justified, however investigators are allowed to treat hyperkalemia at lower levels 
(5.5 mmol/L or greater) if there are signs or symptoms of hyperkalemia or in any instance if it 
is judged clinically warranted. Rescue therapy should be followed by the appropriate dose 
adjustment of SZC/placebo study intervention if appropriate and proper documentation of the 
event. Refer to Appendix E for Hungary-specific rescue therapy text.
All hyperkalemia events that require rescue therapy will be reported as an AE.
6.6
Dose Modification
As outlined in Section 6.1.2 the study intervention dose will be titrated in 5 g increments from 
5 g up to 15 g qd on non-dialysis days depending on the current potassium value as measured 
after the LIDI at the local laboratory to achieve and maintain a pre-dialysis S-K between 4.0 to 
5.0 mmol/L.
It is recommended that if S-K is < 3.0 mmol/L on any non-dialysis day or pre-dialysis, study 
intervention should be withheld, and hypokalemia should be managed as per standard 
practice. The participant should be evaluated for any intercurrent illness or comorbidity that 
may increase the risk of hypokalemia. Study intervention administration can be resumed if 
indicated but only after the intercurrent medical condition that precipitated the hypokalemia 
has improved and S-K has returned to the target range of normal levels (4.0 to 5.0 mmol/L). It 
is suggested to resume treatment at a dose of 5 g or per investigator discretion.
Treatment with study intervention on dialysis days should be judged as a medication error and 
reported in the eCRF (Section 8.3.8). The S-K should be monitored for safety and if S-K 


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< 3.0 mmol/L, study intervention should be withheld, and hypokalemia managed as noted 
above. The participants should receive clear instructions regarding intake of study drug.
6.7
Intervention After the End of the Study
Not applicable. Individual physicians may treat each of their randomized participants 
according to local laboratory values and the local standard of care.
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
Participants may be discontinued from study intervention in the following situations. Note that 
discontinuation from study intervention is NOT the same thing as a complete withdrawal from 
the study.
!
Participant decision. The participant is free at any time to discontinue treatment, without 
prejudice to further treatment.
!
Incorrectly randomized participant in whom the inclusion/exclusion criteria violation 
would put the participant at undue risk.
!
The need for long term chronic/continual use of potassium binders (Section 6.5.2).
!
Adverse event for which the investigator judges continued treatment may put the 
participant at undue risk.
!
Severe noncompliance with the CSP.
!
Pregnancy.
!
Renal transplant.
!
QT prolongation: If an absolute QTc > 550 msec, or an increase in QTc interval 
> 60 msec from baseline to more than 500 msec is reached, the participant should 
immediately receive appropriate medical intervention and be discontinued from the study 
intervention. The QTcF algorithm (QT interval corrected by the Fridericia method) 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. See Appendix E for Italy-specific update.


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Participants who permanently discontinue study intervention, but remain in the study, must 
continue to adhere to the restricted medications requirements; not doing so would be a 
protocol deviation.
See the SoA (Section 1.3) and Section 7.1.4 for data to be collected at the time of 
discontinuation from study intervention and follow-up and for any further evaluations that 
need to be completed.
7.1.2
Temporary Discontinuation
Participants who have temporarily discontinued study intervention for reasons other than 
hypokalemia can resume treatment as soon as, in the opinion of the investigator, the 
participant’s condition is stable, and the participant wishes to resume. No minimum time 
period is necessary before treatment can resume. Whenever possible, restart of randomized 
study intervention should be encouraged. Refer to Section 6.6 for details on hypokalemia 
(S-K < 3.0 mmol/L).
7.1.3
Procedure for Erroneously Randomized Participants
A situation might arise where, despite every effort, a participant is randomized into the study 
while not fulfilling one or several of the inclusion/exclusion criteria. In this case, the 
following steps should be undertaken:
1
The Study Physician should be contacted for an assessment of whether study intervention 
could pose a risk to the participant in light of the new information.
2
If yes, the participant should be immediately discontinued from study intervention (not to 
be confused with study discontinuation).
3
If no, the Study Physician should carefully review the specific Inclusion/Exclusion 
criterion which was not met. If discontinuation of study treatment is deemed detrimental 
to the participant, the study medication will be continued and the decision documented. If 
discontinuation of study medication is not detrimental to the participant, it will be 
discontinued, the participant followed according to the study protocol, and the decision 
documented.
4
The occurrence should be documented as appropriate (Important/Major Protocol 
Deviation).
7.1.4
Procedures for Premature Study Intervention Discontinuation Visit
The investigator should instruct the participant to contact the site before or at the time study 
intervention is stopped. Participants who prematurely and permanently discontinue study 
intervention should return for a PIDV, which should be performed at the earliest possible 
dialysis visit after the last dose of study intervention. See the SoA (Section 1.3) for 
assessments to be performed at the PIDV.


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A participant who decides to discontinue study intervention will always be asked about the 
reason(s). The date of last dose of study intervention should be documented in the eCRF, as 
well as the date of study intervention discontinuation. All study intervention should be 
returned by the participant, and drug accountability should be checked and documented in the 
eCRF.
Discontinuation of study intervention, for any reason, does not impact on the participant´s 
participation in the study. The participant should, if possible, continue attending subsequent 
study visits, including the SCV, and data collection should continue according to the study 
protocol. If, upon discontinuation of study intervention, the participant choses to withdraw 
from the study entirely, procedures described in Section 7.2 should be followed.
Data collection and procedures should continue according to the study protocol until study 
closure. If the participant does not agree to this option (which must be documented), a 
modified follow-up (eg, regular telephone contacts or a contact at study closure) should be 
arranged, if agreed to by the participant and in compliance with local data privacy 
laws/practices in order to collect at least the study endpoint information. If the participant does 
not allow the site to call him/her but allows the site to review the participant’s medical records 
it should be done following the protocol-specified visit schedule or at least every 6 months 
until the study closure, to ensure collection of study endpoint information.
After stopping study intervention, the investigator should ensure that the participant is treated 
according to standard clinical practice and ascertain there is a proper medical follow-up plan 
in place.
7.1.5
Procedures for End of Study Intervention Visit
All participants who are still on study intervention at the SED will be asked to return for an 
EOIV, which should be performed at the earliest possible LIDI dialysis visit but no later than 
3 weeks after the SED. At this visit the participant will be taken off the study intervention. See 
the SoA (Section 1.3) for assessments to be performed at the EOIV.
The date of last dose of study intervention should be documented in the eCRF. All study 
intervention should be returned by the participant, and drug accountability should be checked 
and documented in the eCRF.
After stopping study intervention, the investigator should ensure that the participant is treated 
according to standard clinical practice and ascertain there is a proper medical follow-up plan 
in place.
7.1.6
Procedures for Study Closure Visit
When the SED is determined, all participants (including any participants who have 
discontinued study intervention) will be asked to return for a SCV. For participants who did 


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not discontinue prematurely, the SCV should be performed 14 days (± 7 days) after the 
participant’s EOIV visit. For participants who discontinued prematurely, the SCV should 
occur as soon as possible but no later than 3 weeks after the SED. See the SoA (Section 1.3) 
for assessments to be performed at the SCV.
If the participant who discontinued prematurely decides to withdraw from the study between 
the time of the discontinuation of study intervention and study closure, the SCV should be 
performed for this participant at the earliest possible dialysis visit after the participant has 
decided to withdraw from the study.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw consent 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, behavioral, 
compliance, or administrative reasons.
!
A participant who considers withdrawing consent from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records). Participant Follow-
Up Checklist Form and Withdrawal of Consent Checklist should be used to document the 
process.
!
At the time of withdrawal from the study, if possible and agreed by the patient, a PIDV 
should be conducted at the earliest possible dialysis visit after the last dose of study 
intervention; refer to Section 7.1.4 and the SoA (Section 1.3) for data to be collected at 
the time of study withdrawal. A follow-up visit should be performed 14 days (± 7 days) 
after last dose of the study intervention/ PIDV if agreed by the patient. This visit will be 
considered SCV. Date of SCV, if performed, will be considered date of withdrawal of 
consent.
∀
If the patient does not agree to have PIDV, follow-up visit/ SCV performed, it will 
not be performed, and the date of participant’s consent withdrawal will be 
documented by the Investigator in the source data and EDC.
!
At the time of withdrawal of consent from the study, if possible, a PIDV should be 
conducted at the earliest possible dialysis visit after the last dose of study intervention; 
refer to Section 7.1.4 and the SoA (Section 1.3) for data to be collected at the time of 
study withdrawal and follow-up and for any further evaluations that need to be 
completed. The SCV should be performed 14 days (± 7 days) after the participant’s 
PIDV. 
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.


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!
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws consent from the study, it should be confirmed if he/she still 
agrees for use of participant’s coded data for future research in line with the original 
consent, if applicable in the country. The investigator must document the decision on use 
of existing coded data for future research in the site study records and inform the Global 
Study Team.
!
To ensure validity of study data, it is very important to collect as much data as possible 
throughout the study and especially vital status (dead or alive) at study closure (also for 
participants who have withdrawn their informed consent). The investigator will therefore 
attempt to collect information on all participants’ vital status from publicly available 
sources at study closure, even if informed consent has been withdrawn completely, in 
compliance with local privacy laws/practices.
7.3
Lost to Follow-up
The term lost to follow-up will be limited to only participants with unknown vital status at 
study end (if not dead, participants need to have a date last known alive after randomization).
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Efforts to reach the participant should continue until the end of the study
!
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined, this will be documented, and the participant will 
not be considered lost to follow-up. Sponsor personnel will not be involved in any 
attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.


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8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.
∀
Unscheduled Visits: An unscheduled visit may occur in-between scheduled visits eg, 
to follow up on potential endpoint or safety events.
!
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3).
8.1
Efficacy Assessments
8.1.1
Adjudicated Endpoint Reporting Overview
Potential endpoints will be identified through clinical evaluations, questioning the participants 
about their overall health and symptoms, or through information received through standard 
medical practice. Investigators will be encouraged to have a low threshold to submit any 
potential/possible event that might represent an endpoint.
The information for potential endpoints will be recorded in the eCRF and submitted for 
central adjudication if they are assessed by the investigator as potentially representing 
endpoint-related events. The investigator should also make a high-level characterization of the 
event and as to whether the event fulfills the criteria for the endpoint definition.
!
All Deaths
∀
The investigator will assess cause of death, CV/non-CV/unknown, and if this was a 
SCD.
!
Stroke (including TIA)
∀
For potential stroke and TIA events, the investigator will assess the stroke, and 
whether the stroke is ischemic/hemorrhagic, or unknown.


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!
Hospitalization, intervention, or ED visits due to arrhythmia-related events (defined as 
AF, bradycardia, asystole, and ventricular tachyarrhythmia [such as VF, VT, etc]).
∀
For potential hospitalizations, interventions, and ED visits due to arrhythmias, the 
investigator will assess the type of arrhythmia and will note any interventions for the 
event.
For each potential endpoint, the investigator or delegate will record the endpoint specific 
information in the eCRF. If the event is subject to adjudication, relevant source documents 
will be assembled. The source documents and relevant eCRF data will be sent for central 
adjudication. Detailed instructions regarding endpoint reporting will be provided to the study 
sites. Additional details about the evaluations/definitions of potential endpoints will be 
described in the Adjudication Committee charter and will be provided to the investigator.
All endpoints will also be reported as AEs.
8.1.1.1
Death
The Adjudication Committee members will adjudicate and classify all deaths based on 
definitions described in the Committee’s charter. For the efficacy analysis, deaths will be 
subclassified by SCD, CV death, non-CV death, or undetermined cause of death.
8.1.1.2
Stroke
The Adjudication Committee members will adjudicate and classify all strokes and TIAs based 
on definitions described in the Committee’s charter. 
8.1.1.3
Hospitalizations, Interventions, or Emergency Department Visits
The Adjudication Committee members will adjudicate all potential hospitalizations, 
interventions, or ED visits due to arrhythmias (AF, bradycardia, asystole, and ventricular 
tachyarrhythmia [such as VF, VT, etc]) as specified in the Committee’s Charter.
8.1.2
Serum Potassium Measurements
Blood samples for determination of potassium for the efficacy endpoint will be taken at the 
time points specified in the SoA (Section 1.3). Analyses will be performed at a central 
laboratory contracted by AstraZeneca. Refer to Section 8.2.5 for further details.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations and Height
A brief physical examination (including height) will be performed at time points specified in 
the SoA (Section 1.3), and will include, at a minimum, assessments of the lungs, CV system, 
abdomen, and a brief neurological examination.


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8.2.2
Weight and Interdialytic Weight Gain
Weight must be measured at the dialysis clinic.
Post-dialysis weight from the previous dialysis session will be collected at time points 
specified in the SoA (Section 1.3).
Weight will be assessed pre-dialysis at time points specified in the SoA (Section 1.3).
Interdialytic weight gain will be calculated as the difference between current pre-dialysis 
weight minus previous post-dialysis weight (measured at immediate dialysis session prior to 
the visit) in kilograms. The calculation will be performed as part of the analysis.
8.2.3
Vital Signs
Vital signs (pulse and BP) will be assessed at time points specified in the SoA (Section 1.3). 
Pulse and BP should be measured prior to the hemodialysis procedure and should be measured 
in triplicate after the participant is comfortably at rest in either supine or seated position 
quietly for at least 5 minutes.
8.2.4
Electrocardiograms
A 12-lead ECG will be performed at time points specified in the SoA (Section 1.3). The ECG 
data should be recorded in the eCRF, including QTcF.
The ECGs should be made available to the Adjudication Committee upon request, to facilitate 
adjudication of potential cardiac events.
8.2.5
Clinical Safety Laboratory Assessments
8.2.5.1
Central Laboratory Assessments
Blood samples for determination of clinical chemistry for the study database will be taken at 
the time points specified in the SoA (Section 1.3). All serum samples should be examined and 
any hemolyzed samples MUST be re-drawn. Sample re-tests are allowed for each screening 
visit but there should not be more than one re-test for one screening visit.
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. 
Procedures for collection, processing, and sending samples to the central laboratory will be 
provided in laboratory manuals. Table 7 lists the laboratory variables to be measured.
Table 7
Laboratory Safety Variables
Clinical Chemistry (Serum)
Hematology/Hemostasis (Whole Blood)
S-Potassium
B-Erythrocyte count (RBC) a
S-Calcium, total
B-Hemoglobin a


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Table 7
Laboratory Safety Variables
Clinical Chemistry (Serum)
Hematology/Hemostasis (Whole Blood)
S-Sodium
B-Leukocyte count a
S-Bicarbonate
B-Leukocyte differential count (absolute count and %) a
S-Phosphate
B-Platelet count a
S-Blood urea nitrogen
S-Magnesium
S-Creatinine a
S-Bilirubin, total a
S-Alkaline phosphatase a
S-Aspartate transaminase a
S-Alanine transaminase a
S-Gamma-glutamyl transferase a
S-Albumin a
S-Chloride a
S-Creatine kinase a
S-Glucose a
S-Lactate dehydrogenase a
S-Total protein a
S-Pregnancy test (serum HCG) b
Blood  B; Human chorionic gonadotropin  HCG; Red blood cell  RBC; Serum  S.
a
Randomization/Day 1 Visit 4 only.
b
Screening Visit 1 only. Repeated serum HCG pregnancy tests may be analyzed by the local laboratory.
8.2.5.2
Local Laboratory Assessments
Routine laboratory assessments are to be collected as per usual care for participant 
management. This includes weekly potassium tests at the end of the LIDI during the initial 
up-titration and at least monthly (or more frequent based on clinical judgment), for adjustment 
of the dose of SZC. Additional samples may be collected if clinically indicated at the 
discretion of the investigator (refer to Section 6.1.2). In case of dose adjustment, potassium 
must be measured 1 week after the dosage change. The maximum dose of study intervention 
will be 15 g qd on non-dialysis days. Unless important for AE/endpoint data collection, 
routine laboratory assessments should not be reported in the eCRF.
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.


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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
All potential endpoints (Section 8.1.1) will also be reported as AEs.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
Adverse events will be collected from the time of randomization, 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.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
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 and time when the AE started and stopped
!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
Outcome


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In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE , 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’
For SAEs, causal relationship should also be assessed for other medications and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfill 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 not limited to consideration as 


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to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption). 
Hyperkalemia requiring rescue therapy (see Section 6.5.2) should be reported as an AE 
regardless of whether there are associated signs and symptoms. 
Pre-dialysis hypokalemia (S-K < 3.0 mmol/L based on local laboratory assessment) should be 
reported as an AE regardless of whether there are associated signs and symptoms.
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, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
8.3.6
Reporting of Serious Adverse Events
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 during the study, investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within 1 day, 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.


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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, email or as per local 
approved process.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure.
8.3.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
!
If the pregnancy is discovered before the study participant has received any study 
intervention
!
Pregnancies in the partner of male participants
8.3.7.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the 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) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (Section 8.3.6) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.


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8.3.7.2
Paternal Exposure 
There is no restriction on fathering children or donating sperm during the study.
8.3.8
Medication Error, Drug Abuse, and Drug Misuse
8.3.8.1
Timelines
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 (Section 8.3.6) and within 30 days for all other 
medication errors.
8.3.8.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The definition of a Medication Error can be found in Appendix B 4.
8.3.8.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The definition of a Medication Error can be found in Appendix B 4.
8.3.8.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The definition of a Medication Error can be found in Appendix B 4.
8.4
Overdose
For this study, any dose of study intervention greater than 15 g per day on non-dialysis days 
will be considered an overdose. Treatment with study intervention on dialysis days should be 
judged as a medication error and reported in the eCRF (Sections 6.6 and 8.3.8).


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!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (Section 8.3.6) and within 30 days for 
all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples for the central laboratory 
will be provided in the study-specific laboratory manual. Samples should be stored in a secure 
storage space with adequate measures to protect confidentiality. For further details on 
Handling of Human Biological Samples, see Appendix C.
8.5.1
Pharmacokinetics
Pharmacokinetic samples are not collected in this study.
8.5.2
Immunogenicity Assessments
Immunogenicity samples are not collected in this study.
8.5.3
Pharmacodynamics
Pharmacodynamic samples are not collected in this study.
8.6
Human Biological Sample Biomarkers
Biomarker samples are not collected in this study.
8.7
Optional Genomics Initiative Sample
Optional Genomics Initiative research is not applicable in this study.
8.8
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters/data are 
not collected in this study.


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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
All personnel involved with the analysis of the study will remain blinded until database lock 
has occurred, and protocol violations have been identified and documented.
Control of Type I Error at the final analysis
The Type I error rate for the final analysis of the primary endpoint and subsequent secondary 
endpoints will be adjusted for the interim analysis performed by the DMC. A two-sided 
significance level of 4.46% will be used, assuming one interim analysis for efficacy will be 
conducted (Section 9.5).
To control the familywise Type I error rate, a fixed sequence multiple testing procedure for 
primary and secondary endpoints will be performed.
For the primary endpoint, the following hypothesis will be tested:
H0: HR[SZC:placebo] = 1
Versus
H1: HR[SZC:placebo] ≠1
During the final analysis, once the null hypothesis concerning the primary composite efficacy 
endpoint is rejected, the hypotheses for the secondary efficacy endpoints will be tested 
separately in the order listed in Table 3 (HR for time to event endpoints, odds ratio for binary 
(yes/no) endpoints, and rate ratio for number of event endpoints [Section 9.4.2]) with the same 
alpha level as the primary endpoint. The testing procedure will continue down the hierarchy if 
the current endpoint is rejected at a two-sided 4.46% level and will stop if the current endpoint 
is not rejected at a two-sided 4.46% level.
The final significance level will be adjusted if the actual timing of the interim analysis does 
not correspond to half of the information obtained during the trial, eg, due to the total number 
of events deviating from the planned 730 events.
9.2
Sample Size Determination
The study is event-driven. The primary objective of the study is to evaluate the efficacy of 
SZC versus placebo in reducing the incidence of the primary composite endpoint. Assuming
the true HR for SZC versus placebo is 0.8, 730 primary endpoint events will result in 
approximately 85% power to demonstrate a statistically significant difference at either interim 
analysis (two-sided significance level of 1.64%) or at final analysis (two-sided significance 
level of 4.46%). Based on an assumption that the event rate of the primary composite endpoint 
is approximately 11 per patient-year in the placebo group, it is expected that approximately 


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2800 participants will need to be randomized. The anticipated recruitment period is planned to 
be 32 months. The anticipated average treatment period is approximately 37 months, which in 
practice will be dependent on the actual event rate observed during the study, as the study 
duration is event-driven. Any decision to increase or decrease participant numbers or extend 
or shorten study duration will be based on blinded event rate data.
Assuming a screen failure rate of 50%, approximately 5600 participants will be enrolled to 
achieve approximately 2800 participants randomly assigned (1:1) to study intervention (SZC 
or placebo).
9.3
Populations for Analyses
The following populations are defined in Table 8:
Table 8
Populations for Analysis
Population/Analysis Set
Description
Full Analysis Set (FAS)
All participants who undergo randomization and receive a randomization 
number
Safety Analysis Set (SAS)
All participants who have received at least one dose of study intervention
9.4
Statistical Analyses
An SAP will be finalized prior to database lock, and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses for the primary and secondary endpoints.
9.4.1
General Considerations
All hypothesis testing will be conducted using two-sided tests as specified in Section 9.1.
9.4.2
Efficacy
The efficacy analyses will be performed according to the ITT principle. Thus, the population 
to which the study results will be generalizable are the participants who fulfill 
inclusion/exclusion criteria and are suitable to be randomized.
9.4.2.1
Primary Endpoint(s)
The primary endpoint is time to the first occurrence of SCD, stroke, or 
hospitalization/intervention/ED visit due to arrhythmias (AF, bradycardia, asystole, ventricular 
tachyarrhythmia [such as VF, VT, etc]). In accordance with the ITT principle, participants will 
be censored at the common SED or at the time of withdrawal of informed consent.
Although numerous intercurrent events, including, eg, termination of study intervention or 
initiation of an additional treatment that potentially affects the primary outcome, exist in this 


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setting, the analysis will follow “Treatment Policy Strategy” (ICH E9(R1) 2020). That is, the 
occurrence of such intercurrent events will be ignored. The only exception to this rule is death 
not adjudicated as SCD: participants will be censored at that time point. 
The primary hypothesis of no difference between study intervention arms will be evaluated by 
means of a Cox regression, with time to first event/censoring as response and study 
intervention arm and geographic region as covariates. Other covariates may also be included 
as appropriate; further details of the statistical model will be specified in the SAP. The HR 
estimate, its standard deviation, 95% confidence interval, and p-value will be provided. 
Kaplan-Meier estimates of time to the first occurrence of any event in the composite endpoint 
will be calculated and plotted.
The homogeneity of effect with regards to subgroups (eg, gender, age-groups, etc) will be 
examined as specified in the SAP.
9.4.2.2
Secondary Endpoint(s)
As for the primary endpoint, the secondary endpoints will be analyzed according to the ITT 
principle (ie, the same analysis set as for evaluation of the primary endpoint will be used).
The following time to event endpoints will be analyzed similarly to the primary endpoint (Cox 
regression; Section 9.4.2.1).
!
Time to first occurrence of hospitalization/intervention/ED visit due to arrhythmias (AF, 
bradycardia, asystole, ventricular tachyarrhythmia [such as VF, VT, etc]).
!
Time to first instance of rescue therapy use for hyperkalemia
!
Time to SCD
!
Time to first occurrence of stroke
!
Time to CV death
!
Time to death of any cause
A logistic model with the binary variable (yes/no) as response and study intervention arm and 
geographic region as covariates will be used to evaluate the efficacy of SZC as compared with 
placebo in the following secondary endpoints. As for the primary endpoint analysis, other 
covariates may also be included as appropriate. The proportion of participants fulfilling each 
endpoint criteria will also be presented by study intervention arm. The estimated odds ratio, 
corresponding 95% confidence interval, and two-sided p-value will be presented.
!
S-K of 4.0 to 5.5 mmol/L (yes/no) after the LIDI at the 12-month visit
!
S-K > 6.5 mmol/L (yes/no) after the LIDI at the 12-month visit.


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A negative binomial regression model with number of events as response and study 
intervention arm and geographic region as covariates (other covariates included as 
appropriate) will be used to evaluate the efficacy of SZC as compared with placebo for the 
following secondary endpoint. The logarithm of the participant’s corresponding follow-up 
time will be used as an offset variable in the model to adjust for participants having different 
exposure times during which the events occur. Number of events will also be presented by 
study intervention arm. The estimated rate ratio, corresponding 95% confidence interval, and 
two-sided p-value will be presented.
!
Number of hospitalizations/interventions/ED visits due to arrhythmias (AF, bradycardia, 
asystole, and ventricular tachyarrhythmia [such as VF, VT, etc])
The homogeneity of effect with regards to subgroups (eg, gender, age-groups, etc) may be 
examined as specified in the SAP.
9.4.2.3
Tertiary/Exploratory Endpoint(s)
Analysis of the exploratory endpoints will be presented in the SAP.
9.4.3
Safety
Safety analyses will be performed using the Safety Analysis Set. Safety data will be presented 
using descriptive statistics unless otherwise specified in the SAP.
An overview of AEs will be presented for each study intervention arm: the number and 
percentage of participants with any AE, AEs with outcome of death, SAEs, and AEs leading to 
discontinuation of study intervention. Additionally, for each study intervention arm, AEs will 
be summarized by system organ class/preferred term, intensity, and causality as assessed by 
the investigator. Laboratory data (including instances of hypokalemia), vital signs, and 
interdialytic weight gain measurements will be tabulated by study intervention arm. Full 
details of safety analyses will be provided in the SAP.
9.4.4
Other Analyses 
Details of sensitivity analysis will be provided in the SAP.
9.5
Interim Analysis
A non-binding futility analysis will be performed by the DMC when 40% of the total number 
of primary endpoint events have accrued and have been adjudicated. The threshold for futility 
is defined as the estimated hazard ratio at the interim analysis, SZC versus placebo being 
equal to or larger than 1. This will correspond to a predictive power of < 5.1%. 
An interim analysis is also planned for efficacy by the DMC when 70% of the total number of 
primary endpoint events have accrued and have been adjudicated (ie, a minimum of 


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511 events). If the interim occurs at 70% of the total number of primary endpoint events 
(participants), the hypothesis for the primary endpoint at interim will be tested at the 
two-sided 1.64% level (O’Brian P, Fleming T. Cytel Inc. Software Package East 6.5, 
Copyright 2018).
The DMC will notify the sponsor if the formal stopping criteria for superiority or futility are 
met.
Additional details for the interim analysis will be provided in the DMC charter.
9.6
Data Monitoring Committee
For details on the Executive Committee, National Lead Investigator Committee, Adjudication 
Committee, and DMC, refer to Appendix A 5.


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences 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 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 authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organization, 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.


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


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certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one 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 authorized 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 authorized 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 
requirements, where applicable, and the IRB/IEC or study center.
!
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 authorized 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 
authorized representative.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 60 days from the previous ICF signature date.
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 the participant’s 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 authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.


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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 electronic case report form 
(eCRF), and any protocol amendments needed during the study, liaison with the Adjudication 
Committee and Data Monitoring Committee (DMC), as needed, development of the statistical 
analysis plan, 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
National Lead Investigator Committee
The National Lead Investigator (NLI) Committee will be comprised of NLIs from each 
country where the study is conducted and will be supervized by the Executive Committee. 
Members of the committee will be responsible for providing clinical guidance on study 
implementation and conduct in their respective country.
A 5.3
Adjudication Committee
An independent Adjudication Committee will be appointed and will adjudicate potential 
endpoint events of death to determine if they are sudden cardiac death or other (cardiovascular 
death, non-cardiovascular death, or unknown), all stroke and transient ischemic attacks, and 
arrhythmia-related hospitalizations, interventions, and emergency department visits. The 
committee members will not have access to individual treatment codes for any participant or 
clinical efficacy and safety event. The precise responsibilities and procedures applicable for 
the Adjudication Committee will be detailed in a separate Adjudication Committee charter.
A 5.4
Data Monitoring Committee
An independent DMC will be appointed. The DMC will be responsible for monitoring the 
progress of the study with respect to randomization, 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. The DMC will conduct a non-binding futility analysis when 40% of the number of 
primary endpoint events have accrued and have been adjudicated. In addition, the DMC is 
planning an interim analysis for efficacy when 70% of the planned number of primary 
endpoint events have accrued and have been adjudicated (Section 9.5). The DMC will notify 
the sponsor if the formal stopping criteria for superiority or futility are met. A DMC charter 


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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
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
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 eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.


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!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a different 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 opened and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(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 may 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 multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 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 unfavorable 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.
Hyperkalemia requiring rescue therapy should be reported as an AE regardless of whether 
there are associated signs and symptoms. 
Pre-dialysis hypokalemia (serum potassium < 3.0 mmol/L based on local laboratory 
assessment) should be reported as an AE regardless of whether there are associated signs and 
symptoms.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability or incapacity
!
Is a congenital anomaly or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
The AEs for malignant tumors 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 tumor event should be assessed and reported as a 
non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 


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malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
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).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). 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, hospitalization, disability, or incapacity but may jeopardize 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, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse


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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 B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology 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 recognized feature of overdose of the drug?
!
Is there a known mechanism?


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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.
B 4
Medication Error, Drug Abuse, and Drug Misuse
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 recognized 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


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!
Wrong participant received the medication (excluding Interactive Response Technology 
[IRT]/Randomization 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 standard of care medication in 
open-label studies, even if an AstraZeneca product.
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:
!
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.


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Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:
!
The drug is used with the intention to cause an effect in another person
!
The drug is sold to other people for recreational purposes 
!
The drug is used to facilitate assault in another person
!
The drug is deliberately administered by the wrong route
!
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole
!
Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose
!
Someone who is not enrolled in the study intentionally takes the drug
B 5
Study Event Questionnaire
Study Events Questionnaire:
1
During the past month, have you been hospitalized, visited the emergency room, or had 
any medical procedures for a new condition?  
o
If they respond yes, ask the reason for the visit or procedure.
2
During the past month, have you been told by a doctor or other healthcare provider that 
you have had a stroke?
3
During the past month, have you been told by a doctor or other healthcare provider that 
you have an abnormal heart rhythm?


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their life cycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, 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 organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented, and study site is notified.


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C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
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.


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Appendix D
Management of Study Procedures During the COVID-19 
Pandemic
D 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 COVID-19 outbreak.
D 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. 
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).
D 2.1
Measures to Mitigate the Risks Associated with COVID-19
!
National laws and local recommendations for regarding the pandemic will be strictly 
adhered to.
!
Site is encouraged to contact the participant within one day prior to a study visit; see next 
section.
D 3
COVID-19 Prior to Enrollment
It is important that participants with possible ongoing or not completely resolved COVID-19 
infection are not to be enrolled in the study. If the participant has evidence of COVID-19 
within 2 weeks prior to enrollment (eg, a positive COVID-19 test or a clinical risk that has not 
been satisfactorily excluded), the participant cannot be enrolled and will be treated according 
to standard of care.
D 4
Suspected COVID-19 After Enrollment
D 4.1
Participant is Severely Ill or Hospitalized
If the participant becomes symptomatic after enrollment and has suspected COVID-19 
(regardless of any SARS-Cov-2 test results that may be available), and is severely ill and/or 
hospitalized, the participant may temporarily or permanently discontinue study intervention at 
the discretion of the site investigator.
D 4.2
Participant is NOT Severely Ill or Hospitalized
If the participant becomes symptomatic after enrollment and has suspected COVID-19 
(regardless of whether any SARS-Cov-2 test results are available or not), and is NOT severely 


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ill and/or hospitalized the investigator should determine if continuation of treatment with 
study intervention is in the best interest of the participant.
Regardless of if study intervention is continued or not, the participant is encouraged to attend 
the study visits according to schedule.
D 5
COVID-19 During the Study
D 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 D 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.
D 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, concomitant medication, 
and potential endpoints to be reported and documented.
D 5.3
Data Capture During Telemedicine Visits
Data collected during telemedicine visits will be captured by the qualified healthcare 
professional from the study site.


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Appendix E
Country-specific Changes
HUNGARY-SPECIFIC SCIENTIFIC RATIONALE FOR STUDY 
DESIGN
Justification for use of Placebo
The DIALIZE-Outcomes study tests the unproven hypothesis that treatment of hyperkalemia 
with SZC reduces the risk of arrhythmia-related adverse outcomes in patients on chronic 
hemodialysis. SZC is already established as an effective treatment of hyperkalemia in this 
patient population. While potassium-binding resins (sodium polystyrene sulfonate and 
calcium polystyrene sulfonate) are routinely used in some European countries to manage 
hyperkalemia in patients on chronic hemodialysis, these agents have not been extensively 
studied, are not universally used, and have no established efficacy in the control of 
hyperkalemia when used routinely in this population. Indeed, a prospective, observational 
study conducted in France, which followed 527 chronic hemodialysis patients for 2 years, 
reported that even after dynamic management of Kd (more frequent prescription of 
2.0 mmol/L) and potassium binder treatment (increasing the dose), only 6.3% of patients 
became normokalaemic within 3 months after a serum potassium (S-K) of > 5.5 mmol/L at 
baseline (Rossignol et al 2017).
To date there is no data from interventional studies demonstrating that chronic treatment of 
hyperkalemia reduces the risk of arrhythmia-related outcomes (or any other hard outcomes) in 
the hemodialysis population. Therefore, the hypothesis to be tested is whether reducing 
interdialytic hyperkalemia in a prospective, controlled clinical study reduces the risk of 
arrhythmia-related outcomes. To clarify, the study is not intended to show whether SZC has a 
direct effect on arrhythmia-related outcomes. Given the above, an active control treatment, 
even ignoring that there is no well-established and reliably efficacious treatment for 
interdialytic hyperkalemia available, would be contrary to the purpose of the study.
Importantly, Investigators have the ability/discretion to use hyperkalemia rescue therapy 
(extra hemodialysis sessions, changing potassium concentration in dialysate bath or 
pharmacotherapy like potassium binding resins or other medications) as needed to treat all 
patients requiring acute hyperkalemia treatment in the DIALIZE-Outcomes trial.
Testing the hypothesis requires comparison between a group with well-controlled S-K 
(SZC group) and another with less good control (placebo) - as it stands there is no evidence to 
suggest superiority of well-controlled S-K regarding the primary endpoint. Investigators have 
discretion to use rescue therapy in either arm as needed to keep patients safe.
AstraZeneca applied for scientific advice with the European Medicines Agency concerning the 
design of the study in 2 rounds in 2020 and 2021 respectively.


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Follow up Scientific Advice received by AstraZeneca from the European Medicines Agency 
(Case No: EMA/SA/0000053941, dated 22 April 2021) concerning the study design stated the 
following:
“Placebo control is considered acceptable to test the hypothesis that strict control of 
serum potassium will reduce arrhythmia-related adverse outcome. In such a study, less 
intense potassium control is expected in placebo-arm. The strict rescue criterion of 
serum potassium of ≥ 6.0 mmol/L for treatment with potassium binders is considered 
to be too high.”
Use of rescue therapy is permitted by this protocol when it is needed by investigator judgment 
and according to local clinical practice (Section 6.5.2). This protocol allows for treatment at 
S-K > 6.0 mmol/L, if clinically justified, however investigators are allowed to treat 
hyperkalemia at lower levels (5.5 mmol/L or greater) if there are signs or symptoms of 
hyperkalemia or in any instance if it is judged clinically warranted. A pre-LIDI S-K may be 
managed by the HD session (increasing treatment time, reducing the potassium content of
concentrate). The protocol also permits modification of the dialysate K (this would be 
considered “rescue therapy” if K+ decreased) as the investigator warrants to manage the
participant longer term. This applies to both arms of the study.
JAPAN-SPECIFIC INCLUSION CRITERIA
3
Must be ≥ 18 years of age, at the time of signing the ICF.
Updated inclusion criterion #3 by removing, “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.” Text no longer required due to civil code 
change.
AUSTRIA-SPECIFIC INCLUSION CRITERIA
8
Female participants must be 1 year postmenopausal or surgically sterile. (Women will be 
considered postmenopausal if they have been amenorrhoeic for 12 months prior to the 
planned date of randomization without an alternative medical cause. Surgical sterilization 
includes: hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.)
ITALY-SPECIFIC EXCLUSION CRITERIA
10 Participation in another clinical study with an investigational product administered within 
one month before screening or 5 IMP half-lives, whichever is longer.


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HUNGARY-SPECIFIC RESCUE THERAPY UPDATE
Rescue therapy should be guided by local clinical practice patterns and limited to the setting 
of severe hyperkalemia. Rescue therapy is recommended for treatment of S K > 6.0 mmol/L, 
if clinically justified, however investigators are allowed to treat hyperkalemia at lower levels 
(5.5 mmol/L or greater) if there are signs or symptoms of hyperkalemia or in any instance if it 
is judged clinically warranted. The use of rescue medications is permissible at any time during 
the study.” There is no strict rescue criterion.
ITALY-SPECIFIC PERMANENT DISCONTINUATION OF STUDY 
INTERVENTION
Participants may be discontinued from study intervention in the following situations. Note that 
discontinuation from study intervention is NOT the same thing as a complete withdrawal from 
the study.
!
QT prolongation: If an absolute QTc > 550 msec, or an increase in QTc interval 
> 60 msec from baseline to more than 500 msec is reached, or more than 470 msec based 
upon investigator judgment, the participant should immediately receive appropriate 
medical intervention and be discontinued from the study intervention. The QTcF 
algorithm (QT interval corrected by the Fridericia method) 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.


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11
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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: d9487c00001-csp-v3
Document Title:
D9487C00001 Clinical Study Protocol version 3
Document ID:
Doc ID-004401116
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Apr-2023 20:21 UTC
Content Approval
19-Apr-2023 10:29 UTC
Content Approval
17-Apr-2023 12:58 UTC
Content Approval
13-Apr-2023 17:33 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
AstraZeneca
D9487C00001 – ed. 4.0
13-Dec-2023
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STATISTICAL ANALYSIS PLAN
Study Code
D9487C00001
Edition Number
4.0
Date
13-Dec-2023
An International, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Effect of Sodium Zirconium 
Cyclosilicate on Arrhythmia-Related Cardiovascular Outcomes 
in Participants on Chronic Hemodialysis with Recurrent 
Hyperkalemia 
(DIALIZE-Outcomes)
Redacted
ct
n Internatio
n Internatio
ed Study 
d Study
e on
e on
for 
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................2
LIST OF ABBREVIATIONS .......................................................................................5
AMENDMENT HISTORY...........................................................................................6
1
INTRODUCTION......................................................................................8
2
CHANGES TO PROTOCOL PLANNED ANALYSES..............................8
3
DATA ANALYSIS CONSIDERATIONS ..................................................8
3.1
Timing of Analyses.....................................................................................8
3.2
Analysis Populations...................................................................................8
3.3
General Considerations...............................................................................9
3.3.1
General Study Level Definitions ...............................................................10
3.3.1.1
Study End Date (SED)..............................................................................10
3.3.1.2
Withdrawal of consent (WoC) ..................................................................10
3.3.1.3
Lost to follow-up (LTFU) .........................................................................10
3.3.1.4
During the study and on-treatment definitions...........................................10
3.3.1.5
Others.......................................................................................................10
3.3.2
Visit Window ...........................................................................................11
3.3.3
Handling of Unscheduled Visits................................................................11
3.3.4
Handling of Protocol Deviations in Study Analysis...................................11
4
STATISTICAL ANALYSIS.....................................................................12
4.1
Study Population.......................................................................................12
4.1.1
Subject Disposition and recruitment..........................................................12
4.1.1.1
Definitions and Derivations ......................................................................12
4.1.1.2
Presentation ..............................................................................................12
4.1.2
Analysis Sets ............................................................................................13
4.1.2.1
Definitions and Derivations ......................................................................13
4.1.2.2
Presentation ..............................................................................................13
4.1.3
Protocol Deviations...................................................................................13
4.1.3.1
Definitions and Derivations ......................................................................13
4.1.3.2
Presentation ..............................................................................................13
4.1.4
Demographics...........................................................................................14
4.1.4.1
Definitions and Derivations ......................................................................14
4.1.4.2
Presentation ..............................................................................................14
4.1.5
Baseline and Disease Background Characteristics.....................................14
4.1.5.1
Definitions and Derivations ......................................................................14
4.1.5.2
Presentation ..............................................................................................15
4.1.6
Disease Related Medical and Surgical History..........................................15
4.1.6.1
Definitions and Derivations ......................................................................15
4.1.6.2
Presentation ..............................................................................................15
4.1.7
Dialysis History........................................................................................15
4.1.7.1
Definitions and derivations .......................................................................15


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4.1.7.2
Presentation ..............................................................................................15
4.1.8
Prior and Concomitant Medications ..........................................................15
4.1.8.1
Definitions and Derivations ......................................................................15
4.1.8.2
Presentation ..............................................................................................16
4.1.9
Study Drug Compliance............................................................................16
4.1.9.1
Definitions and Derivations ......................................................................16
4.1.9.2
Presentation ..............................................................................................16
4.1.10
Duration of follow-up ...............................................................................16
4.1.10.1
Definitions and Derivations ......................................................................16
4.1.10.2
Presentation ..............................................................................................16
4.1.11
Exposure...................................................................................................16
4.1.11.1
Definitions and Derivations ......................................................................16
4.1.11.2
Presentation ..............................................................................................17
4.2
Endpoint Analyses....................................................................................17
4.2.1
Primary Endpoint......................................................................................21
4.2.1.1
Definition .................................................................................................21
4.2.1.2
Derivations ...............................................................................................21
4.2.1.3
Handling of Dropouts and Missing Data ...................................................21
4.2.1.4
Main Analysis of the Primary Endpoint ....................................................22
4.2.1.5
Sensitivity analyses of the Primary Endpoint ............................................22
4.2.1.6
Supplementary Analyses of the Primary Endpoint.....................................23
4.2.1.7
Subgroup Analyses ...................................................................................23
4.2.2
Secondary and Exploratory Objectives......................................................24
4.2.2.1
Time to first event analyses.......................................................................25
4.2.2.2
Number of events analyses........................................................................26
4.2.3
Multiplicity/Multiple Comparisons ...........................................................26
4.2.4
Handling of Dropouts and Missing Data ...................................................27
4.3
Pharmacodynamic Endpoint(s) .................................................................27
4.3.1.1
Pharmacokinetics......................................................................................28
4.4
Immunogenicity........................................................................................28
4.5
Safety Analyses ........................................................................................28
4.5.1
Adverse Events.........................................................................................28
4.5.1.1
Definitions and Derivations ......................................................................28
4.5.1.2
Presentation ..............................................................................................29
4.5.2
Clinical Laboratory, Vital Signs and ECG.................................................31
4.5.2.1
Definitions and Derivations ......................................................................31
4.5.2.2
Presentations.............................................................................................31
4.5.3
Other Safety Assessments.........................................................................32
4.5.3.1
Definitions and Derivations ......................................................................32
4.5.3.2
Presentations.............................................................................................32
5
INTERIM ANALYSES............................................................................33
6
REFERENCES.........................................................................................34
7
APPENDIX 1:  MISSING DATE IMPUTATION RULES .......................35
APPENDIX 2:  TIPPING POINT ANALYSIS ...........................................................37


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APPENDIX 3 : ATC TERMS FOR POTASSIUM BINDERS ....................................39


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LIST OF ABBREVIATIONS
List abbreviations and definitions of specialized or unusual terms, measurements, or units. 
Abbreviation or 
Specialized Term
Definition
AE
Adverse event
BMI
Body mass index
CEA
CRF
Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
eCDF
Empirical Cumulative Distribution Function
ED
Emergency Department
FAS
Full Analysis Set
GCP
Good Clinical Practice
HR
Hazard Ratio
IM
Immunogenicity
IPD
Important Protocol Deviation
ITT
Intent-To-Treat
IXRS
Interactive voice/web response system
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
LTFU
Lost to follow up
PD
Pharmacodynamic
PK
Pharmacokinetics
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SS
Safety Set
SED
Study End Date
SID
Subject ID
VF
Ventricular Fibrillation
VT
Ventricular Tachycardia
WoC
Withdrawal of consent


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AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line 
with 
CSP?
Rationale
N/A
Click 
or tap 
here to 
enter 
text.
Initial approved SAP
N/A
N/A
Interim Analysis
13-
Jan-
2022
Added text to Section 5.0 of the 
SAP from CSP version 1.0 on 
interim analysis
Yes
Administrative 
change
Interim Analysis
19-
Apr-
2022
Clarified the planned number of 
interim analyses, as well as the type 
I error rate that is planned to use.
Added secondary endpoints in 
interim analysis.
to be 
updated
The two-sided alpha 
to be used for the 
interim analysis 
relies on timing of 
the analysis, in terms 
of Information 
Fraction at Interim 
Look. Further 
clarifications were 
added.
Interim analysis will 
be conducted and 
tested for each 
secondary 
endpoint. Therefore, 
more details were 
provided.
Multiplicity/Multiple 
Comparisons
19-
Apr-
2022
Deleted “Further adjustment to the 
significance level will be done if 
more than one formal interim 
analysis for efficacy is performed 
(Section 5).” In Section 3.3.4 and 
clarified how to adjust type I error 
rate for the final analysis
To be 
updated
This change is in 
line with Section 
Interim Analysis 
updates.
Section 4.2.2.3 Handling of 
Dropouts and Missing Data
19-
Apr-
2022
Added tipping point analyses for 
following secondary endpoints:
! Time to first occurrence 
of
hospitalization/intervention/ED 
visit due to arrhythmias (AF, 
bradycardia, asystole, VT)
! Time to SCD
! Time to first occurrence 
of stroke
! Time to CV death
! Time to death of any 
cause
Yes
The changes are in 
line of handling of 
missing data for 
those key secondary 
endpoints
Hospitalizations/interventions/ED 
visits due to arrhythmias (AF, 
bradycardia, asystole, or VT)
19-
Apr-
2022
Added definition on number of 
hospitalizations/interventions/ED 
visits due to arrhythmias (AF, 
bradycardia, asystole, or VT) in 
Section 4.2.2.2
Yes
The definitions were 
not clearly defined 
initially. Both the 
definitions and what 
constitutes 


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intervention have 
been clarified
Sample size determination
19-
Apr-
2022
Added text to Section 3 of the SAP 
from CSP version 2.0 on Sample 
size determination
Yes
Administrative 
change
Sample Size
15-
Nov 
2023
Sample size was increased from 
2300 to 2800 which is documented 
in Section 3
Yes
Sample size 
modified to 
accelerate primary 
event accrual
Timing of the final analysis
15-
Nov 
2023
Number of primary events at the 
final analysis decreased 
Yes
To shorten duration 
of the trial
Interim Analysis
15-
Nov 
2023
Two interim analyses were 
introduced in SAP Edition 4 to 
replace single interim analysis in 
SAP Edition 3. The first interim 
analysis is for futility and the 
second interim analysis is for 
efficacy. 
Yes
To optimize decision 
making and allow 
early stopping for 
futility and efficacy 
Section 4.2.2 
15-
Nov 
2023
Sensitivity analysis was added for
binary endpoints based on 
potassium levels at the 12 months
Yes
To assess sensitivity 
of the result to 
missing data 
assumptions
Section 4.2.3 Multiplicity/
Multiple Comparisons
15-
Nov 
2023
Significance levels for the efficacy 
interim and final analyses were 
updated.
Yes
To account for 
modification to 
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1
INTRODUCTION
The purpose of this document is to give details for the statistical analysis of study 
D9487C00001 (DALIZE-Outcomes), supporting the clinical study report. The details of 
study conduct and data collection are provided in the clinical study protocol (CSP) and the 
case report form (CRF).
2
CHANGES TO PROTOCOL PLANNED ANALYSES
There are no changes to protocol planned analyses. However, safety analysis dataset was 
renamed as safety set (SS).
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
The study involves two interim analyses (the first interim analysis is for futility and the 
second interim analysis is for efficacy) and the final analysis.
Thus, there are three timepoints for planned analyses in the study: one corresponding to 
study completion, planned to take place when 730 subjects had an adjudicated primary 
composite event, and the other two corresponding to interim analyses planned to take place 
when 292 (40% information fraction) and 511 (70% information fraction) subjects,
respectively had an adjudicated primary composite event. The interim analyses will be 
conducted by independent data monitoring committee (DMC) and will mainly be aimed at 
evaluating the primary objective of the study with the possibility of early stopping for either 
futility (at n=292 events) and for efficacy (at n=511 events). In case of an early stopping of 
the study at efficacy interim analyses, all analyses as specified in this document will be 
conducted. However, if the study stops for futility, only selected analyses covering key 
efficacy and safety outcomes will be conducted.
3.2
Analysis Populations
Two analysis sets are defined according to International Conference on Harmonization 
(ICH) E9 guideline.
Full analysis set (FAS) includes all subjects who underwent randomization and received a 
randomization number, irrespective of their protocol adherence and continued participation 
in the study. Subjects will be analysed according to their randomized study intervention 
assignment, irrespective of the treatment actually received. The FAS will be used as the 
analysis set for all efficacy analyses.


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Safety Set (SS) includes all subjects who are randomised and have received at least one 
dose of study intervention (SZC or Placebo). Subjects will be analysed according to the 
treatment randomised. The SS will be used as the analysis set for all safety analyses.
3.3
Sample Size Determination
The study is event-driven. The primary objective of the study is to evaluate the efficacy of 
SZC versus placebo in reducing the incidence of the primary composite endpoint. 
Assuming the true HR for SZC versus placebo is 0.8, 730 primary endpoint events will 
result in 84.7% statistical power to demonstrate a statistically significant difference at either 
second interim analysis using two-sided significance level of 1.64% or at the final analysis 
using two-sided significance level of 4.46%. Based on an assumption that the event rate of 
the primary composite endpoint is approximately 0.11 per patient-year in the placebo 
group, it is expected that approximately 2800 participants will need to be randomized. The 
anticipated recruitment period is planned to be 32 months. The anticipated average 
treatment period is approximately 37 months, which in practice will be dependent on the 
actual event rate observed during the study, as the study duration is event driven. Any 
decision to increase or decrease participant numbers will be based on blinded event rate 
data (e.g., observed overall event rate), and study discontinuation rate.
Assuming a screen failure rate of 50%, approximately 5600 participants will be enrolled to 
achieve approximately 2800 participants randomly assigned (1:1) to study intervention 
(SZC or placebo).
3.4
General Considerations
In order to provide an overview of the data, descriptive statistics will be utilized. The type 
of descriptive statistic will depend on the variable being summarized, with number of 
patients with available data (n), mean, standard deviation, median, quartiles, minimum, and 
maximum used to summarize continuous variables, and counts and percentages used to 
summarize categorical variables. 
Missing data will be ignored in the descriptive statistical summaries, and only subjects with 
non-missing data at the relevant timepoint will be included. For the percentage calculation 
for the categorical variables, the number of subjects randomized to each of the treatment 
arms, as well as the total number of subjects in the relevant study population (e.g FAS), 
will be used as a rule, unless otherwise specified in the detailed analyses descriptions given 
below.
Kaplan-Meier estimates will be used to illustrate the distribution of time-to-event data. If 
Cox regressions are used for a more formal time to event analysis, no hazard ratio estimates 
with confidence interval and p-values will be given when less than 15 events in total are 
observed during the relevant time period, both treatment groups combined.


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All of analyses will be conducted by AstraZeneca using SAS version 9.4 or higher.
3.4.1
General Study Level Definitions
3.4.1.1
Study End Date (SED)
The executive committee and AstraZeneca will monitor the accrual of endpoint events and, 
when appropriate, define the study end date as the date at which the pre-defined target 
number of 730 subjects are expected to have experienced a primary adjudicated event. The 
SED will be used as a global censoring time point for all main time to event analyses 
performed for the study. However, if the study is stopped before the planned stop date (e.g. 
based on the results of interim analyses), then the SED will be determined as per early 
stopping decision.
3.4.1.2
Withdrawal of consent (WoC)
Withdrawal of consent (WoC) refers to the date when the patient withdrew their consent for 
participation in the study.
3.4.1.3
Lost to follow-up (LTFU)
Lost to follow-up (LTFU) refers to the last date of contact with the patient if the contact 
with the patient was lost during the course of the study.
3.4.1.4
During the study and on-treatment definitions
For every patient, the following definitions will be used in safety analyses. 
During the study
“During the study” is defined as time from the randomization day to the date of last contact 
or death. 
On-treatment 
“On-treatment” is defined as the period between the first day of planned intake of study 
intervention to one day after the day of the last actual dose of study intervention. 
3.4.1.5
Others
Baseline value
For both efficacy and safety analyses the baseline value for all variables is defined as the 
last value obtained during screening period on or prior to the date of randomization. 
Geographic Region
Geographic regions are defined as follows: 
!
Asia (China, Japan, Taiwan, Vietnam, India, Malaysia, Thailand)
!
Europe (Austria, Bulgaria, Czech Republic, Germany, Hungary, Italy, Poland, 
Russia, Slovakia, Spain, Ukraine, UK, Turkey)


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!
North America (Canada, US)
!
South America (Argentina, Brazil, Mexico, Peru)
The determination of the region will be based on the country recorded in interactive 
voice/web response system (IxRS) as a stratification factor.
Incomplete dates
All efforts should be made to obtain complete dates of clinical assessments and events.  For 
analyses requiring complete dates, partially missing dates will be imputed based on 
available corroborating information.  Appendix 1 presents the dates that will be imputed 
and the associated rules.
Study day
Study day related to event day or censoring day is derived using following formula: (event 
or censoring date – randomization date) + 1.
3.4.2
Visit Window
No visit windowing be applied.
3.4.3
Handling of Unscheduled Visits 
Data obtained on unscheduled visits (e.g., safety laboratory evaluations) will be excluded 
from any analyses and presentations that are done for each visit separately. It will, however, 
be included in analyses of extreme values observed during a particular period of time, such 
as tabulations of high/low/out-of-range test results observed while a subject was on 
treatment. Data obtained on unscheduled visits will also be listed.
3.4.4
Handling of Protocol Deviations in Study Analysis
The section covers the list of potential Important Protocol Deviations (IPDs) that might 
potentially impact the results of the analyses and/or are a serious breach of Good Clinical 
Practice (GCP).
The IPDs will be categorized as follows:
1. Written informed consent not obtained prior to mandatory study specific 
procedures, sampling and analyses.
2. Received alternative protocol specific therapy than that which they were 
randomised.
3. Developed discontinuation of study intervention criteria during the study, but 
remained on the study intervention.
4. Site procedure for unblinding of the subject is not complaint with the CSP.
5. Received prohibited/excluded concomitant medication.


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As the main efficacy analyses for the study follow the intention-to-treat principle, presence 
of protocol deviations for a subject will not imply exclusion of the subject, or any data 
obtained from the subject, from these analyses. However, supplementary analyses aimed at 
e.g., evaluating potential efficacy for subjects who remain on the assigned study treatment 
regimen might be conducted. As such analyses are per protocol in nature, they would 
exclude data obtained following a protocol deviation, see Section 4.2.
4
STATISTICAL ANALYSIS
This section provides information on definitions, derivation and analysis/data presentation 
per domain (study population, efficacy, safety).
4.1
Study Population
This section covers the presentation of subject recruitment, disposition, analysis sets, 
protocol deviations, demographics, baseline characteristics, medical history, prior and 
concomitant medication, exposure and study drug compliance. Data will be summarised by 
treatment arm and overall using FAS except for disposition and analysis sets overview. 
4.1.1
Subject Disposition and recruitment
4.1.1.1
Definitions and Derivations
Complete follow-up of the primary endpoint                                                             
Subject having experienced the primary endpoint event, or the subject reaching SED is 
defined as having completed the follow-up for primary endpoint.
Study completers
Randomised subjects who stayed in the study until the SED irrespective whether they 
discontinued IP or had any event will be considered as study completers.
Vital Status of subjects at the end of the study will be recorded, if available, as dead or 
alive in the eCRF, along with the relevant dates. Vital status of the subjects that are lost to 
follow up (LTFU) will be recorded as 'unknown’. 
4.1.1.2
Presentation
Disposition
The presentation of patient disposition will include information on enrolment, 
randomization, receiving at least one dose of IP, completing the treatment and completing 
the study. It will summarise whether a subject did or did not experience these milestones 
and, if not, the reason. The presentation will also include the number of subjects with 


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complete follow-up of the primary endpoint and vital status of subjects at the end of the 
study (dead, alive or unknown).
The tabulation will include an overview of the number and percentage of subjects 
experiencing a particular disposition event, per treatment arm and in total, with number of 
randomized subjects in the respective treatment group, and in total, used as the denominator 
for the percentage calculation.
Number of subjects enrolled, but not randomized, as well as number of subjects with a 
certain reason for not being randomized, will only be displayed for all subjects combined, 
with no percentage calculated.
Disposition due to Country/Global Situation
The number, and percentage, of subjects discontinuing treatment and discontinuing study 
due to Country/Global Situation (e.g. COVID-19), will be presented separately.
Randomised Subjects 
Randomized subjects by region, country and site will be presented in terms of number and 
percentage of patients randomized at a particular location, by treatment arm and in total. 
4.1.2
Analysis Sets
4.1.2.1
Definitions and Derivations
Please refer to Section 3.2 for definitions of analysis sets. Note that only one reason for not 
being included in SS, while being included in FAS, is possible, namely failing to receive 
study intervention.
4.1.2.2
Presentation
An overview of the number of subjects included in, and, for SS, excluded from, the 
respective analysis set will be provided. The reasons for not being randomized, and, 
consequently, not being included in FAS or SS, will not be included in this presentation. 
4.1.3
Protocol Deviations
4.1.3.1
Definitions and Derivations
All protocol deviations, regardless of the method of identification (e.g. manual vs 
programmatic), will be stored in the Veeva Clinical Vault (VCV) system, from which the 
final protocol deviation data set will be extracted and included as part of the data base. This 
data set will be the basis for the summaries and listings of protocol deviations. 
4.1.3.2
Presentation
The number of subjects with any IPD, as well as the number of subjects experiencing an 
IPD in a particular category, will be summarized descriptively as categorical variables, as 


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described in Section 3.3. The presentation will also include the corresponding information 
specifically on the occurrence of Country/Global Situation related protocol deviations.
4.1.4
Demographics
4.1.4.1
Definitions and Derivations
Demographic data is recorded in the eCRF at the Screening Visit. Demographic variables 
summarized as part of the description of the study population are as follows:
•
Age (years) as a continuous variable, and categorically as:
o
≥18 to 50, 51 to 64, 65 to 84 and ≥85 years 
o
<65, 65 to 74, and ≥75 years 
o
<65 and ≥65 years
•
Sex (Male, Female)
•
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other)
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
•
Geographic region and country as defined in Section 3.4.1.5)
4.1.4.2
Presentation
The demographic attributes as described above will be summarized descriptively as 
described in Section 3.3.
4.1.5
Baseline and Disease Background Characteristics
4.1.5.1
Definitions and Derivations
Baseline characteristics summarized as part of the description of the study population are as 
follows: height (cm), pre- and post-dialysis weight (kg) and body mass index (BMI) 
(kg/m2), continuous and categorical (30<, ≥30). 
The BMI (kg/m2), defined as post-dialysis weight (kg) / (height (m))2, will be derived for 
each subject.
Disease related background characteristics will include pulse (BPM), blood pressure (BP), 
S-K (mmol/L), continuous and categorical (<5.5, 5.5-6.5, >6.5) and inter-dialytic weight 
gain (IDWG).
Interdialytic weight gain (IDWG) will be calculated as the difference between current 
pre-dialysis weight and the previous post-dialysis weight (measured at preceding dialysis 
session prior to the visit) in kilograms. If current pre-dialysis weight or previous post-
dialysis weight is missing, no interdialytic weight gain will be derived.         


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4.1.5.2
Presentation
The presentation of the baseline characteristic will follow the same rules as that for 
demographics.
4.1.6
Disease Related Medical and Surgical History
4.1.6.1
Definitions and Derivations
Disease related medical and surgical history will be coded using the version Medical 
Dictionary for Regulatory Activities (MedDRA) implemented in the study at the time of 
database lock.
4.1.6.2
Presentation
Presence of disease related medical or surgical history will be summarized descriptively by 
system organ class and preferred term, as a categorical variable, as described in Section 3.3. 
The MedDRA version used will be included in the relevant outputs as a footnote. 
4.1.7
Dialysis History
4.1.7.1
Definitions and derivations
Dialysis history recorded on the eCRF at screening visit includes: (I) dialysis vintage (time 
since first dialysis in years); (II) type of access: AV fistula, AV graft, tunneled central 
venous catheter, other (specify).
4.1.7.2
Presentation
Time since first dialysis (years) will be summarized as a continuous variable and dialysis 
access type as a categorical variable, as described in Section 3.3. 
4.1.8
Prior and Concomitant Medications
4.1.8.1
Definitions and Derivations
Concomitant medication is defined as a medication taken by the subject after the date of 
randomization, regardless of when it has been initiated. 
Please see Appendix 1 for imputation rules for missing medication start and stop dates. 
Disallowed medication is defined as a potassium binder that is taken post-randomization 
and is not identifiable as rescue therapy. Potassium binders are defined by the ATC terms 
listed in Appendix 3.
Rescue is defined as any potassium lowering treatment (e.g. a medication, an extra dialysis, 
a change in dialysate K concentration in the existing dialysis regimen) given in connection 
to an adverse event (AE) of hyperkalaemia requiring rescue. 


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4.1.8.2
Presentation
All concomitant medications and disallowed medications will be summarized separately in 
a descriptive manner, by presenting the number and percentage of subjects receiving the 
medication by ATC classification and generic drug name. Rescue treatments will be 
similarly summarized, the presentation including additional categories for dialysis initiation 
and change in dialysate K concentration. 
4.1.9
Study Drug Compliance
4.1.9.1
Definitions and Derivations
Compliance will be derived from an estimate of the actual exposure (in grams of IP), 
obtained through sachet counts, and the planned exposure to IP as indicated by the 
investigator (also in grams of IP), from first planned dose date to last planned dose date, 
accounting for dose interruptions. No compliance will be derived for subjects who did not 
receive study treatment. The last planned dose for subjects who withdraw from the study or 
withdraw from the treatment is the date of respective withdrawal.
Compliance will be analysed as a continuous variable, as well as a categorical variable, 
with categories defined as <80%, 80% to 120% and >120%.  
4.1.9.2
Presentation
Compliance during the study will be presented by means of descriptive summary statistics, 
as described in Section 3.3. 
4.1.10
Duration of follow-up
4.1.10.1
Definitions and Derivations
Time in study to SED (months) is defined as: 
(min(withdrawal of consent, death, LTFU, SED) date – randomization date + 1) / 30.4  
4.1.10.2
Presentation
Duration of follow-up as described above will be summarized using descriptive statistics, 
as a continuous variable. Empirical Cumulative Distribution Function (eCDF) plots will 
also be produced, by treatment group. 
4.1.11
Exposure
4.1.11.1
Definitions and Derivations
The duration of total planned exposure (months) to study drug is defined as the length of 
period on study drug, calculated for each subject as (date of last actual dose – date of first 
planned dose +1)/30.4.


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The duration of planned exposure excluding interruptions (months) to study drug is defined 
as total planned exposure (months) minus total interruptions. Interruptions will be identified 
from eCRF EX module. Similarly, duration of exposure to a particular dose will be defined 
as the time the dose was prescribed to the date it was dose stop plus one day.
4.1.11.2
Presentation
Duration of exposure and exposure excluding interruptions will be summarized using 
descriptive statistics as described in Section 3.3 by treatment group. Duration of exposure 
to a particular dose level will be summarized in a similar manner, by treatment group and 
dose level.  
Number of subjects (%) with any treatment interruption, as well as reasons for interruption, 
will be summarized descriptively based on the SS data set for each treatment group. 
A figure with number of subjects on study drug vs days from randomisation will be 
produced.
A plot of the proportion of subjects on each dose (including dose 0) over time will be 
produced by treatment group. This will be complimented by a table summarizing the 
average doses the subjects receive during the course of the study, as well as a one 
presenting the proportions of time a subject spends on each dose level.
A listing of subjects by batch number of study medication and dosage over time will be 
generated.
4.2
Endpoint Analyses
This section covers details related to endpoints, intercurrent event strategies, handling of 
missing data and analyses pre-specified for the efficacy objectives. All defined analyses 
will be performed using FAS if not otherwise stated. This implies that the population to 
which the results are generalizable is the population of all subjects that satisfy inclusion and 
exclusion criteria. For all analyses, the treatments, or, in terms of estimands, “treatment 
conditions”, will be SZC or Placebo administrated according to the dosing regimen, as 
detailed in CSP Section 6.1.2.  
Unless otherwise specified, for all analyses for which a statistical test is performed, the null 
hypothesis corresponds to no difference between SZC and Placebo treatment arms. 
The unit of time for all time to event analysis will be days.
Endpoints, intercurrent event strategies and censoring rules, as well as population level 
summaries, are given in Table 1 for primary objective, Table 2  for secondary objectives, 
and Table 3 for exploratory objectives. 


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Table 1 Summary of endpoints, intercurrent event strategy, and population level 
summary for the primary objective
Purpose
Endpoint
Intercurrent event strategy 
and censoring rules
Population level 
summary 
Primary objective: To evaluate the efficacy of SZC compared with placebo in reducing the time event of the primary 
composite endpoint of SCD, all stroke, or hospitalization/intervention/ED visit due to arrhythmias
Establishing the 
efficacy of treatment 
with regards to risk 
for the occurrence of 
the primary endpoint 
events 
Time to first occurrence of 
SCD, stroke, or hospitalization 
/intervention /ED visit due to 
arrhythmias (atrial fibrillation 
[AF], bradycardia, asystole, 
ventricular tachyarrhythmias 
[such as
VF, VT, etc])
Events included in analysis 
regardless of treatment 
discontinuation and additional 
therapy (treatment policy).
Patients censored at the earliest 
of death that is non-SCD, WoC, 
LTFU, study discontinuation for 
other reason, and SED. 
Hazard Ratio 
(SZC/placebo)
Sensitivity analyses of primary analysis. Details in Section 4.2.1.5
Sensitivity to 
classification of 
cause of death 
Time to the first occurrence of 
SCD or death adjudicated as 
undetermined, stroke, or 
hospitalization /intervention 
/ED visit due to arrhythmias 
(atrial fibrillation [AF], 
bradycardia, asystole, 
ventricular tachyarrhythmias 
[VT]).
Events included in analysis 
regardless of treatment 
discontinuation and additional 
therapy (treatment policy).
Patients censored at the earliest 
of death that is non-SCD and 
has a known cause, WoC, 
LTFU, study discontinuation for 
other reason, and SED. 
Hazard Ratio 
(SZC/placebo)
Sensitivity to 
inclusion of post-
SED events
Time to first occurrence of a 
primary endpoint event
Events included in analysis 
regardless of treatment 
discontinuation and additional 
therapy (treatment policy).
Patients not censored at SED. 
All other censoring rules used in 
the main analysis apply.
Hazard Ratio 
(SZC/placebo)
Supplementary analyses of the primary objective. Details in Section 4.2.1.6 


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Purpose
Endpoint
Intercurrent event strategy 
and censoring rules
Population level 
summary 
Impact of non-SCD 
as a component in the 
primary endpoint 
composite
Time to first occurrence of all 
cause death, stroke, or 
hospitalization /intervention 
/ED visit due to arrhythmias 
(atrial fibrillation [AF], 
bradycardia, asystole, 
ventricular tachyarrhythmias 
[VT])
Events included in analysis 
regardless of treatment 
discontinuation and additional 
therapy (treatment policy).
Patients censored at the earliest 
of WoC, LTFU, study 
discontinuation for other reason,
and SED.
Hazard Ratio 
(SZC/placebo)
Impact of drop-in 
(patients starting 
treatment with non-
protocolized SZC 
during study)
Time to first occurrence of a 
primary endpoint event
Events occurring post “drop-in” 
excluded from the analysis 
(while not on non-protocolised 
SZC).
Patients censored at the earliest 
of non-SCD, WoC, LTFU, 
study discontinuation for other 
reason, SED and the time of 
initiation of non-protocolized 
SZC, if such occurs.
Hazard Ratio 
(SZC/placebo)
Further details can be found in Section 4.2.1
Table 2 Summary of secondary endpoints, intercurrent event strategy, and population 
level summary for the secondary objectives (endpoints are listed in 
statistical testing order)
Testing 
Order
Endpoint
Intercurrent event strategy and censoring rules
Population 
level 
summary 
1
S-K of 4.0-5.5 mmol/L 
(yes/no) after the long 
interdialytic interval (LIDI) 
at the 12-month visit
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy)
Odds Ratio 
(SZC/placebo)
2
Time to first occurrence of
hospitalization/intervention/E
D visit due to arrhythmias 
(AF, bradycardia, asystole, 
ventricular tachyarrhythmias 
[such as VF, VT, etc]).
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy).
Patients censored at the earliest of death, WoC, 
LTFU, Other reasons of discontinuation and SED.
Hazard Ratio 
(SZC/placebo)


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Testing 
Order
Endpoint
Intercurrent event strategy and censoring rules
Population 
level 
summary 
3
Number of 
hospitalizations/interventions
/ED visits due to arrhythmias 
(AF, bradycardia, asystole, or 
VT [such as VF, VT, etc])
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy)
Patients censored at the earliest of death, WoC, 
LTFU, Other reasons of discontinuation or SED.
Rate ratio 
(SZC/placebo)
4
Time to first instance of 
rescue therapy use for 
hyperkalemia
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy). 
Patients censored at the earliest of death, WoC, 
LTFU, Other reasons of discontinuation and SED
Hazard Ratio 
(SZC/placebo)
5
S-K > 6.5 mmol/L (yes/no) 
after the LIDI at the 12-
month visit
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy)
Odds Ratio 
(SZC/placebo)
6
Time to SCD
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy).
Patients censored at the earliest of non-SCD, 
WoC, LTFU, Other reasons of discontinuation and 
SED
Hazard Ratio 
(SZC/placebo)
7
Time to first occurrence of 
stroke
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy),  
Patients censored at the earliest of death, WoC, 
LTFU, Other reasons of discontinuation and SED
Hazard Ratio 
(SZC/placebo)
8
Time to CV death
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy),  
Patients censored at the earliest of non-CV death,
WoC, LTFU, Other reasons of discontinuation and 
SED
Hazard Ratio 
(SZC/placebo)
9
Time to death of any cause
Observations included in analysis regardless of 
treatment discontinuation and additional therapy 
(treatment policy),  
Patients censored at the earliest of WoC, LTFU, 
Other reasons of discontinuation and SED
Hazard Ratio 
(SZC/placebo)


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Table 3 Summary of endpoints, intercurrent event strategy, and population level 
summaries for the exploratory objectives
Endpoint
Intercurrent event strategy
Population level summary 
S-K of 4.0-5.0 mmol/L 
(yes/no) after the LIDI at the 
12-month visit
Observations included in analysis regardless 
of treatment discontinuation and additional 
therapy (treatment policy)
Odds Ratio (SZC/placebo)
Time to first occurrence of 
SCD, stroke, or 
hospitalization/intervention/E
D visit due to arrhythmias 
(AF, bradycardia, asystole, 
VT [such as VF, VT, etc]), or 
use of rescue therapy
Observations included in analysis regardless 
of treatment discontinuation and additional 
therapy (treatment policy).
Patients censored at the earliest of non-SCD, 
WoC, LTFU, other reasons of discontinuation 
and SED.
Hazard Ratio (SZC/placebo)
Number of events of rescue 
therapy use for hyperkalemia
Observations included in analysis regardless 
of treatment discontinuation and additional 
therapy (treatment policy).
Patients censored at the earliest of death, 
WoC, LTFU, other reasons of discontinuation
or SED.
Rate ratio (SZC/placebo)
4.2.1
Primary Endpoint
4.2.1.1
Definition
The primary endpoint is the composite endpoint of time to first occurrence of adjudicated 
events of SCD, stroke, or hospitalization/ intervention/ ED visit due to arrhythmias (AF, 
bradycardia, asystole, ventricular tachyarrhythmia [VT, VF etc.]). The potential 
components of the primary endpoint will be individually adjudicated by an independent 
committee. Only events that are positively adjudicated will be used in deriving the primary 
composite endpoint and the individual components.
4.2.1.2
Derivations
Censoring: See Table 1 for the censoring rules for the different analyses.
Time to event or censoring: See Section 3.3.1.5 for the definition of the study day.
4.2.1.3
Handling of Dropouts and Missing Data
The missing data in the context of the main analysis of the primary objective are potential 
events that might have occurred after subjects have been prematurely censored (i.e. due to 
causes other than SED). Since the time-to-event analysis using the Cox regression depends 
on the assumption of noninformative censoring, corresponding to the missing-at-random 


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missing data pattern, sensitivity analyses will be performed to assess the robustness of the 
results with regards to this assumption. Explicitly, in case of a statistically significant result, 
a ‘tipping point’ analysis, where the risk of censored subjects in the SZC group 
experiencing an event post-censoring is increased until the statistical significance is lost, 
will be performed. Appendix 2 provides the technical details of the tipping point analysis.
The missing data will also be described in terms of the number and percentage of subjects 
in the respective treatment arm that do not experience a primary endpoint event and that are 
censored before the SED, as well as reasons for censoring.
4.2.1.4
Main Analysis of the Primary Endpoint
The analysis of the primary composite endpoint will be based on a Cox regression model 
that includes the following factors/covariates: treatment group, geographic region. The 
Efron method for handling ties will be used.
The estimate of the HR corresponding to the difference between treatment arms, the 
corresponding 95% two-sided confidence interval (CI) as well as the two-sided p-value for 
the null hypothesis of no difference will be reported. If the p-value falls below the 
significance limit as specified in Section 4.2.3 , the null hypothesis will be rejected. 
The contribution of each component of the primary composite endpoint to the overall 
treatment effect will be assessed. In the analysis of the components, all first events of the 
given type will be included, irrespective of any preceding non-fatal component of a 
different type. Each component in the composite endpoint will be analysed similarly to the 
composite primary endpoint, i.e. by means of a Cox regression.
Kaplan-Meier estimates will be calculated and plotted, both for the composite endpoint and 
for individual components. The KM estimate at 12, 24 and 36 months will be included in 
the tabular presentation of the primary endpoint analysis.
4.2.1.5
Sensitivity analyses of the Primary Endpoint
The majority of the sensitivity, and supplementary, analyses will be performed by means of 
replicating the main analysis using different censoring rules and different event definitions. 
For all such analyses, no KM plots of the CDFs will be produced, but the KM estimates for 
the two treatment arms evaluated at particular timepoints will be included in the tabular 
presentation.  
Undetermined cause of death
Deaths adjudicated as ‘undetermined’ cause will be included in the composite endpoint, 
along with the components used for the main analysis of the primary endpoint. The Cox 
regression analysis as described in Section 4.2.1.4 will then be replicated using this 
endpoint. 


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Events occurring post SED
The main analysis will be replicated using the entire follow-up time available for a patient, 
i.e. including events occurring post SED. 
4.2.1.6
Supplementary Analyses of the Primary Endpoint
Non-SCD events
All the deaths will be included in the composite endpoint along with the rest of the 
components, used for the main analysis of the primary endpoint. The Cox regression 
analysis as described in Section 4.2.1.5 will be replicated using this endpoint. 
Drop-in 
The sensitivity of the results observed in the main analysis to the “drop-in”, i.e. instances of 
patients starting on non-protocolized SZC, will be examined. This will be done by 
censoring such patients at the time of drop-in, correspondingly ignoring events that occur 
after the fact, and replicating the main analysis using the resulting time to event / censoring. 
Assumption of proportional hazards for Cox model
The underlying assumption of proportional hazards for Cox model will be assessed. The 
assessments will include: visual examination of the negative logarithms of the KM curves, 
with a crossing of the curves indicating that the assumption is not met, and by introducing, 
and testing, the significance of a time-dependent covariate in the Cox regression model, 
with a significant interaction indicating that the assumption is not met. This will be done for 
the main analysis of the primary endpoint only.
4.2.1.7
Subgroup Analyses
The consistency of the treatment effect observed in the main analysis will be evaluated with 
respect to the following demographic/baseline characteristic and prognostic factors:  
!
Sex
!
Age at baseline 
o
categorization 1 (<65, 65 - 84, ≥85)
o
categorization 2 (<65, 65 - 74, ≥75)
o
categorization 3 (<65, ≥65)
!
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Not reported)
!
Geographic Region (Asia, Europe, North America, South America)
!
Region (USA, Non-USA)
!
Baseline S-K (<5.5, 5.5-6.5, >6.5)
!
BMI (<30, ≥ 30 kg/m²)
!
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
!
Haemodialysis access type (Arteriovenous Fistula, Arteriovenous Graft, Tunnelled 
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!
Historical arrhythmia (yes/no) at baseline.
!
Prior History of
o
Atrial Fibrillation (Yes, No)
o
Ventricular Tachycardia (Yes, No)
o
Ventricular Fibrillation (Yes, No)
o
Stroke/TIA (Yes, No)
The Cox proportional hazards model used for the primary analysis (Section 4.2.1.4), 
including a factor for the relevant subgroup and the treatment-by-subgroup interaction, will 
be used for each subgroup analysis. HR for each level of the subgroup will be estimated 
separately.
The presentation of the results will include the estimate of the HR between treatment arms 
in the respective sub-group, the corresponding 95% CI and the p-value for the interaction 
term.
Results will also be plotted using a forest plot.
4.2.2
Secondary and Exploratory Objectives
Potassium levels at 12 months visit
The primary analyses of potassium levels at 12 months will be based on the available data 
(i.e. no imputation performed). 
Normokalemia 
Two definitions of normokalemic will be used to assess the likelihood of a patient being 
normokalemic at the 12 months visit. For the purpose of analyzing the corresponding 
secondary objective, normokalemia will be defined as:
!
S-K of 4.0-5.5 mmol/L (yes/no), as measured by the central lab, after the long 
interdialytic interval (LIDI). 
For the purpose of analyzing the corresponding exploratory objective, normokalemia will 
be defined as:
!
S-K of 4.0-5.0 mmol/L (yes/no), as measured by the central lab, after the long 
interdialytic interval (LIDI). 
A logistic regression model with the binary variable (yes/no) as response and the same 
covariates as for the main analysis of the primary objective described in Section 4.2.1.4 will 
be used. The estimated odds ratio, corresponding 95% confidence interval, and two-sided 
p-value will be presented. The proportion of normokalemic subjects in each treatment arm 


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will also be presented, with the number of patients with available SK data in the respective 
treatment arms used as the denominator. 
Severe hyperkalemia
Severe hyperkalemia will be defined as S-K > 6.5 mmol/L (yes/no) after the LIDI. The 
same analysis as for the classification of potassium into normal / abnormal (i.e. a logistic 
regression) will be performed.
Sensitivity Analysis
To assess sensitivity of the result to missing data assumptions, binary endpoints based on 
potassium levels at the 12 months will be analysed using Full Analysis Set (all randomized 
subjects). Subjects with missing values will be considered as non-responders. For severe 
hyperkalemia endpoint (S-K > 6.5 mmol/L (yes/no)), subjects with missing values will be 
considered as having severe hyperkalemia.
Supplementary analyses
The distribution of the SK values at the 12 months visit, as well as at baseline, in each 
treatment arm, will be illustrated by means of a box plot. A complimentary table presenting 
the summary statistics (mean, SD, median, min, max, quartiles) describing the distribution 
of SK, as well as the distribution of difference in SK as compared to baseline, per treatment 
arm, will also be provided.
4.2.2.1
Time to first event analyses
In addition to the main analysis of the composite primary endpoint, and its components, the 
difference between the two treatment arms in time to the following events (in days) will be 
analyzed: 
!
Time to first instance of use of rescue therapy for hyperkalemia
!
Time to CV death
!
Time to death from any cause
!
Time to first occurrence of SCD, stroke, or hospitalization/intervention/ED visit due 
to arrhythmias (AF, bradycardia, asystole, VT), or use of rescue therapy 
(exploratory objective)
For all of these endpoints, the analysis described in Section 4.2.1.4 (i.e. the main analysis of 
the primary objective) will be replicated, with the censoring rules given in Table 2 and 
Table 3. KM estimates of the CDF in the respective treatment arms will be plotted as a 
supportive illustration.
Sensitivity analyses
A sensitivity analysis of the analysis of time to CV death, where deaths adjudicated as 
‘undetermined’ cause are included as endpoint events, instead of being treated as censoring 


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events, will be performed using the same approach as for the main analysis of time to CV 
death. No plots of KM estimates will be produced.
4.2.2.2
Number of events analyses
Two analyses aimed at examining the difference in the expected number of events of 
interest, per a unit of time, between treatment arms will be performed. In the first analysis, 
aimed at evaluating the corresponding secondary objective, the events of interest are 
hospitalizations /interventions /ED visits due to arrhythmias. Only arrhythmias events that 
are positively adjudicated will be considered.  Multiple hospitalizations /interventions /ED 
visits due to a single positively adjudicated arrhythmias will be counted as one event. In 
the second analysis, aimed at evaluating the corresponding exploratory objective, the events 
of interest are use of rescue therapy for hyperkalemia.
For both of these endpoints, a negative binomial regression model with number of events as 
response and the same covariates as in the main analysis of the primary endpoint (Section 
4.2.1.4) will be used. The logarithm of the subject’s corresponding follow-up time will be 
used as an offset variable in the model to adjust for subjects having different follow-up 
times during which the events can occur. See Table 2 and 3 for the definition of the follow-
up time (censoring).
The estimated event rate in the respective treatment arm, rate ratio between these, 
corresponding 95% confidence interval, and two-sided p-value will be presented. Total 
number of events that occurred up to the point of censoring will also be presented, by 
treatment group.
Time to event analysis for recurrent events may be conducted as a supplementary analysis.
4.2.3
Multiplicity/Multiple Comparisons
Testing for efficacy will be performed at two time points, first at 0.7 information fraction 
and at the final analysis. The significance levels for the interim and the final analyses will 
be adjusted to control the overall type I error rate at two-sided 5%. At the efficacy interim 
analysis, the hypothesis for the primary endpoint will be tested at two-sided 1.64% 
significance level (O’Brian and Fleming method implemented by East 6.5, Copyright © 
2018 Cytel Inc.).  If the outcome of the interim analysis is to stop the trial for efficacy, then 
the interim analysis results will be considered as the primary efficacy results. However, a 
supplementary analysis will be performed with the additional data up to the study 
termination. 
If the trial does not stop at any interim, then the final analysis planned at 730 adjudicated 
events, will be performed at a two-sided significance level of 4.46%. If the actual 
information fraction at the efficacy interim look deviates from 0.70, the significance level 


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for the final analysis will be adjusted based on the actual number of adjudicated primary 
events at the interim and final analyses.  
To control the familywise Type I error rate, a fixed sequence multiple testing procedure for 
primary and secondary endpoints will be performed.
For the primary endpoint, the following hypothesis will be tested:
H0: HR[SZC:placebo] = 1
Versus
H1: HR[SZC:placebo] ≠ 1
If study is terminated early prior to conducting efficacy and futility interim analyses and for 
reasons unrelated to efficacy, primary endpoint will be tested at 5% two-sided significance 
level.
Once the null hypothesis concerning the primary efficacy endpoint is rejected, the 
hypotheses for the secondary efficacy endpoints will be tested separately in the order listed 
in Table 2, with the same alpha level as the primary endpoint. The testing procedure will 
continue down the hierarchy if the current endpoint is rejected and will stop if the current 
endpoint is not rejected. 
No multiplicity correction will be applied to the family of exploratory analyses. Hence, the 
results obtained from these should be regarded as hypothesis generating, rather than 
confirmatory.
4.2.4
Handling of Dropouts and Missing Data
Missing data imputation will not be adopted for secondary, or exploratory endpoints and no 
supplementary analyses of the same type as the tipping point analysis described in Section 
4.2.1.3 will be performed.  
The missing data will also be described in terms of the number and percentage of subjects 
in the respective treatment arm that do not experience an endpoint event and that are 
censored before the SED, as well as reasons for censoring.
4.3
Pharmacodynamic Endpoint(s) 
Not applicable.


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4.3.1.1
Pharmacokinetics 
Not applicable.
4.4
Immunogenicity 
Not applicable.
4.5
Safety Analyses 
The domain safety covers adverse events, clinical laboratory, vital signs, and ECG. 
Tables and listings are, as a rule, provided for the SS, except for an SAE listing that 
displays SAEs for non-randomised subjects that occur during screening. 
The primary method for presentation of summary of safety will be “during the study” (see 
Section 3.3.1.4 for the definition of this time period), reflecting the ITT approach used for 
the efficacy analyses. However, a selection of tabulations will be replicated for “on 
treatment” period, as supportive information.  
4.5.1
Adverse Events
Occurrence of AEs during the course of the study will be summarized descriptively, using 
frequencies and percentages.
4.5.1.1
Definitions and Derivations
Adverse events will be coded using the latest version of MedDRA implemented at the time 
of database lock. The MedDRA version will be stated in a footnote in the relevant outputs. 
Oedema-related events are defined as AEs with the following PT terms: Fluid overload, 
Fluid retention, Generalised oedema, Hypervolemia, Localised oedema, Oedema, Oedema 
Peripheral, Peripheral swelling.
Pre-dialysis hypokalemia (S-K < 3.0 mmol/L based on local laboratory assessment) will 
be reported as an AE regardless of whether there are associated signs and symptoms, and is 
indicated directly by the investigator in the appropriate eCRF form (note that hypokalemia 
could also be determined based on the central lab potassium evaluation, and would then be 
reported separately, see Section 4.6.2.1).
Pre-dialysis hyperkalemia requiring rescue is collected as an adverse event, and is 
indicated directly by the investigator in the appropriate eCRF form.
Dialysis adequacy (Kt/V) will be collected in eCRF only in Indian sites during visit 1 
(screening), visit 4 (randomization) and thereafter during subsequent protocol specified 
onsite visits until the end of study intervention visit (EOIV) or premature study intervention 
discontinuation visit (PIDV).


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Duration variables to be presented, where applicable (e.g. key subject information tables), 
are defined as follows:
!
Time from planned treatment start date to onset of AE (days)
!
Time from planned treatment start date to death (days)
!
Time from planned treatment start date to AE becoming serious (days)
!
Time from planned treatment start date to discontinuation of IP (days)
!
Time from actual last dose date to death (days)
!
Time from actual last dose date to AE start date (days) 
The derivations for these variables will be the difference between the two dates stated 
above + 1 day.
4.5.1.2
Presentation
Overall overview
An AE overview table will be created, with AEs falling within the following categories 
summarized by treatment group.
•
Any AE
•
Any SAE
•
Any AE with outcome death
•
Any AE leading to discontinuation of IP
•
Any AE possibly related to IP
•
Any event of hypokalaemia
•
Any event of hyperkalemia requiring rescue therapy
This summary will be replicated for on-treatment analysis period.
AEs, SAEs, DAEs and deaths, by system organ class and preferred term
A detailed overview of number, and percentage, of subjects with AEs, SAEs, DAEs and 
deaths in a particular SOC and PT class will be presented. In addition, for AEs and SAEs, a 
corresponding overview of the number of AEs in a particular SOC/PT class, and the rate of 
AEs, will be created. 
The summaries of SAEs and DAEs will be replicated for on-treatment analysis period.
Most common AEs


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A tabulation of the PT terms for most common AEs, i.e. AE PT terms that occur in more 
than 10% of the patient population (both treatment arms combined), will be provided. It 
will be replicated for the on-treatment study period.
Intensity of AEs
An overview of the number and the percentage of subjects with AEs in a particular SOC, 
PT and intensity class (mild, moderate, severe) will be created. Subjects will be counted 
only once in each category. A subject with two AE in the same SOC and PT class of e.g. 
both high and moderate intensity will be assigned the “high” intensity category, i.e. the 
more severe class.
Causality of AEs
Number and percentage of subjects with AEs considered as possibly related to IP will be 
tabulated by SOC and PT.
Events of special interest: oedema, hypokalemia and hyperkalemia
An overview of oedema-related AEs, with number and percentage of subjects with an event 
with a particular PT term, will be presented.
Number of subjects with AE classified as hypokalemia, or hyperkalemia requiring rescue, 
will be tabulated in a similar manner.
Both of these overviews, oedema-related AEs and hypo-hyperkalemia AEs, will be 
replicated for the on-treatment period as well as during study.
Dialysis adequacy (Kt/V) as a continuous variable will be summarized descriptively as 
described in Section 3.3.
Key subject information tables
Key subject information will be provided for all SAEs, AEs with an outcome of death, and 
all AEs leading to IP discontinuation. This will include e.g. the duration variables defined 
in the beginning of this section, outcome of an AE and action taken with respect to IP. 
Listings
The listings provided will include, but may not be limited to: 
!
All AE
!
All AE of hypokalemia. The listing will e.g. include information on the actual SK 
value observed during the AE.
!
SAE for enrolled, but not randomized, subjects. 


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All listings will be created for during the study time period, and will include planned 
treatment arm, actual treatment arm, planned dose, actual dose and time since the actual last 
IP administration date.
4.5.2
Clinical Laboratory, Vital Signs and ECG
Blood samples will be taken at Visit 1, 2, 3, 4 (randomization), and 8 (12-month) for the 
determination of clinical chemistry by a central laboratory; a full list of the laboratory 
variables for this study is provided in Table 7 of the CSP. For the definition of baseline, see 
Section 3.3.1.5. 
Vital signs (pulse and BP) will be assessed at Visit 1, 4 (randomization) and end of study 
intervention visit (EOIV) or premature study intervention discontinuation visit (PIDV). 
A 12-lead ECG will be performed at Visit 1 and 4 (randomization). That is, only the 
baseline ECG value will be available for this study. 
4.5.2.1
Definitions and Derivations
All summaries of clinical chemistry and hematology variables will be based on samples 
analyzed at the central laboratory and presented in SI units. 
Hyper- and hypokalemia: Based on the S-K obtained from the central laboratory at visit 
8, a set of classification variables reflecting different degrees of hyperkalemia (> 5.0, > 5.5, 
> 6.0 mmol/L, > 6.5 mmol/L) and hypokalemia (< 3.5, < 3.0, < 2.5 mmol/L) will be 
created.
Lab abnormalities: Abnormality status (“low”, “high”) of the laboratory values will be 
derived based on the normality ranges provided by the central laboratory. 
Vital signs abnormalities: Abnormal vital signs will be indicated directly in the eCRF by 
the investigator.
4.5.2.2
Presentations
Summary of measurements over time
The result and the change from baseline of each clinical chemistry and vital sign variable 
will be summarized, by treatment group, at baseline and 12-month visit (for labs) or 
EOIV/PIDV (for vital signs), using descriptive statistics as appropriate for continuous 
variables. For the ECG variables, only the baseline measurements will be presented, with 
no change from baseline, as there are no planned post-baseline ECG measurement 
occasions. The absolute values, as well as the changes, will also be illustrated by means of 
box plots.


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Haematology, clinical chemistry and vital signs, treatment emergent abnormalities 
The number, and percentage, of subjects falling into the different categories as defined 
above, at any post-baseline visit including unscheduled, for each variable, will be tabulated. 
The number of subjects with a baseline and a post-baseline value in the respective treatment 
arms will be used as the denominator for the calculation of the percentages.
The tabulations will be replicated for on-treatment time period.
Instances of hyper- and hypokalemia
Number, and percentage, of subjects experiencing different degrees of hyper- and 
hypokalemia at the 12-month visit, as defined above, will be tabulated. The number of 
subjects with observations available at visit 8 in the respective treatment arm will be used 
as the denominator for the percentages.
Listings 
The listings provided will include, but may not be limited to: 
!
Instances of lab measurements classified as abnormal.
!
Instances of vital sign measurements classified as abnormal.  
4.5.3
Other Safety Assessments
4.5.3.1
Definitions and Derivations
Pre-dialysis weight will be collected at Visit 1, 4 (randomization), and all the visits 
specified in the protocol. Post-dialysis weight from the previous dialysis session will be 
collected at Visit 4 (randomization), and all other visits specified in the protocol, except 
SCV.
Interdialytic weight gain (IDWG) will be calculated as the difference between current 
pre-dialysis weight and the previous post-dialysis weight (measured at proceeding dialysis
session prior to the visit) in kilograms. If current pre-dialysis weight or previous post-
dialysis weight is missing, no interdialytic weight gain will be derived.         
4.5.3.2
Presentations
An overview of pre-dialysis weight and IDWG over time will be created. That is, the result 
obtained at baseline and each scheduled post-baseline visit, as well as the change from 
baseline, will be summarized by treatment group as appropriate for continuous variables.
The IDWG profile over time will also be illustrated by means of box plots.


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5
INTERIM ANALYSES
The DMC will conduct interim analyses for futility and efficacy when respectively 40%, 
and 70% of the total number of primary endpoint events have accrued and have been 
adjudicated (i.e, a minimum of 292 and 511 events).
The futility threshold for non-binding futility analysis is defined as the estimated hazard 
ratio, SZC versus placebo being equal to or larger than 1. This will correspond to a 
predictive power of < 5.1%. 
At the efficacy interim analysis, the hypothesis for the primary endpoint will be tested at 
the two-sided 1.64% level (p < 0.0164) (O’Brian and Fleming, East 6.5, Copyright © 2018 
Cytel Inc.) given that information fraction at the efficacy interim analysis is equal to 0.70.  
The actual information fraction for the efficacy interim will be recalculated at the final 
analysis as number of adjudicated primary events at the interim divided by total number of 
actual primary events for the trial.  The two-sided α level for the final analysis will be 
recalculated using East 6.5 if information fraction rounded to 2 decimal places is not equal 
to 0.70.
The DMC will notify the sponsor if the formal stopping criteria for superiority or futility 
are met.


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6
REFERENCES
ICH E9(R1) 2020
ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-addendum-
estimands-sensitivity-analysis-clinical-trials-guideline-statistical-principles_en.pdf.


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7
APPENDIX 1:  MISSING DATE IMPUTATION RULES
(a) Missing data imputation for AEs
Missing scenario
Imputation rule
If only the day part of the AE 
onset date is missing
If the month and year are the same as that of first dose of study 
medication, the date of first dose of study medication will be 
used as the onset date of the AE. Otherwise, the first day of the 
month will be used to complete the onset date of the AE
If the day and month parts of the 
AE onset date are missing
If the year is the same as that of the first dose of study 
medication, the date of the first dose of study medication will 
be used as the onset date of the AE. Otherwise, January 1st will 
be used to complete the onset date of the AE.
If the AE onset date is completely 
missing and end date missing, or 
after first dose of study 
medication
The date of the first dose of study medication will be used as 
the onset date of the AE.
If only the day part of the AE end 
date is missing
The last day of the month will be used to complete the end date 
of the AE.
If the day and month parts of the 
AE end date are missing
December 31st will be used to complete the end date of the AE.
If the end date of the AE is 
completely missing and the AE is 
not ongoing, and the onset date of
the AE occurs after the date of the 
first dose of study medication
Then the onset date of the AE will be used as the AE end date. 
Otherwise, the date of the first dose of study medication will be 
used as the AE end date.


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(b) Missing data imputation for concomitant medications dates
Start Date
Stop Date
Imputation rule
Known
Partial
Impute stop date as latest possible date (i.e., last day of 
month if day unknown or 31st December if day and 
month are unknown).
Known
Missing
Assume on-going
Partial
Known
Impute start date as earliest possible date (i.e., first day 
of month if day unknown or 1st January if day and 
month are unknown)
Partial
Partial
Impute start date as earliest possible date (i.e., first day 
of month if day unknown or 1st January if day and 
month are unknown) and impute stop date as latest 
possible date (i.e., last day of month if day unknown or 
31st December if day and month are unknown)
Partial
Missing
Assume on-going
Missing
Known
If stop date ≥randomisation date, assign as concomitant
Missing
Partial
Impute stop date as latest possible date (i.e., last day of 
month if day unknown or 31st December if day and 
month are unknown)
Missing
Missing
Assume on-going


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APPENDIX 2:  TIPPING POINT ANALYSIS
Missing data in the context of the primary analysis is defined as the time interval 
between the premature censoring date and SED or date of non-sudden cardiac death, 
whichever came first. Tipping point analysis will be conducted to assess the 
robustness of the statistically significant results of the primary endpoint. Following 
steps will be used in tipping point analysis.
Step 1. Identification of patients and time interval requiring imputation 
Randomized patients (the FAS population) with a censoring date prior to SED, 
regardless of the reason for incomplete follow-up (except death), will be flagged as 
requiring imputation. The time interval subjected to imputation will be defined by the 
censoring date and SED or date of death, whichever was earlier.
Step 2. Estimation of placebo and SZC event rates 
The placebo event rate will be estimated based on available follow-up data among all 
placebo patients using accelerated failure time model (LIFEREG in SAS). Based on 
the estimated placebo event rate, the SZC event rate will be estimated as placebo 
event rate multiplied by the estimated hazard ratio in the primary analysis.
The estimated event rates will be used to inform the time to event in the next step.  
Step 3. Estimation of event time 
For patients requiring imputation, the event time will be estimated separately within 
placebo and active treatment groups, based on exponential distribution using 
corresponding rate parameters.  A seed will be used in exponential random generator 
of event time. 
Simulated follow-up time (placebo)  = 360* (RV / ERplacebo)
Simulated follow-up time (SZC)  = 360* (RV / (ERplacebo* Hazard Ratio ))
Where RV = exponential random variate (λ=1), ERplacebo= Placebo event rate, Hazard 
Ratio=hazard ratio from primary analysis.  
Step 4. Imputation of events
A simulated date of event is defined as the original censoring date plus the simulated 
time to event. If the simulated date of event is prior to both SED and the date of 
death, if applicable, an event will be imputed for this patient with the new time to 
event calculated based on the simulated date of event. Otherwise the patient will be 
censored at SED or the date of death, whichever is earlier. 


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Step 5. Combining results from imputations
Step 4  will be repeated 1000 times, generating 1000 imputed datasets. Each of the 
imputed dataset together with the observed data for the patients with complete 
follow-up will be analyzed using the same Cox proportional hazards model as the 
primary analysis. The 1000 hazard ratio estimates will be then combined using the 
Rubin’s combination rule (PROC MIANALYZE). Hazard ratio, 95% CI and p-value 
will be reported.  
Step 6. Identifying the tipping point 
The imputations in Step 4 will be repeated while SZC event rates will be 
systematically increased in small increments from observed rates.  Placebo event 
rates will be held at observed rates. The p-value from the combined results will be 
compared to the alpha threshold for primary analysis. The process will be repeated 
until the tipping point, as expressed as the ratio of the assumed event rate between the 
active and placebo groups, is found where the statistical significance is lost.  


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APPENDIX 3: ATC TERMS FOR POTASSIUM BINDERS
ATC 
CODE
RECNO
SEQNO1
SEQNO2
INGREDIENTS
V03AE
000677
01
001
SODIUM POLYSTYRENE SULFONATE
V03AE
003281
01
001
CALCIUM POLYSTYRENE SULFONATE
V03AE
075390
01
001
PATIROMER
V03AE
075390
02
001
PATIROMER CALCIUM
V03AE
075390
03
001
PATIROMER SORBITEX CALCIUM
V03AE
087714
01
001
SODIUM ZIRCONIUM CYCLOSILICATE


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