Clinical trial NCT04217590
Conditions: Hyperkalemia
Sponsor: AstraZeneca
Start date: 2020-11-16; Completion date: 2022-01-03
Enrollment: 134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of Sodium Zirconium Cyclosilicate (SZC), as well as the appropriateness of the dosing mechanism, in Chinese end-stage renal disease (ESRD) patients on chronic haemodialysis.

Detailed description:
This is a randomized, double-blind, placebo-controlled study to determine the safety and efficacy of SZC in ESRD subjects with hyperkalaemia and on stable haemodialysis. This study consists of a screening period, an 8-week randomized treatment period, and a follow-up period. Approximately 134 stable haemodialysis subjects with persistent pre-dialysis hyperkalaemia will be enrolled in the study across research sites in China.

Arms: arm 1: Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of SZC 5g depending on dose level assigned to a patient per non-dialysis days. arm 2: Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of Placebo depending on dose level assigned to a patient per non-dialysis days.
Interventions: intervention 1: Sodium Zirconium Cyclosilicate intervention 2: Placebo
Intervention descriptions: intervention 1: Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of SZC 5g depending on dose level assigned to a patient per non-dialysis days. intervention 2: Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of Placebo depending on dose level assigned to a patient per non-dialysis days.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
Sodium Zirconium Cyclosilicate 
(SZC)
Study Code
D9485C00001
Version
3.0
Date
23 March 2021
A Phase 3b, Multicentre, Prospective, Randomized, Double-Blind, Placebo-
Controlled Study to Reduce Incidence of Pre-Dialysis Hyperkalaemia with 
Sodium Zirconium Cyclosilicate in Chinese Subjects (DIALIZE China)  
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): Not applicable




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and the study physician should be 
contacted to discuss further 
participation of the subject in the 
study.” was changed to “If at any 
time during the study a potassium 
value (i-STAT, c-Lab or local lab) 
measured on a non-dialysis day or 
pre-dialysis is < 3.0 mmol/L, study 
drug should be withheld and 
hypokalaemia should be managed as 
per standard practice. The patient 
should be evaluated for any 
intercurrent illness or comorbidity 
that may increase the risk of 
hypokalaemia. The study physician 
should be contacted to discuss 
further participation of the subject 
in the study.”
Section 6.3
“The randomization codes will be 
computer generated in blocks using 
the AstraZeneca global 
randomization system (AZRand) in 
a way that ensures approximate 
balance (1:1) between the 2 
treatment arms.” was changed to “A 
blocked randomization will be 
generated in order to reach 
approximate balance (1:1) between 
the 2 treatment arms.”
It’s modified as “AZRand” is not 
a system. 
Section 6.5.2
Add the statement: “All 
hyperkalaemia events that require 
rescue therapy will be reported as an 
AE.”
To clarify definition of 
hyperkalaemia related AE.
Section 9.1
“Hypothesis tested” was changed to
“Null Hypothesis tested”. 
“The event of being a responder is 
independent of treatment 
To be more clear.






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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
Appendix E........................................................................................................................... 4
TABLE OF CONTENTS...................................................................................................... 7
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Schedule of Activities (SoA)............................................................................. 11
1.2
Synopsis ........................................................................................................... 16
1.3
Schema............................................................................................................. 19
2
INTRODUCTION............................................................................................ 20
2.1
Study rationale.................................................................................................. 20
2.2
Background ...................................................................................................... 20
2.3
Benefit/risk assessment..................................................................................... 21
3
OBJECTIVES AND ENDPOINTS................................................................... 22
4
STUDY DESIGN ............................................................................................. 24
4.1
Overall design................................................................................................... 24
4.2
Scientific rationale for study design .................................................................. 26
4.2.1
Justification of endpoints .................................................................................. 26
4.2.2
Methods for blinding and unblinding ................................................................ 27
4.3
Justification for dose......................................................................................... 27
4.4
End of study definition...................................................................................... 27
5
STUDY POPULATION ................................................................................... 27
5.1
Inclusion criteria............................................................................................... 28
5.2
Exclusion criteria.............................................................................................. 29
5.3
Lifestyle restrictions ......................................................................................... 30
5.3.1
Meals and dietary restrictions............................................................................ 30
5.3.2
Caffeine, alcohol, and tobacco .......................................................................... 30
5.3.3
Activity............................................................................................................. 31
5.3.4
Pregnancy......................................................................................................... 31
5.3.5
Other ................................................................................................................ 31
5.4
Screen failures .................................................................................................. 32
6
STUDY TREATMENTS.................................................................................. 32
6.1
Treatments administered................................................................................... 33
6.1.1
Investigational products.................................................................................... 33
6.1.2
Dose and treatment regimens ............................................................................ 33
6.1.3
Medical devices................................................................................................ 35
6.2
Preparation/handling/storage/accountability...................................................... 35
6.3
Measures to minimise bias: randomisation and blinding.................................... 35


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6.4
Treatment compliance....................................................................................... 36
6.5
Concomitant therapy......................................................................................... 36
6.5.1
Other concomitant treatment............................................................................. 38
6.5.2
Rescue medication............................................................................................ 38
6.6
Dose modification............................................................................................. 38
6.7
Treatment after the end of the study.................................................................. 38
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 39
7.1
Discontinuation of study treatment.................................................................... 39
7.1.1
Temporary discontinuation ............................................................................... 39
7.1.2
Procedures for discontinuation of study treatment............................................. 39
7.2
Lost to follow-up .............................................................................................. 40
7.3
Withdrawal from the study................................................................................ 40
7.4
Procedure for erroneously randomized subjects................................................. 41
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 41
8.1
Efficacy assessments......................................................................................... 42
8.1.1
Serum potassium measurements........................................................................ 42
8.1.2
Dialysate potassium concentration prescription................................................. 42
8.1.3
Other assessments............................................................................................. 42
8.1.3.1
i-STAT potassium............................................................................................. 42
8.2
Safety assessments............................................................................................ 42
8.2.1
Laboratory safety assessments .......................................................................... 42
8.2.2
Physical examinations....................................................................................... 44
8.2.3
Vital signs......................................................................................................... 44
8.2.4
Electrocardiograms........................................................................................... 45
8.2.5
Other safety assessments................................................................................... 45
8.2.5.1
Dialysis prescription ......................................................................................... 45
8.2.5.2
Dialysis adequacy............................................................................................. 45
8.2.5.3
Interdialytic weight gain ................................................................................... 46
8.3
Collection of adverse events ............................................................................. 46
8.3.1
Method of detecting AEs and SAEs .................................................................. 46
8.3.2
Time period and frequency for collecting AE and SAE information.................. 46
8.3.3
Follow-up of AEs and SAEs ............................................................................. 47
8.3.4
Adverse event data collection............................................................................ 47
8.3.5
Causality collection........................................................................................... 48
8.3.6
Adverse events based on signs and symptoms................................................... 48
8.3.7
Adverse events based on examinations and tests ............................................... 48
8.4
Safety reporting and medical management........................................................ 49
8.4.1
Reporting of serious adverse events .................................................................. 49
8.4.2
Pregnancy......................................................................................................... 50
8.4.2.1
Maternal exposure ............................................................................................ 50
8.4.3
Overdose .......................................................................................................... 50
8.4.4
Medication error ............................................................................................... 51
8.4.5
Management of IP-related toxicities.................................................................. 51


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8.5
Pharmacokinetics.............................................................................................. 51
8.6
Pharmacodynamics........................................................................................... 51
8.7
Genetics............................................................................................................ 51
8.8
Biomarkers ....................................................................................................... 51
8.9
Health Economics............................................................................................. 51
9
STATISTICAL CONSIDERATIONS............................................................... 52
9.1
Statistical hypotheses........................................................................................ 52
9.2
Sample size determination ................................................................................ 52
9.3
Populations for analyses.................................................................................... 53
9.4
Statistical analyses............................................................................................ 53
9.4.1
Efficacy analyses .............................................................................................. 53
9.4.1.1
Primary endpoint .............................................................................................. 53
9.4.1.2
Secondary endpoint: S-K below 5.5 mmol/L and S-K between 3.5 and 5.5 
mmol/L............................................................................................................. 54
9.4.1.3
Secondary endpoint: Gradient........................................................................... 55
9.4.1.4
Secondary endpoint: Number of normokalaemic instances................................ 55
9.4.1.5
Exploratory endpoints....................................................................................... 56
9.4.2
Safety analyses ................................................................................................. 56
9.4.3
Other analyses .................................................................................................. 56
9.4.4
Methods for multiplicity control ....................................................................... 56
9.5
Interim analyses................................................................................................ 56
9.5.1
Independent Data Monitoring Committee (IDMC)............................................ 56
10
REFERENCES................................................................................................. 58
11
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................ 60
LIST OF TABLES
Table 1
Schedule of assessments – screening........................................................ 11
Table 2
Schedule of assessments – treatment and follow-up phase........................ 13
Table 3
Study Objectives...................................................................................... 22
Table 4
Study Treatments..................................................................................... 33
Table 5
Restricted medications............................................................................. 37
Table 6
Prohibited medications............................................................................. 37
Table 7                Drug interactions ..................................................................................... 37
Table 8                Laboratory Safety Variables..................................................................... 43


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LIST OF FIGURES
Figure 1               Study design............................................................................................ 24
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................. 61
Appendix B
Adverse event definitions and additional safety information .................... 66
Appendix C
Handling of Human Biological Samples .................................................. 71
Appendix D
Abbreviations .......................................................................................... 73
Appendix E
Guidance related to COVID-19 pandemic................................................ 75


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1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
Table 1
Schedule of assessments – screening
Visit
1
2
3
For details 
see Section
Day
-7
-5
-3
Type of visit
L
S
S
Informed consent
X
Appendix 
A2
Inclusion /exclusion criteria
X
X
X
5.1, 5.2
Demographics 
X
Medical/surgical history a,b
X
Physical examination
X
8.2.2
Vital signs and BP c
X
8.2.3
Weight d
X
X
X
Height
X
Safety lab assessments
X
8.2.1
Serum hCG pregnancy test e
X
12-lead ECG
X
8.2.4
Serum Potassium (S-K) f
X
X
X
8.1.1
Concomitant medication 
X
X
X
6.5
Dialysate K prescription
X
X
X
8.1.2
Dialysis prescription g
X
8.2.5.1
Dialysis adequacy h
X
8.2.5.2
Post-dialysis weight after the 
prior dialysis session i
X
X
X
8.2.5.3
AE review
X
X
X
8.4
a
Including dialysis history: (I) dialysis vintage (time since first dialysis in years); (II) type of access: AV 
fistula, AV graft, tunnelled central venous catheter, other (specify)
b
Including cause of end-stage renal disease (ESRD)
c
Vital signs and BP should be measured prior to the haemodialysis procedure. HR and BP should be measured 
in triplicate after being comfortably at rest in either supine or seated position quietly for at least 5 min.
d
Dry weight and pre-dialysis weight on Visit 1; pre-dialysis weight on all other visits.
e
Collect from female subjects of childbearing potential only. A suspected pregnancy should be confirmed by 
increasing levels of serum beta HCG (repeated after one or two weeks) or a uterine ultrasound if pregnancy 
test result is questionable.


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f
Serum Potassium sampling: pre-dialysis central laboratory (c-Lab) during screening. 
g
Blood flow (Qb, ml/min), time on dialysis (minutes), prescribed ultrafiltration rate (ml), dialysate flow (Qd, 
ml/hr). 
h
spKt/V and/or urea reduction ratio (URR); record the most recent value but this should be no older than 5 
weeks.
i
The prior session post-dialysis weight, measured at immediate dialysis session prior to the study visit. To be 
used in the calculation of Interdialytic weight gain.
L: Long inter-dialytic interval (LIDI)
S: Short inter-dialytic interval (SIDI)


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Table 2
Schedule of assessments – treatment and follow-up phase
Visit description
Rando
mizati
on
EOT
EOS
PSDV
For 
details 
see 
Section
Period
Dose-adjustment
Evaluation
FU
Visit
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Day
1
3
5
8
10
12
15
17
22
24
29
31
36
38
43
45
50
52
57
71
+/- 3 
Type of visit
L
S
S
L
S
S
L
S
L
S
L
S
L
S
L
S
L
S
L
Physical examination
X
X k
X k
X k
X k
X
X
8.2.2
Vital signs and BP a
X
X
X
X
X
X
X
X
X
X
8.2.3
Weight b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety lab assessments
X
X
X
X
X
X
X
X
8.2.1
Serum hCG pregnancy 
test c
X
X
X
X
X
12-lead ECG
X
X
X
X
8.2.4
Serum Potassium d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
i-STAT K e
X
X
X
X
X
8.1.3
Inclusion/Exclusion 
criteria
X
5.1, 5.2
Randomization
X
4.2.2, 
6.3, 7.4
Dialysate K 
prescription
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.2


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Visit description
Rando
mizati
on
EOT
EOS
PSDV
For 
details 
see 
Section
Period
Dose-adjustment
Evaluation
FU
Visit
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Day
1
3
5
8
10
12
15
17
22
24
29
31
36
38
43
45
50
52
57
71
+/- 3 
Type of visit
L
S
S
L
S
S
L
S
L
S
L
S
L
S
L
S
L
S
L
Dialysis prescription f
X
X
X
X
8.2.5.1
Dialysis adequacy g
X
X 
X
8.2.5.2
Post-dialysis weight 
after the prior 
dialysis session h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
8.2.5.3
Drug dispensation/ 
Drug accountability i
X l
X
X
X
X
X
X
X
X m
6.2
Dose adjustment 
review j
X
X
X
6.1.2
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
AE review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.4
a
Vital signs and blood pressure (BP) should be measured prior to the haemodialysis procedure. Heart rate (HR) and BP should be measured in triplicate 
after being comfortably at rest in either supine or seated position quietly for at least 5 min.
b
Dry weight and pre-dialysis weight on Visit 4; pre-dialysis weight on all other visits.
c
Collect from female subjects of childbearing potential only. A suspected pregnancy should be confirmed by increasing levels of serum beta HCG (repeated 
after one or two weeks) or a uterine ultrasound if pregnancy test result is questionable.
d
S-K sampling: pre- and post-dialysis c-Lab is measured after LIDI throughout the study; only pre-dialysis c-Lab is measured after SIDI throughout the 
study on visits as indicated in the table.


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e
Pre-dialysis i-STAT is measured during dose adjustment period after LIDI on V4 and subsequent dose review visits. 
f
Blood flow (Qb, ml/min), time on dialysis (minutes), prescribed ultrafiltration rate (ml), dialysate flow (Qd, ml/hr). 
g
spKt/V and/or urea reduction ratio (URR), record the most recent value but this should be no older than 5 weeks.
h
The prior session post-dialysis weight, measured at immediate dialysis session prior to the study visit. To be used in the calculation of Interdialytic weight 
gain.
i
Dosing Schedule Card will be reviewed to assess treatment compliance and drug accountability
j
Dose adjustment review will be done weekly during the dose adjustment period, based on the pre-dialysis i-STAT whole blood K concentration measured 
following the long interdialytic interval.
k
Targeted physical examination only.
l
Drug accountability will not be assessed on Visit 4, only dispensation will take place.
m
No drug dispensation will take place on the EOT Visit, only drug accountability will be assessed.
L: Long inter-dialytic interval (LIDI)
S: Short inter-dialytic interval (SIDI)
EOT:   End of treatment 
EOS:  End of study 
PSDV: Premature study discontinuation visit 
FU: Follow-up


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1.2
Synopsis
National co-ordinating investigator: 
 
China. 
Protocol Title: A Phase 3b, Multicentre, Prospective, Randomized, Double-Blind, Placebo-
Controlled Study to Reduce Incidence of Pre-Dialysis Hyperkalaemia with Sodium Zirconium 
Cyclosilicate in Chinese Subjects (DIALIZE China) 
Short Title: DIALIZE China
Rationale: 
Recently, efficacy of Sodium Zirconium Cyclosilicate (SZC) in treatment of hyperkalaemia in 
subjects with end-stage renal disease (ESRD) on chronic haemodialysis was demonstrated in 
DIALIZE study (randomized, placebo-controlled, double-blind, Fishbane et al 2019). In the 
study, 41% of subjects in SZC group achieved normokalaemia on at least 3 (out of 4) long inter-
dialytic interval (LIDI) visits during a 4-week long evaluation period while not receiving any 
rescue therapy, as compared to 1% in the Placebo group. The DIALIZE study was conducted 
in four countries: Japan, Russia, United Kingdom and United States. The current study has the 
aim of confirming efficacy and safety of SZC, as well as the appropriateness of the dosing 
mechanism, in Chinese ESRD subjects on chronic haemodialysis. 
Study Objectives  
Primary Objective:
Endpoint/Variable:
To evaluate the efficacy of SZC as compared 
to placebo in keeping the S-K concentration 
between 4.0 and 5.0 mmol/L in subjects on 
haemodialysis
Classification of each subject as either a 
“responder” or a “non-responder”, with a 
responder defined as a subject who, during 
the evaluation period (last 4 weeks of the 
treatment period), maintained a pre-dialysis 
S-K between 4.0-5.0 mmol/L on at least 3 
out of 4 dialysis treatments following the 
long interdialytic interval, and who do not 
receive rescue therapy






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Statistical methods
 
 
 
 
 
 
 
 
 
 
67 subjects per group will be required to achieve an approximate power of 90%.
1.3
Schema
The general study design is summarised in Section 4.1 “Overall design”. 


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2
INTRODUCTION
2.1
Study rationale
Recently, efficacy of SZC in treatment of hyperkalaemia in subjects with end-stage renal disease 
(ESRD) was demonstrated in DIALIZE study (randomized, placebo-controlled, double-blind, 
Fishbane et al 2019). In the study, 41% of subjects in SZC group achieved normokalaemia on 
at least 3 (out of 4) long inter-dialytic interval (LIDI) visits during a 4-week long evaluation 
period while not receiving any rescue therapy, as compared to 1% in the Placebo group. The 
DIALIZE study was conducted in four countries: Japan, Russia, United Kingdom and USA. 
The current study has the aim of confirming efficacy and safety of SZC, as well as the 
appropriateness of the dosing mechanism, in the Chinese ESRD subjects on chronic 
haemodialysis.   
2.2
Background
Hyperkalaemia is defined as an abnormally high (commonly, greater than 5.0 mmol/L) serum 
potassium (S-K) concentration. The incidence of hyperkalaemia is up to 10% in hospitalized 
subjects, and 2-3% in the general population (Kovesdy 2015). Potassium homeostasis is 
essential for maintaining the cellular membrane potential and proper neuromuscular 
functioning, with hyperkalaemia impairing neuromuscular, cardiac, and gastrointestinal 
function.  Hyperkalaemia often presents without symptoms or with non-specific symptoms 
including malaise, confusion, muscle weakness or signs of cardiac arrhythmias (Henneman et 
al 2016).  The risk of fatal cardiac arrhythmias is increased, especially at S-K concentration 
above 6.0 mmol/L and the mortality risk is also increased, even with modest elevations of S-K 
(Collins et al 2017, Nakhoul et al 2015).
The most common underlying cause of hyperkalaemia is decreased urinary potassium excretion 
due to reduced kidney function, as in subjects with chronic kidney disease (CKD) and heart 
failure (HF), or due to pharmacologic treatments, such as renin angiotensin-aldosterone 
inhibitors (RAASi) (Einhorn et al 2009, Fleet et al 2012, Kovesdy 2015). As the underlying 
causes of hyperkalaemia are often chronic conditions that worsen over time, there is a need for 
treatments that not only correct S-K into the normal range, but also maintain S-K within this 
range over longer periods of time.
The kidney plays a major role in eliminating potassium. Subjects with ESRD have reduced renal 
potassium excretion ability which frequently leads to hyperkalaemia. These subjects depend on 
the administration of renal replacement therapies (e.g. haemodialysis including low K dialysates 
as necessary), dietary potassium restriction, and, occasionally, the use of oral potassium binding 
resins to maintain serum potassium concentration in a physiologic range (Luo et al 2016, 
Kovesdy et al 2007).  Despite dialysis, the prevalence of hyperkalaemia remains high in this 
population: as high as 62.9 per 100 subjects-months at the end of the long interdialytic interval 
(LIDI) (Yusuf et al 2016). Although potassium-binding resins are used in some instances to 


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treat hyperkalaemia in dialysis subjects, these agents have not been systematically studied, they 
are not universally used, and have no specific indications in this population. 
High serum potassium can lead to ventricular arrhythmias and cardiac death. Recent studies 
have shown that among subjects with ESRD on haemodialysis therapy, S-K > 5.6 mmol/L is 
associated with increased mortality, both all-cause and cardiovascular, as compared to a referent 
category of S-K concentration between 4.6 to 4.99 mmol/L (Kovesdy et al 2007, Yusuf et al 
2016). Importantly, sudden cardiac death (SCD) is the leading cause of death in haemodialysis 
subjects. In the United States Renal Data System (USRDS) database, 26.9% of all-cause 
mortalities in prevalent dialysis subjects between 2009 and 2011 were attributed to cardiac 
arrest or arrhythmias. The incidence of SCD in haemodialysis subjects was 49.2 per 1000 
subjects-years in 2011, which is much higher than that of the general population (Huang et al 
2015). Hyperkalaemia is also associated with greater short-term risk of hospitalization and 
emergency department visits, and with greater hospital costs in subjects on haemodialysis 
(Brunelli et al 2017). Hence prevention and treatment of hyperkalaemia in haemodialysis 
subjects are of paramount importance.
Sodium zirconium cyclosilicate (SZC) is a non-absorbed, inorganic crystalline compound that 
selectively captures potassium ions in exchange for sodium and hydrogen ions in the 
gastrointestinal tract after oral administration.  Thereby, excess potassium is removed from the 
body through faecal excretion and serum potassium is decreased.  The effect of SZC in reducing 
S-K was consistently demonstrated in the clinical development programme. In randomized, 
double-blind, placebo-controlled studies in non-dialysis subjects, SZC rapidly, effectively and 
safely reduced S-K into the normokalaemic range across a broad population of subjects with 
hyperkalaemia and with various underlying comorbidities, concomitant treatments, and 
demographic characteristics. Furthermore, continued SZC administration effectively 
maintained normokalaemia for up to 12 months. Importantly, DIALIZE study demonstrated 
SZC is effective in maintaining normokalaemia during LIDI in the segment of the 
hyperkalaemia patient population on chronic haemodialysis. 
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 subjects randomized to SZC treatment is expected to be the maintenance 
of normokalaemia during the long interdialytic interval, in line with what was observed in 
DIALIZE study, potentially including the relief of associated signs and symptoms and an 
improved quality of life. The likelihood of treatment with SZC raising safety concerns is deemed 
to be low, as no clinically relevant safety findings were observed in DIALIZE.
Subjects treated with placebo may not obtain any benefit in terms of hyperkalaemia correction 
and maintenance but may benefit from the closer follow-up.  Subjects will receive alternative 
therapies whenever clinically indicated. 


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An established dose adjustment algorithm will be used during the study to titrate investigational 
product (IP) doses to enable subjects to achieve and maintain pre-dialysis normokalaemia after 
the LIDI, while evaluating any changes in prescribed dialysate potassium concentrations. In 
accordance with the algorithm, the IP dose may be increased, reduced or kept unchanged, 
depending on the current potassium concentration, adapting the dosing regimen to each subject 
and preventing unnecessarily high exposure to the product.
The risks identified with SZC treatment include hypokalaemia and oedema-related events 
(includes fluid overload, fluid retention, generalised oedema, hypervolaemia, localised oedema, 
oedema, oedema peripheral, peripheral swelling). In the study, the risk for hypokalaemia is 
mitigated by periodic monitoring of K and adjustment of the dose of IP as necessary. Oedema 
can be managed by conservative measures in line with standard clinical practice. No additional 
safety risks were identified in DIALIZE study. 
In conclusion, the favourable benefit-risk ratio that has been established for SZC in the clinical 
development programme remains positive when SZC is used to treat hyperkalaemia in subjects 
on chronic haemodialysis, as shown in DIALIZE study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SZC may be found in the Investigator’s Brochure.
See Section 9.5.1 “Independent Data Monitoring Committee” for information regarding the 
Independent Data Monitoring Committee.
3
OBJECTIVES AND ENDPOINTS
The objectives of the study, as well as the associated endpoints, are listed in table below. For 
all the objectives, the analyses performed in order to address them will be reported in CSR. For 
a detailed discussion of these analyses, including the definition of statistical hypotheses and 
estimands, see Section 9 “Statistical Considerations”. 
Table 3
Study Objectives
Primary Objective:
Endpoint/Variable:
To evaluate the efficacy of SZC as compared 
to placebo in keeping the S-K concentration 
between 4.0 and 5.0 mmol/L in subjects on 
haemodialysis
Classification of each subject as either a 
“responder” or a “non-responder”, with a 
responder defined as a subject who, during 
the evaluation period (last 4 weeks of the 
treatment period), maintained a pre-dialysis 
S-K between 4.0-5.0 mmol/L on at least 3 
out of 4 dialysis treatments following the 
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Each subject will spend approximately 11 weeks in the study and take part in at least two visits 
per week, with the exception of the follow-up period, on a LIDI day (long inter-dialytic interval, 
two consecutive days between dialyses) and at least one of the two SIDI days (short inter-
dialytic interval, only one day between dialyses sessions). In the figure, the LIDI visits are 
marked by “L” and it is these visits that are of primarily interest in the study.   
The study will consist of four study periods as follows:
Screening period, one week. This period starts on visit 1 and ends on the day prior to 
randomization day. At screening, consenting subjects are assessed to ensure that they meet 
eligibility criteria. Subjects can be re-screened once during the clinical trial period, see Section 
5.4 “Screen failures” for details. 
Dose Adjustment period, four weeks. This period starts with visit 4, when randomization takes 
place, and ends at visit 14. During this period, the dose is titrated to achieve and maintain pre-
dialysis after-LIDI S-K between 4.0 and 5.0 mmol/L. The maximum allowable IP dose is 15g. 
See Section 6.1 “Treatments administered” for details.
Evaluation period, four weeks. This period starts day after visit 14 and ends with visit 22 (end 
of treatment visit, EOT). During evaluation period the dose is held stable. This is the period that 
will be used for the majority of the efficacy evaluations.
Follow-up period, approximately two weeks. This is an off-treatment period that starts day 
after visit 22 and ends with visit 23 (end of study visit, EOS), with the primary purpose of 
capturing potential post-treatment safety issues.
The following visits are of special importance: 
Visit 1, enrolment. This is the very first visit of the study on which the informed consent form 
(ICF) should be signed and first study procedure undertaken. Premature signing of ICF, i.e. 
signing before visit 1, should be avoided. A subject will be considered as enrolled in the study 
from the time the first ICF is signed (signing multiple ICFs might be necessary e.g. in case of 
re-screening). See Appendix 
A2 “Informed consent process” for further information regarding ICF.
Visit 4, randomization. This is the visit at which the randomization code is obtained, and a 
subject is randomized to either SZC or Placebo, provided they have fulfilled the eligibility 
criteria and were not withdrawn (e.g. subject decision). For further information regarding 
randomization process, see Sections 4.2.2 “Methods for blinding and unblinding” 6.3
“Measures to minimise bias: randomisation and blinding” and 7.4 “Procedure for erroneously 
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Visit 22, end of treatment (EOT). This is the last visit of the evaluation period, as well as 
treatment period overall. If no premature treatment discontinuation occurred, this is also the day 
after which no IP should be taken. For details on the process of premature treatment 
discontinuation see Section 7.1 "Discontinuation of study treatment".
Visit 23, end of study (EOS). This is the very last scheduled visit of the study with no 
assessments planned to take place after it. It should take place 14 +/- 3 days after the EOT visit 
to match the dialysis schedule. 
Extra visit, premature study discontinuation visit (PSDV). This visit is only relevant for 
subjects that are withdrawn from the study (note that this differs from treatment 
discontinuation). It might occur at any point during the study and no information should be 
collected after the visit takes place. In particular, such subjects will not have an EOS visit, with 
the premature study discontinuation visit replacing it. For further details on the process of 
premature study discontinuation see Section 7.3 “Withdrawal from the study”.
For an overview of the study design see Figure 1 “Study design”, Section 4.1“Overall design”. 
For details on treatments given during the study, see Section 6.1 “Treatments Administered”.  
For details on what is included in the efficacy and safety endpoints, see Section 3 “Objectives 
and Endpoints”.  
4.2
Scientific rationale for study design
The study is designed to provide efficacy data for the SZC clinical development program and 
provide information relevant to the efficacy of SZC in the treatment of hyperkalaemia in 
Chinese haemodialysis subjects with ESRD. The study is a randomized, double-blind study with 
two treatment groups, SZC or placebo, and includes haemodialysis subjects that have been on 
dialysis for a minimum of 3 months and receive treatment 3 times a week. No clinically justified 
therapy for severe acute hyperkalaemia will be withheld in study subjects. Rescue therapy will 
be available according to local practice patterns. Thus, placebo is deemed to be the appropriate 
comparator in this study.
Although it is the LIDI visits that are of primary interest for the purpose of demonstrating 
efficacy, scheduled SIDI visits are also included for closer safety monitoring to identify 
potential hypokalaemia. 
The duration of the study (four weeks dose adjustment and four weeks evaluation) reflects the 
clinical practice monthly potassium monitoring.
4.2.1
Justification of endpoints
The primary and secondary endpoints of the study reflect the desired claim of SZC being 
superior to Placebo in terms of decreasing, and maintaining, S-K, as well as K gradient, within 


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low-risk ranges for ESRD subjects on haemodialysis. The secondary endpoints support the 
primary claim and capture additional aspects of S-K profiles for individual subjects.    
4.2.2
Methods for blinding and unblinding
The randomized treatment phase will have a double-blind design. Subjects will take by mouth 
assigned dose from the sachet(s) containing either SZC or placebo. Individual sachets are 
enclosed in a carton with a tamper evident seal intended to be broken exclusively by subjects 
just before taking the study drug. The randomization will be performed using IVRS/IWRS.
In case of unblinding situation, individual treatment codes, indicating the treatment 
randomisation for each randomised subject, will be available to the Investigator(s) or 
pharmacists from the IVRS/IWRS. Routines for this will be described in the IVRS/IWRS user 
manual that will be provided to each centre. 
For further details, see Section 6.3 “Measures to minimise bias: randomisation and blinding”.
4.3
Justification for dose
Initial (hyperkalaemia correction) and maintenance doses of SZC were studied extensively in 
the Phase 2 and Phase 3 programs. The doses to be used in this study are consistent with those 
found to be effective for maintenance of normokalaemia in the non-dialysis population and in 
DIALIZE study. Dose adjustments were allowed in DIALIZE study according to pre-specified 
rules in order to normalize S-K concentration and minimize hypokalaemia. 
For details regarding the dosing regimen, see Section 6.1 “Treatments administered”.
4.4
End of study definition
The end of study is defined as the date of the last visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study if he/she has completed visit 23, EOS, 
which is the last scheduled visit at which study-related measurements are obtained. 
See Appendix A4 “Dissemination of clinical study data” for guidelines for the dissemination 
of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention. Under no circumstances can 


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there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, see Section 5.4 “Screen failures” for details.
In this protocol, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1
Provision of signed and dated, written informed consent form prior to any mandatory study 
specific procedures, sampling, and analyses. 
       The ICF process is described in Appendix 
A2 “Informed consent process”. 
Age
2
Subject must be ≥ 18 years of age inclusive, at the time of signing the informed consent 
form.
Type of subject and disease characteristics
3
Subjects must have haemodialysis access consisting of an arteriovenous fistula, AV graft, 
or tunnelled (permanent) catheter which is expected to remain in place for the entire 
duration of the study.
4
Receiving haemodialysis (or hemodiafiltration) 3 times a week for treatment of end-stage 
renal disease (ESRD) for at least 3 months before randomization. 
5
Pre-dialysis S-K > 5.4 mmol/L after long inter-dialytic interval and > 5.0 mmol/L after at 
least one short inter-dialytic interval during screening (as assessed by central lab).
6
Prescribed dialysate K concentration ≤ 3 mmol/L during screening.
7
Sustained Qb ≥ 200 ml/min and spKt/V ≥ 1.2 (or URR ≥ 63) on stable haemodialysis / 
haemodiafltration prescription during screening with prescription (time, dialyzer, blood 
flow [Qb], dialysate flow rate [Qd] and bicarbonate concentration) expected to remain 
unchanged during study.
8
Subjects must be receiving dietary counselling appropriate for ESRD subjects treated with 
haemodialysis / haemodiafiltration as per local guidelines, which includes dietary 
potassium restriction.


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5.2
Exclusion criteria 
Medical conditions
1
Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic / 
thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding 
vascular access thrombosis) within 12 weeks prior to randomization.  
2
Pseudohyperkalaemia secondary to haemolyzed blood specimen (this situation is not 
considered screening failure, sampling or full screening can be postponed to a later time as 
applicable).
3
Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization.
4
Presence of cardiac arrhythmias or conduction defects that require immediate treatment.
5
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 subject in this 
study, which may confound safety or efficacy assessment and jeopardize the quality of the 
data, or may interfere with study participation.
6
History of QT prolongation associated with other medications that required discontinuation 
of that medication; congenital long QT syndrome or QTc(f) > 550 msec; uncontrolled atrial 
fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects 
with atrial fibrillation controlled by medication or with transient atrial fibrillation 
associated with dialysis or peridialytic period are permitted.
Prior/concomitant therapy
7
Subjects treated with sodium polystyrene sulfonate (e.g. SPS, Kayexalate, Resonium), 
calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 
days before screening or anticipated in requiring any of these agents during the study.
Prior/concurrent clinical study experience
8
Participation in another clinical study with an investigational product administered in the 
last 1 month before screening.
Diagnostic assessments
9
Haemoglobin < 9 g/dL on screening (as assessed on Visit 1).
10 Laboratory diagnosis of hypokalaemia (K < 3.5 mmol/L), hypocalcemia (Ca < 8.2 mg/d or
albumin-corrected Ca < 8.0 mg/dL if the latter is used in local practice), hypomagnesemia 
(Mg < 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks 
preceding randomization.


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11 Severe leukocytosis (> 20 × 109/L) or thrombocytosis (≥ 450 × 109/L) during screening.
12 Polycythaemia (Hb > 14 g/dL) during screening.
Other exclusions
13 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
14 Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements.
15 Previous randomisation in the present study. 
16 For women only - currently pregnant (confirmed with positive pregnancy test or uterine 
ultrasound if pregnancy test is questionable) or breast-feeding.
17 Females of childbearing potential, unless using contraception as detailed in the protocol or 
sexual abstinence (see Section 5.3 “Lifestyle restrictions”).
18 Lack of compliance with haemodialysis prescription (both number and duration of 
treatments) during the two-week period preceding screening (100% compliance required).
19 Subjects unable to take investigational product drug mix.
20 Scheduled date for living donor kidney transplant.
21 Subjects with a life expectancy of less than 6 months.
22 Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
23 History of alcohol or drug abuse within 2 years prior to randomization.
5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
Subject will have to follow dietary counselling and be compliant with diet. Dialysis clinics 
included in the study should provide subjects dietary advice compiled from clinical sources and 
local Nephrology societies’ recommendations that are consistent with the KDOQI (US) and 
KDIGO (global) guidelines. Subjects should be instructed on avoidance of high potassium foods 
as well as selection of low potassium foods in order to restrict daily dietary potassium intake to 
between 2 and 2.5 g or as described by local guidelines.  
Although details may vary across sites (from general advice to detailed instructions), the overall 
approach should be to give subjects 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 subjects 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
Pregnancy
Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable 
method of contraception (an acceptable method of contraception is defined as a barrier method 
in conjunction with a spermicide) for the duration of the study (from the time they sign consent) 
and for 1 month after the last dose of SZC/Placebo to prevent pregnancy. In addition, oral 
contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine 
device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional 
barrier methods in conjunction with spermicide must be used.
Sexual abstinence (true abstinence in line with the subjects preferred and usual lifestyle) is 
considered an acceptable method of birth control. Subjects practicing abstinence will agree to 
have a documented second acceptable method of birth control such as a combination of the 
following: (1) oral contraceptive, depo progesterone or intrauterine device; and (2) a barrier 
method (condom or diaphragm), should they become sexually active during the course of study 
participation.
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 two weeks) or a uterine ultrasound.
5.3.5
Other
Subject should be compliant with haemodialysis prescription (both number and duration of 
treatments)
The following should remain unchanged during the entire study unless, in the judgment of the 
investigator, an unanticipated urgent clinical situation requires a change.
!
Haemodialysis prescription including treatment time and frequency (3/week), dialyzer 
size and type, blood flow (Qb) ≥ 200 ml/min and dialysate bicarbonate concentration 
(dialysate potassium concentration can be modified as specified in the protocol, see 
Section 6.1.2 “Dose and treatment regimens” for details).
!
Haemodialysis access consisting of an arteriovenous fistula, AV graft, or tunnelled 
(permanent) catheter.The study physician should be informed if the investigator deems 


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that changes in any of these parameters is necessary or if a subject is noncompliant with 
haemodialysis prescription. 
Any changes should be recorded in the eCRF.
5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in 
the clinical study but did not fulfil the eligibility criteria and, as a consequence, were not 
subsequently randomized to a treatment group via the IVRS/IWRS. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, any serious adverse event (SAE) and information 
necessary to link laboratory assessments with c-Lab data. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once. Re-screened subjects will keep the originally assigned enrolment number. 
Repeated assessments will be documented as re-screening visits in the eCRF. Subjects who 
cannot complete the screening process due to sample issue is not considered screening failure, 
sampling or full screening can be postponed to a later time as applicable.
Enrolled subjects who are not randomized (this could e.g. be due to screen failure or subject 
decision) should have the reason for study withdrawal recorded in the eCRF.
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to SZC or Placebo.


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6.1
Treatments administered
6.1.1
Investigational products
Table 4
Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Sodium Zirconium 
Cyclosilicate (SZC) 5 g
Placebo
Dosage formulation:
Powder for oral suspension in 
a sachet
Powder for oral suspension in a 
sachet
Route of administration 
Oral
Oral
Dosing instructions:
Single dose contains 1 to 3 
sachets that should be 
suspended in 45 mL of water 
by subject and administered 
on non-dialysis days
Single dose contains 1 to 3 
sachets that should be suspended 
in 45 mL of water by subject and 
administered on non-dialysis 
days
Packaging and labelling
Study treatment will be provided in sachet. Each sachet will be 
labelled in accordance with Good Manufacturing Practice (GMP) 
Annex 13 and per country regulatory requirement.
Labels will be prepared in accordance with Good Manufacturing 
Practice (GMP) and local regulatory guidelines. The labels will 
fulfil GMP Annex 13 requirements for labelling. Label text will 
be translated into local language.
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 a treatment period of eight weeks. The initial IP dose will be 5 g once daily and may 
be adjusted to a maximum of 15 g per non-dialysis day to maintain a pre-dialysis S-K between 
4.0 and 5.0 mmol/L. Subjects on nocturnal haemodialysis should wait at least 6 hours after the 
end of their dialysis session to take the corresponding investigational product dose.
The adjustment will take place during the first 4 weeks of the treatment period (on visits 4, 7, 
10 and 12). All dose adjustments will be based on pre-dialysis potassium (K) values measured 
by i-STAT (whole blood). Management of dialysis prescription will be according to local 
clinical pattern practices. In particular:
1) If pre-dialysis LIDI K as measured by i-STAT is > 5.0 mmol/L. For subjects taking 5 
g on non-dialysis days, the dose should be increased to 10 g on non-dialysis days. For 
subjects taking 10 g, the dose should be increased to 15 g on non-dialysis days. 
2) If pre-dialysis LIDI K as measured by i-STAT is 4.0-5.0 mmol/L. The dose should 
remain unchanged.


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3) If pre-dialysis LIDI K as measured by i-STAT is < 4.0 mmol/L. The action to be 
taken depends on whether an increase in dialysate K concentration is feasible 
according to local practice. Explicitly:
3a) For sites that adopt the clinical practice of modifying the prescribed 
dialysate potassium concentration when the pre-dialysis potassium 
concentration decreases.
If pre-dialysis K is below 4.0 mmol/L the dialysate K concentration should be 
increased by 0.5 or 1 mmol/L according to standard of care, e.g. increase 
dialysate K from 1 K (1 K= 1 mmol/L) to 1.5 or 2 K, from 2 K to 2.5 or 3 K, or 
from 3 K to 3.5 or 4 K. If dialysate K concentration cannot be increased further 
(e.g. subject already using 4 K dialysate bath), the dose of IP can be decreased by 
5 g. This will result in dose 0, i.e. no IP given, if already at 5 g.
3b) For sites where local clinical practice does not include increasing the 
dialysate K concentration when pre-dialysis potassium concentration decreases.
The dose of IP can be decreased by 5 g. This will result in dose 0, i.e. no IP 
given, if already at 5 g. 
If during the treatment phase (initial 4 weeks) the dose of IP has been reduced, 
and the pre-dialysis potassium value after the next long interdialytic interval is 
above 5.0 mmol/L, every effort should be made to increase the dose by 5 g or 
restart IP 5 g.
After the first 4 weeks, no additional adjustments of IP dose or dialysate potassium 
concentration should be made unless, in the judgement of the principal investigator (PI), there 
is a compelling medical need to treat an abnormal K concentration, i.e. severe hypokalaemia 
with clinical manifestations. If such an event were to occur, the appropriate IP dose 
adjustment (reduction) can be made with documentation of the event. In the case of 
hyperkalaemia with clinical manifestations deemed to require urgent treatment, rescue therapy 
can be administered, followed by proper documentation of the event. See Section 6.5.2
“Rescue medication” for definition of rescue therapy.
If at any time during the study a potassium value (i-STAT, c-Lab or local lab) measured on a 
non-dialysis day or pre-dialysis is < 3.0 mmol/L, study drug should be withheld and 
hypokalaemia should be managed as per standard practice. The patient should be evaluated for 
any intercurrent illness or comorbidity that may increase the risk of hypokalaemia. The study 
physician should be contacted to discuss further participation of the subject in the study. In 
addition, if the potassium value is < 2.5 mmol/L (severe hypokalaemia) the subject should be 


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promptly discontinued from study treatment as per Section 7.1 “Discontinuation of study 
treatment”.
6.1.3
Medical devices
The i-STAT medical device (manufactured by Abbott®) is provided for use in this study. 
Instructions for i-STAT use are provided in the i-STAT Reference Manual. 
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label specifies the appropriate storage. The investigator, institution, or 
the head of the medical institution (where applicable) is responsible for study treatment 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the IP management plan.   
6.3
Measures to minimise bias: randomisation and blinding
All subjects will be centrally assigned to randomised study treatment using an interactive 
voice/web response system (IVRS/IWRS). Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log-in information and directions for the IWRS 
will be provided to each site. 
A blocked randomization will be generated in order to reach approximate balance (1:1) between 
the 2 treatment arms. No stratification will be employed.
If a subject withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn subjects will not be replaced. 
The randomization process should proceed as follows. The investigator(s) will:
1. Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.


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2. Assign the potential subject a unique enrolment number, beginning with ‘E#’, via 
IWRS/IVRS.
3. Determine subject eligibility. See Section 5.1 “Inclusion criteria” and 5.2 “Exclusion 
criteria”
4. Eligible subjects to be assigned unique randomization code via IWRS/IVRS system
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the subject requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected 
to be causally related to an investigational product and that potentially require expedited 
reporting to regulatory authorities.  Randomisation codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual subject 
have been made and documented.
Routines for all measures listed in Section 6.3 “Measures to minimise bias: randomisation and 
blinding” will be described in the IVRS/IWRS user manual that will be provided to each centre.
6.4
Treatment compliance
Any change from the dosing schedule, does interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF. Dosing Schedule Card will be completed by 
subjects to assess treatment compliance and IP accountability.
The study site staff is responsible for managing the IP from receipt by the study site until the 
destruction or return of all unused IP. The Investigator(s) is responsible for ensuring that the 
subject has returned all unused IP.
6.5
Concomitant therapy
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplement that the subject is receiving at the time of enrolment or receives during 
the study must be recorded along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
Any treatment given in violation of restrictions given in Table 5 “Restricted medications” will 
be classified as “disallowed” in the CSR.


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Table 5
Restricted medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):
Loop Diuretics: Bumetanide (Bumex), 
Ethacrynic acid (Edecrin), Furosemide (Lasix), 
Torsemide (Demadex)
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 eCRF.
Any prohibited treatment present in Table 6 “Prohibited medications” will be classified as 
“disallowed” in the CSR. 
Table 6
Prohibited medications
Prohibited medication/class of drug:
Sodium polystyrene sulfonate (SPS, 
Kayexalate, Resonium), calcium polystyrene 
sulfonate (CPS, Resonium calcium) or 
patiromer (Veltassa)
These drugs should be avoided during the study and 
can only be used as rescue therapy.
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 IP 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 below:
Table 7                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
Changes to RAAS inhibitor (including adding a new, changing the dose or discontinuation or 
switching of RAAS inhibitor) during the study are discouraged. Similarly discouraged are 
changes to traditional Chinese medicine (including adding a new, changing the ingredient 


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content or frequency or discontinuation of traditional Chinese medicine decoction). Should such 
a change be required, the instance should be recorded in the eCRF.
6.5.1
Other concomitant treatment
Other medication than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.
6.5.2
Rescue medication
Rescue medication will be provided by the site or the institute where the subject is treated with 
rescue medication.  
The use of rescue medications is allowable at any time 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 therapy can be one of the following:
1) A treatment belonging to potassium binders: sodium polystyrene sulfonate (e.g. SPS, 
Kayexalate, Resonium), calcium polystyrene sulfonate (e.g. CPS, Resonium calcium) 
and patiromer (e.g. Veltassa). It could also be a beta-adrenergic agonist, sodium 
bicarbonate, insulin/glucose. 
2) Any additional dialysis or other forms of renal replacement treatments when used 
specifically for the treatment of severe hyperkalaemia. 
3) Any reduction in the dialysate K concentration that is prescribed for the treatment of 
severe hyperkalaemia during the study is also considered rescue therapy. 
Rescue therapy should be guided by local clinical practice patterns and preferably limited to the 
setting of severe hyperkalaemia (>6 mmol/L). Rescue therapy should be followed by the 
appropriate dose adjustment if appropriate and proper documentation of the event. 
All hyperkalaemia events that require rescue therapy will be reported as an AE.
6.6
Dose modification
As outlined in Section 6.1.2 “Dose and treatment regimens” the IP dose will be titrated from 5 
g to 0, 5, 10 or 15 g depending on current potassium value as measured by i-STAT. As indicated 
in the same section, dose can also be modified during the evaluation period in presence of a 
compelling medical need to treat an abnormal potassium concentration. No other dose 
modifications should be performed. 
6.7
Treatment after the end of the study
Not applicable.


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7
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
At any time, subjects are free to discontinue investigational product or withdraw from the study, 
without prejudice to further treatment.
7.1
Discontinuation of study treatment 
Subjects may be discontinued from IP in the following situations. Note that discontinuation 
from study treatment is NOT the same thing as a complete withdrawal from the study.
!
Subject decision. The subject is at any time free to discontinue treatment, without prejudice 
to further treatment
!
Incorrectly randomized subject in whom the inclusion/exclusion criteria violation would 
put the subject at undue risk
!
Adverse Event for which the investigator judges continued treatment may put the subject 
at undue risk
!
Severe non-compliance with the Clinical Study Protocol 
!
Pregnancy
!
Renal transplant
!
Development of any study specific criteria for discontinuation, namely:
1. Severe hypokalaemia - if severe hypokalaemia (defined by potassium values < 2.5 
mmol/l on any test) occurs at any time on non-dialysis days or pre-dialysis the subject 
should receive appropriate medical intervention and be promptly discontinued from the 
study treatment. Post-dialysis hypokalaemia should be managed as per established 
dialysis clinic protocols and local practices. Subjects considered for discontinuation 
from study treatment due to post-dialysis hypokalaemia should be discussed with the 
study physician
2. 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 subject should immediately 
receive appropriate medical intervention and be discontinued from the study treatment. 
The QTc(f) algorithm is recommended. All subjects meeting the QTc > 500 msec 
criterion should immediately have potassium assessed by i-STAT and central lab, if not 
already done within 1 hour of the collection of the ECG.
7.1.1
Temporary discontinuation 
Subjects are allowed to resume treatment if treatment has been temporarily stopped.
7.1.2
Procedures for discontinuation of study treatment
The investigator should instruct the subject to contact the site before or at the time if study 
treatment is stopped.  A subject that decides to discontinue study treatment will always be asked 
about the reason(s) and the presence of any AEs. The date of last intake of study treatment 


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should be documented in the eCRF, as well as the date of treatment discontinuation. In addition, 
a safety evaluation including physical examination, collection of safety lab samples (including 
pregnancy testing), as well as vital signs, ECG and IDWG data, should be performed at the 
earliest possible dialysis visit after last dose of IP.  
All study treatment should be returned by the subject at their next planned or unscheduled on-
site study visit. Subjects permanently discontinuing study treatment should be given locally 
available standard of care therapy, at the discretion of the Investigator.
Discontinuation of study treatment, for any reason, does not impact on the subject´s 
participation in the study.  The subject should, if possible, continue attending subsequent study 
visits and data collection should continue according to the study protocol. If, upon 
discontinuation of treatment, the subject choses to withdraw from study entirely, procedures 
described in Section 7.3 “Withdrawal from the study” should be followed. 
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site. In such cases, every attempt to contact the 
subjects, or their next of kin, should be made.  Should the subject be unreachable at the end of 
the study, they should be considered to be lost to follow up. 
7.3
Withdrawal from the study
A subject may withdraw from the study (withdraw consent) at any time (investigational product 
and assessments) at his/her own request, without prejudice to further treatment.
If the subject 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 subject 
withdraws from the study, he/she may request destruction of any samples taken, and the 
investigator must document this in the site study records.  
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up subjects as medically indicated. 
A subject who chooses to withdraw from the study should be asked to return for PSDV, 
premature study-discontinue visit, which should then take place at earliest possible dialysis visit. 
If the subject agrees, assessments as indicated in SoA (Section 1.1 “Schedule of Activities”, 
Table 2 “Schedule of assessments- treatment and follow-up phase”) should be performed. All 
study treatment should be returned by the subject. Withdrawal of consent from the study must 
be ascertained and documented by the investigator and recorded in the appropriate electronic 
Case Report Form (eCRF). If a subject withdraws from participation in the study, then his/her 
enrolment and randomisation code cannot be reused. Withdrawn subjects will not be replaced.


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7.4
Procedure for erroneously randomized subjects
A situation might arise where, despite every effort, a subject 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) Study physician should be contacted for an assessment of whether IP could pose a risk 
to the subject in light of the new information.
2) If yes, the subject should be discontinued from treatment (not to be confused with study 
discontinuation).
3) The occurrence should be documented as appropriate.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Section 1.1 “Schedule of 
Activities”).  
The investigator will ensure that data are recorded on the electronic Case Report Forms (eCRF). 
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. Serum potassium concentrations, as well as safety laboratory data, will be provided 
in form of third-party data by central laboratory (Covance) and reconciliated with the 
information obtained through the eCRF. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded in the 
eCRF, and of the provision of answers to data queries according to the Clinical Study 
Agreement (CSA). The investigator will sign the completed eCRFs. A copy of completed 
eCRFs will be archived at the study site after data base lock.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue Study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management and obtained before 
signing of the ICF may be utilised for screening or baseline purposes, provided the procedures 
met the protocol-specified criteria.


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8.1
Efficacy assessments 
8.1.1
Serum potassium measurements
S-K concentrations will be measured using central laboratory (c-Lab).
Blood samples for determination of potassium will be taken at the times indicated in the SoA 
(see Table 1 “Schedule of assessments-screening” and Table 2 “Schedule of assessments-
treatment and follow-up phase”). Serum samples will be prepared and shipped to the Central 
Laboratory. Results obtained from Central Laboratory will be used for statistical analyses of the 
study. All serum samples should be examined and any haemolyzed samples MUST be re-drawn. 
In the event that haemolysis or other artefacts are suspected based on the reported i-STAT result 
(see Section 8.1.3 “Other assessments”) the sample may be re-drawn to confirm the result. Only 
the confirmatory sample result needs to be reported in the eCRF.
8.1.2
Dialysate potassium concentration prescription
The dialysate K concentration is used in obtaining K gradient, which is one of the secondary 
endpoints. See Section 9.4.1.3 “Secondary endpoint: Gradient” for definition of K gradient. See 
Section 6.1.2 “Dose and treatment regimens” for guidance on alteration of Dialysate K 
concentration prescription. 
8.1.3
Other assessments
8.1.3.1
i-STAT potassium
Whole blood Potassium will be measured by i-STAT during the dose-adjustment period. The 
primary purpose for these measurements is to advice the investigators on whether the dose 
(alternatively, dialysate K concentration) should be adjusted or kept stable. Potassium values 
obtained from i-STAT will not be used in the analysis of efficacy, with possible exception of a 
sensitivity analysis aimed at evaluating the impact of missing c-Lab potassium values.
8.2
Safety assessments
Safety will be assessed throughout the study. During the course of the study, vital signs, physical 
examinations and laboratory tests will be performed at regular intervals. 
Planned time points for all safety assessments are provided in the SoA (Section 1.1 “Schedule 
of Activities”).
8.2.1
Laboratory safety assessments
See Table 8 “Laboratory Safety Variables” for the list of clinical safety laboratory tests to be 
performed and to the SoA for the timing and frequency. All protocol-required laboratory 
assessments, as defined in the table, must be conducted in accordance with the laboratory 
manual and the SoA. All safety laboratory measurements should be obtained pre-dialysis.


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Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator when associated with an adverse event. The date and time of collection will be 
recorded as appropriate in the eCRF.
The clinical chemistry and haematology 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 above-mentioned manuals.
The following laboratory variables will be measured:
Table 8                Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum)
B-Erythrocyte count (RBC)
B-Haemoglobin (Hb)
S-Creatinine
B-Leukocyte count
S-Bilirubin, total
B-Leukocyte differential count (absolute count and %)
S-Alkaline phosphatise (ALP)
B-Platelet count
S-Aspartate transaminase (AST)
S-Alanine transaminase (ALT)
S-Gamma-glutamyl transferase (GGT)
S-Albumin
S-Potassium
S-Calcium, total
S-Sodium
S-Chloride
S-Creatine kinase (CK)
S-Bicarbonate
S-Phosphorus
S-Glucose
S-Blood urea nitrogen
S-Magnesium
S-Lactate dehydrogenase
S-Total protein
S Pregnancy test (serum hCG)


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The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at centre 
as source data for laboratory variables.  For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 8.3.7 “Adverse events based on examinations and 
tests”.
8.2.2
Physical examinations
A physical examination will be performed as specified in SoA (Section 1.1 “Schedule of 
Activities”).
A complete physical examination includes the following: general appearance, skin, height (Day 
-7 only) and weight, head and neck ((including ears, eyes, nose and throat), lymph nodes, 
thyroid, musculoskeletal (including spine and extremities), respiratory, cardiovascular 
including assessment of signs of heart failure, abdomen, and neurological systems.
The targeted physical examination includes the following: weight (weighed on the same scale 
in the same state of dress), skin, extremities, respiratory, cardiovascular including assessment 
of signs of heart failure, and abdomen. 
A complete physical examination should be performed on Day -7, Day 1 and Day 71, and 
targeted physical examination will be conducted as specified in the SoA. Investigators should 
pay special attention to clinical signs related to previous serious illnesses, new or worsening 
abnormalities may qualify as adverse events, see Section 8.3.7 “Adverse events based on 
examinations and tests” for details. The results of the physical exam will not be registered in 
the eCRF, unless an AE is identified. In that case, the appropriate AE pages should be filled in. 
8.2.3
Vital signs
Vital signs will be assessed at visits as specified in SoA (Section 1.1 “Schedule of Activities”). 
Any clinically significant changes in vital signs should be investigated and reported as AEs (see 
Section 8.3.7 “Adverse events based on examinations and tests”). 
Heart rate and blood pressure will be measured in triplicate after the subject has been 
comfortably at rest in either supine or seated position for at least 5 minutes. The position of the 
subject should be comfortable with the arm where the blood pressure is recorded to be within 
the level of heart (the middle of the cuff on the upper arm is at the level of the right atrium (the 
midpoint of the sternum). The subject will be instructed to relax as much as possible and to not 
talk during the measurement procedure. Preferably measurement will be done with an electronic 
automated oscillometric device. The same device should preferably be used for the subject 
during the course of the study and in the same arm. Blood pressure will be measured in triplicate 


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with at least one-minute intervals between measurements. All the three readings will be reported 
in the eCRF. 
The heart rate will be assessed by pulse palpation of radial artery for 30’s immediately after 
each recording of the blood pressure. It could be also performed with an oscillometric device if 
this is used for blood pressure measurement. The triplicate heart rate assessments will be 
recorded in the eCRF. 
8.2.4
Electrocardiograms
Standard 12-lead ECG will be performed as safety measurement pre-dialysis at timepoints as 
per SoA (Section 1.1 “Schedule of Activities”). ECG will be assessed by Investigators 
according to local practice.
A single ECG will be taken after the subject has been resting in the supine position for 5 minutes. 
The following ECG measurements will be obtained: P, PR, QRS, QT, and QTc(f) intervals. 
Refer to Section 7 “Discontinuation of treatment and subject withdrawal” for QTc(f) withdrawal 
criteria and any additional QTc(f) readings that may be necessary.
Any abnormalities must be evaluated in clinical context (based on subject’s medical history and 
concomitant medication) and the investigator should determine if it is clinically significant. 
Clinically significant abnormalities should be reported as an AE. 
Only the visit, ECG date and time, heart rate (HR), P and QRS durations, PR, QT and QTc(f) 
intervals, overall interpretation and relevant comments will be recorded in the eCRF. ECG 
recordings will be kept as source documents. 
8.2.5
Other safety assessments
In addition, the following safety assessments below will be made.
8.2.5.1
Dialysis prescription
Dialysis prescription parameters including blood flow (Qb, ml/min), time on dialysis 
(minutes), prescribed ultrafiltration rate (ml) and dialysate flow (Qd, ml/hr) should be 
recorded at the times specified in Table 1 “Schedule of assessments-screening” and Table 2
“Schedule of assessments-treatment and follow-up phase”.
8.2.5.2
Dialysis adequacy
Dialysis adequacy indices including spKt/V and/or urea reduction ratio (URR) should be 
recorded at the times specified in Table 1 "Schedule of assessments-screening" and Table 2
"Schedule of assessments-treatment and follow-up phase". Investigators should record the 
most recent values, but these should be no older than 5 weeks. If no values within 5 weeks are 
available, a new assessment of spKt/V and/or URR should be performed on the next weekly 


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visit. Sites should consistently use either spKt/V or URR in determining dialysis adequacy. A 
combination of both is not acceptable.
8.2.5.3
Interdialytic weight gain
Interdialytic weight gain (IDWG) 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, see SoA) in kilograms. The calculation will be performed as part of the 
analysis. 
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B “Adverse event definitions and 
additional safety information”.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
Section 8.3.3 “Follow-up of AEs and SAEs”.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events will be collected from randomisation throughout the treatment period and the 
follow-up period, up to end of study or premature study discontinuation visit.
SAEs will be recorded from the time of signing of informed consent form until end of study or 
premature study discontinuation visit.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 8.4.1 “Reporting of serious adverse events”. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject’s last visit 


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and he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 8.4.1 “Reporting of serious 
adverse events”.  
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All AEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the subject is lost to follow-up. 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity (mild, moderate or severe)
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product(s) (yes or no)
!
Action taken with regard to Investigational Product(s)
!
AE caused subject’s withdrawal from the study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
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!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication
!
Description of AE
It is important to distinguish between serious and severe AEs. 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 need not be an SAE. On the other hand, a stroke that results in 
only a limited degree of disability may be considered a mild stroke but could be an SAE. Criteria 
for SAE can be found in Appendix B “Adverse event definitions and additional safety 
information”. 
8.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B “Adverse event 
definitions and additional safety information” to the Clinical Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject 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 
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.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
assessments should therefore only be reported as AEs if they fulfil any of the SAE criteria or 
are the reason for discontinuation of treatment with the investigational product.
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 


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will be considered as additional information. Wherever possible the reporting Investigator uses 
the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel should 
inform the appropriate AstraZeneca representatives within one day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., 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 WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
For further guidance on the definition of a SAE, see Appendix B2 “Definitions of serious 
adverse event”.  


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8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca, unless the 
pregnancy is discovered before the study subject has received any study drug.
8.4.2.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs. Elective abortions without complications should not 
be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed up 
and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1 “Reporting of serious adverse events”) and within 30 
days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.3
Overdose
For this study, any dose of IP in excess of what is specified in the protocol will be considered 
an overdose.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF module
If an overdose of an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel should inform appropriate AstraZeneca representatives 
immediately, or 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.


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For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.4.1
“Reporting of serious adverse events”. For other overdoses, reporting must occur within 30 
days.
8.4.4
Medication error
For the purposes of reporting in this clinical study, a medication error is an unintended deviation 
from the allowable schedule as per protocol in administering any study drug that either causes 
harm to the subject or has the potential to cause harm to the subject. If a medication error occurs 
in the course of the study, then the Investigator or other site personnel should inform the 
appropriate AstraZeneca representatives within 1 day i.e., immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative should work with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2 “Time period and frequency for 
collecting AE and SAE information”) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B8 “Medication error”. 
8.4.5
Management of IP-related toxicities
See Section 6.1.2 “Dose and treatment regimens” for details on dose / dialysate K adjustment 
related to hypokalaemia. See Section 7.1 “Discontinuation of study treatment” for 
hypokalaemia-based discontinuation criteria.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
Genetic testing is not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.




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9.3
Populations for analyses
For the purpose of the analysis, the following populations are defined: 
Population
Description
Enrolled 
All subjects who sign the ICF.
Full analysis set (FAS)
All randomized subjects.
Safety analysis set (SAS)
All subjects included in FAS who take at least 
one dose of IP and for whom any post-dose data 
are available.  
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until the database is 
locked and Clinical Study Protocol deviations identified and properly documented.  
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalised before database lock and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing, 
unused and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. Any deviations from this plan will be reported in the clinical 
study report.
9.4.1
Efficacy analyses
All efficacy analyses will be performed using FAS. The subjects will be analysed using the 
treatment group they have been randomized to.
9.4.1.1
Primary endpoint
The analysis of the primary (and the secondary) endpoints will be conducted according to the 
intention to treat principle using FAS. Thus, the population under study consists of all subjects 
that are deemed as suitable for randomization by the investigators.
As stated above, the primary endpoint is a classification of each randomized subject into a 
responder or a non-responder category (i.e. a 0-1 type of response), with a subject being a 
responder if they:


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a.
Have pre-dialysis S-K between 4.0 and 5.0 mmol/L on at least 3 out of 4 LIDI visits 
that occur during the evaluation period
b. Do not receive any rescue therapy during the evaluation period
Note that this implies that, if a subject has 2 or more missing S-K values during the evaluation 
period, they will be classified as a non-responder.
One intercurrent event of concern has been identified in this setting, namely the use of rescue 
therapy. For the primary analysis, rescue therapy use is included as part of a composite endpoint, 
hence the addition of b) in the primary endpoint definition (this is referred to as a “Composite 
strategy” in ICH E9 (R1) 2017 p. 17).  
The primary endpoint will be analysed using Fisher's exact test applied to the contingency table 
of counts of responders and non-responders in a particular treatment group with the rejection / 
non-rejection of the null hypothesis based on the resulting p-value. For illustrative purposes, 
proportions of responders in the respective treatment groups, as well as the difference in 
proportions with the corresponding CI, will be presented. 
The primary analysis will be repeated for selected pre-specified sub-groups in order to examine 
the consistency of the observed effect. The list of sub-groups will be provided in SAP.
9.4.1.2
Secondary endpoint: S-K below 5.5 mmol/L and S-K between 3.5 and 5.5 
mmol/L
In the analyses of these endpoints the individual S-K measurements obtained during the 
evaluation period will be used (at the planned LIDI and, for analysis of S-K below 5.5 mmol/L, 
SIDI visits). Unlike the primary endpoint, the intercurrent event will not be managed through 
construction of a composite. Instead, the S-K measurements obtained while a subject was 
receiving rescue therapy will be excluded from the analysis, reflecting a hypothetical scenario 
where rescue therapy is not available to subjects (i.e. a “hypothetical strategy” type of approach, 
see ICH E9 (R1) 2017 p. 18). 
In what follows, the analysis of S-K below 5.5 mmol/L is described. The analysis of S-K 
between 3.5 and 5.5 mmol/L will be conducted in the same manner. 
The probability that the maximum S-K value is less than or equal to 5.5 (or between 3.5 and 
5.5), denoted by p, during the evaluation period for a particular subject is of interest. In order to 
mitigate the possible impact of missing values, this probability will be estimated by fitting a 
multivariate normal distribution to the S-K values in each treatment arm and defining p = F (5.5, 
…, 5.5), with F indicating the fitted cumulative distribution function (cdf). The variance of this 
estimator can be approximated using bootstrap. The p-value from a test of no difference between 
treatment groups, estimates of probabilities in each treatment group and the difference between 


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the two with the corresponding CI (constructed using normal approximation, if appropriate), 
will be presented.    
9.4.1.3
Secondary endpoint: Gradient
The endpoint in this analysis are the 0-1 indicators of whether potassium gradient, defined as 
the difference between pre-dialysis S-K and dialysate K concentration, is below 3.0 mmol/L for 
each LIDI visit in the evaluation period. That is, similarly to the first secondary endpoint, 
multiple measurements for each subject will be considered. Again, similarly to the first 
secondary endpoint, the intercurrent event of rescue therapy will be incorporated through 
omission of observations that coincide with rescue therapy use from the analysis, resulting in 
the hypothetical scenario of no rescue therapy being available. 
For this objective, the probability that the potassium gradient for a particular LIDI visit is below 
3.0 mmol/L is of interest. This probability can be estimated for each treatment group though 
application of a generalized linear mixed model with random intercept and logit link. The p-
value from a test of no difference between treatment groups, estimates of probability of 
observing a gradient below 3.0 mmol/L in each treatment group and the difference between the 
two groups with the corresponding CI, will be presented. The presented p-value will be obtained 
from the test of equality of odds ratios using the aforementioned generalized linear mixed 
model.
9.4.1.4
Secondary endpoint: Number of normokalaemic instances
The endpoint in this analysis are the 0-1 indicators of whether S-K is between 4.0 and 5.0 
mmol/L for each LIDI visit in the evaluation period. The intercurrent event of rescue therapy 
will, again, be incorporated through omission of observations that coincide with rescue therapy 
use from the analysis. 
This endpoint will be analysed through application of a generalized linear mixed model with 
random intercept. P-value of a test of no difference, estimates of the expected number of 
normokalaemic instances in the respective treatment groups, the difference between the two 
groups and the corresponding CI will be presented. The presented p-value will be obtained from 
the test of equality of odds ratios using the generalized linear mixed model. 
Note that the rejection of this null hypothesis implies the rejection of the null hypothesis of no 
difference between the expected number of visits with S-K between 4.0 and 5.0 mmol/L, as 
equivalence of odds ratios implies equivalence of probabilities (of S-K between 4.0 and 5.0 
mmol/L in the respective treatment groups at a particular visit) which, in turn, implies 
equivalence of expected number of normokalaemic visits. Similar logic applies to the test of 
secondary endpoint described in the previous section.


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9.4.1.5
Exploratory endpoints
 
 
 
 
9.4.2
Safety analyses
All safety analyses will be performed using the Safety analysis set. The subjects will be analysed 
using the actual treatment they have been taking during the study. If a subject takes several 
treatments during the study, they will be analysed using the treatment they have been 
randomized to.
The analyses will include a tabulation of AEs, SAEs and DAEs (per SOC and/or PT, intensity, 
causality) in the respective treatment group, a tabulation of safety laboratory evaluations as 
listed in Section 8.2.1 “Laboratory safety assessments” (summary statistics such as mean, 
standard deviation, median, minimum and maximum), a tabulation of vital signs and ECG 
(similar to the one employed for safety laboratory measurements) and a tabulation of IDWG. 
Listings of AEs, with detailed information such as day of AE occurrence and outcome of AE, 
will also be provided.
9.4.3
Other analyses
Other analyses will include a tabulation of baseline demography and subject characteristics, 
medical history including dialysis history, compliance and exposure.  
9.4.4
Methods for multiplicity control
In case of rejection of the null hypothesis corresponding to the primary endpoint, the four 
secondary efficacy hypotheses will be considered. A multiplicity testing procedure that controls 
the family-wise Type I error rate will be applied, and statistical significance will be claimed in 
case of rejection at the family-wise significance level of 0.05. The multiplicity testing procedure 
will be a fixed sequence procedure, with the hypotheses ordered as in Table 3 “Study 
Objectives”. 
9.5
Interim analyses
No interim analyses are planned for the study.
9.5.1
Independent Data Monitoring Committee (IDMC)
An independent data monitoring committee (IDMC) will be utilized for this study. 
The IDMC will be the external advisory group for the study which, on a regular basis, reviews 
accumulating study efficacy and safety data, to determine whether the overall integrity and 


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conduct of the study remain acceptable, and makes recommendations to the Sponsor. The IDMC 
will function independently of all other individuals associated with the conduct of the studies, 
including AstraZeneca. The committee will operate in accordance with an Independent Data 
Monitoring Committee Charter. 


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10
REFERENCES
Fishbane et al 2019
Fishbane S, et al. (2019). "A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study 
of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalaemia".
JASN, ASN.2019050450. 
Henneman et al 2016
Henneman A., et al. (2016). "Emerging therapies for the management of chronic hyperkalaemia 
in the ambulatory care setting". Am J Health Syst Pharm 73(2): 33-44. 
Nakhoul et al 2015
Nakhoul, G. N., et al. (2015). "Serum Potassium, End-Stage Renal Disease and Mortality in 
Chronic Kidney Disease". Am J Nephrol 41(6): 456-463. 
Einhorn et al 2009
Einhorn, L. M., et al. (2009). "The frequency of hyperkalaemia and its significance in chronic 
kidney disease". Arch Intern Med 169(12): 1156-1162. 
Fleet et al 2012
Fleet JL, Shariff SZ, Gandhi S, et al. (2012). "Validity of the International Classification of 
Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an 
emergency department and at hospital admission". BMJ Open 2012; 2: e002011 
Kovesdy 2015
Kovesdy, C. P. (2015). "Management of Hyperkalaemia: An Update for the Internist." Am J 
Med 128(12): 1281-1287.
Collins et al 2017
Collins AJ, Pitt B, Reaven N, et al. (2017). "Association of Serum Potassium with All-Cause 
Mortality in Patients with and without Heart Failure, Chronic Kidney Disease, and/or 
Diabetes". Am J Nephrol. 46(3):213-221. 
Luo et al 2016
Luo J, Brunelli SM, Jensen, DE, Yang A (2016). "Association between Serum Potassium and 
Outcomes in Patients with Reduced Kidney Function". Clin J Am Soc Nephrol 11: 90-100.
Kovesdy et al 2007
Kovesdy CP, Regidor DL, et al. (2007) "Serum and Dialysate Potassium Concentrations and 
Survival in Hemodialysis Patients". Clin J Am Soc Nephrol 2: 999-1007.
Yusuf et al 2016
Yusuf AA, Hu Y, Singh B, Menoyo JA, Wetmore JB (2016). "Serum Potassium Levels and 
Mortality in Hemodialysis Patients: A Retrospective Cohort Study". Am J Nephrol 44:179-186.


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Huang et al 2015
Huang CW, Lee MJ, et al. (2015). "Low Potassium Dialysate as a Protective Factor of Sudden 
Cardiac Death in Hemodialysis Patients with Hyperkalaemia". PLoS One. 2015 Oct 6;10(10): 
e0139886. 
Brunelli et al 2017
Brunelli SM, et al. (2017). "Serum Potassium and Short-term Clinical Outcomes Among 
Hemodialysis Patients: Impact of the Long Interdialytic Interval". Am J Kidney Dis 70:21-29. 
ICH E9 (R1) 2017
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline 
on statistical principles for clinical trials. 
EMA/CHMP/ICH/436221/2017, Committee for Human Medicinal Products


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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, ethical and study oversight considerations  
A1 
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
!
Applicable ICH Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
!
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study 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, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), 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 (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements.
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A2 
Informed consent process
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre.  
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained.  The 
authorised person obtaining the informed consent must also sign the ICF.
Subjects 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 subject or the subject’s legally authorised 
representative.  
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
60 days from the previous ICF signature date.
A3 
Data protection
Each subject will be assigned a unique identifier by the sponsor. Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  
The subject 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 must also be explained to 
the subject.  


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The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A4
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical trial 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.
A5
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic eCRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
A6 
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.


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Data reported on 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.
A7 
Study and Site Closure
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. The study may be stopped if, in the judgment 
of AstraZeneca, trial subjects are placed at undue risk because of clinically significant findings 
that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests
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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A8 
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse event definitions and additional safety information
B1 
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(e.g. an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B2 
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity.  
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed and 
reported as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not 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 tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy.


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B3 
Life threatening
‘Life-threatening’ means that the subject 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 subject’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
B4 
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B5 
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B6 
Intensity and scale
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3     severe (incapacitating, with inability to perform normal activities)


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It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B2 “Definitions of serious adverse 
event”. An AE of severe intensity need not necessarily be considered serious.  For example, 
nausea that persists for several hours may be considered severe nausea, but not a SAE unless it 
meets the criteria shown in Appendix B2 “Definitions of serious adverse event” On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild stroke 
but would be a SAE when it satisfies the criteria shown in Appendix B2 “Definitions of serious 
adverse event”. 
B7 
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 subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous knowledge 
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class? Or could the AE be anticipated from its pharmacological properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.


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The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that 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.
B8 
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.  
!
occurred
!
was identified and intercepted before the participant received the drug
!
did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g. 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 e.g. tablet dissolved in water when it should be taken as a solid 
tablet 
!
Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature 
!
Wrong participant received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - 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) e.g. forgot to take medication


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!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in open 
label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C1 
Chain of custody for biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
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 documentation of receipt of arrival.
AstraZeneca 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
C2 
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations


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!
Clinical trial samples will routinely be packed and transported at ambient
!
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk 
of infection or contamination by using approved couriers and packaging/containment 
materials at all times. The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used.


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Appendix D
Abbreviations
Abbreviation or special 
term
Explanation
AE
Adverse Event
ALP
Alkaline Phosphatise 
ALT
Alanine Transaminase 
AST
Aspartate Transaminase 
BP 
Blood Pressure
CDF
Cumulative Distribution Function 
CIOMS
Council for International Organizations of Medical Sciences 
CK
Creatine Kinase 
CKD
Chronic Kidney Disease 
c-Lab
Central Laboratory
CONSORT
Consolidated Standards of Reporting Trials 
CPS
Calcium Polystyrene Sulfonate 
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
EC
Ethics Committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC)
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EOS
End of Study 
EOT
End of Treatment
ESRD
End-Stage Renal Disease
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
GGT
Gamma-glutamyl Transferase 
GMP
Good Manufacturing Practice 
HF
Heart Failure
HIPAA
Health Insurance Portability and Accountability Act 
HR
Heart Rate
IATA
International Airline Transportation Association 
ICF
Informed Consent Form 


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Abbreviation or special 
term
Explanation
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IDWG
Interdialytic Weight Gain
IEC
Independent Ethics Committee 
IP
Investigational Product
IRB
Institutional Review Board 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LIDI
Long Inter-dialytic Interval 
LIMS
Laboratory information management system
LSLV
Last subject last visit
PI
Principal Investigator 
PSDV
Premature Study Discontinuation Visit
PTDV
Premature Treatment Discontinuation Visit
Qb
Blood Flow (dialysis) 
Qd
Dialysate Flow Rate
RAASi
Renin Angiotensin-aldosterone Inhibitors
S-K
Serum Potassium
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SCD
Sudden Cardiac Death 
SIDI
Short Inter-dialytic Interval 
SoA
Schedule of Activities
SPS
Sodium Polystyrene Sulfonate 
SZC
Sodium Zirconium Cyclosilicate 
URR
Urea Reduction Ratio 
USRDS
United States Renal Data System
WBDC
Web Based Data Capture


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Appendix E
Guidance related to COVID-19 pandemic
E1 
Management of Study Procedures During the COVID-19 
Pandemic
In view of the ongoing and emerging novel coronavirus (COVID-19) pandemic spreading 
worldwide, the safety and well-being of our study participants is of primary importance. To 
protect the safety and well-being of study participants, this section will provide guidelines on 
study assessments and procedures during this period.
1. 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. Every effort should be made to 
follow the clinical study protocol (CSP). Participant safety is paramount, and the 
investigator should continue to reassess the risk/benefit of continued study involvement 
for each study participant.
2. Investigational study sites must comply with local public health rules.
3. If a study participant is suspected or diagnosed with COVID-19, they should follow the 
local guidance for COVID19 diagnosis, quarantine, and treatment procedures.
a) Please accurately document all diagnoses, procedures, assessments, dosing 
interruptions, and sequelae in the eCRFs. All AEs/SAEs should be reported in line 
with instructions for safety reporting documented in the CSP.
b) If a COVID-19 AE/SAE is reported, the investigator should determine whether the 
participant’s investigational product should continue, be interrupted, or stopped in 
accordance with the CSP.
4. If a study participant is unable to attend clinic visits either due to quarantine for being 
infected with or suspected for COVID-19 or due to site closure for COVID-19, the 
investigational product should be discontinued, and every effort should be made to 
conduct safety assessment (e.g., potassium value and ECG measurement), this could be 
done at an alternative healthcare facility or by home visit if possible. Local lab results will 
not be collected or stored in the study database but will help the investigator to assess 
patient safety. The site staff should keep in close contact with the study participant(s), 
preferably through telephone calls, to maintain awareness of their status.
E2          Guidance on Covid-19 vaccination in clinical studies of SZC
Covid-19 vaccination of subjects participating in clinical studies of SZC should follow 
national/local guidelines. SZC is a locally acting drug in the GI tract with no systemic toxicity, 
immunogenic effects or a potential to interfere with the biological action of drugs affecting the 
immune system, including Covid-19 vaccines. An approved Covid-19 vaccine is therefore 
treated like any allowed medication in clinical studies with SZC.


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!
Vaccination prior to or during a clinical study of SZC does not limit enrolment or 
continued participation in the study.
!
Vaccine use should be recorded in the eCRF:
o
The specific vaccine used (brand name) and each dose administered after enrolment 
should be recorded as concomitant medication.
o
Vaccination taking place before enrolment should be captured under “medical 
history”.
o
Adverse events suspected of being related to vaccinations should be reported as for 
any other AEs.
!
In accordance with general rules for AstraZeneca clinical studies, a subject participating in 
any other clinical study with an investigational product administered within a month 
before the screening, e.g. clinical study of a vaccine, is not eligible to participate in a 
clinical study of SZC.
The guidance above only applies to vaccines approved by health authorities including 
Emergency Use Authorisation by the FDA or similar authorisation by other Regulatory 
Agencies. Vaccines which are still in development, i.e. not yet approved, are not permitted. 


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: d9485c00001-csp-v3
Document Title:
D9485C00001 Clinical Study Protocol version 3
Document ID:
Doc ID-004081719
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
29-Mar-2021 02:37 UTC
Content Approval
26-Mar-2021 14:16 UTC
Content Approval
29-Mar-2021 08:18 UTC
Content Approval
29-Mar-2021 07:06 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

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