A Phase 3b, Multicenter, Prospective, Randomized, Double Blind, Placebocontrolled Study to Reduce Incidence of Pre-dialysis Hyperkalemia With Sodium Zirconium Cyclosilicate (DIALIZE)
Phase: PHASE3
Conditions: Hyperkalemia
Sponsor: AstraZeneca

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EudraCT number 2017-003029-14
Clinical Study Protocol 
Drug Substance
Sodium Zirconium 
Cyclosilicate (ZS)
Study Code
D9480C00006
Version
4.0
Date
05 February 2018
A phase 3b, multicenter, prospective, randomized, double blind, placebo-
controlled study to reduce incidence of pre-dialysis hyperkalemia with 
Sodium Zirconium Cyclosilicate (DIALIZE)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
(Japan) AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku Osaka 530-0011, Japan

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VERSION HISTORY
Version 4.0, 05 February 2018
-
Visit schedule updated (additional potassium sampling visits after Short Inter-
Dialytic Interval)
-
EOT/EOS requirements updated for premature treatment discontinuation
-
Contraception and pregnancy restrictions updated to reflect EU guidelines
-
Outcome measure for primary objective updated
-
IDMC related wording added 
-
Eligibility criteria updated (EC #2 removed; IC #9 added; IC #7 and EC #6 clarified)
-
Patient dietary counseling and compliance with diet restrictions added
-
Dialysis adequacy and Interdialytic Weight Gain assessment clarified
-
Dosing instruction for Investigational Product updated
-
The list of pH-dependent drugs updated 
-
EOS visit window updated
-
Study requirements for safety assessments and rescue treatment clarified
-
Minor typos/errors corrected
Version 3.0, 11 September 2017
-
Cardiac monitoring/arrhythmia endpoint and related wording removed
-
Visit schedule updated (Visit 14 and 16 removed)
-
Medications restrictions updated to reflect new information
Version 2.0, 28 July 2017
Stratification changed from site to country (section 3.5).
Version 1.0, 19 July 2017
Initial creation
 
 

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CLINICAL STUDY PROTOCOL SYNOPSIS
A phase 3b, multicenter, prospective, randomized, double blind, placebo-
controlled study to reduce incidence of pre-dialysis hyperkalemia with 
Sodium Zirconium Cyclosilicate (DIALIZE)
International Co-ordinating Investigator
Steven Fishbane, MD 
Study site(s) and number of patients planned
180 patients at approximately 70 sites
Phase of development 3b 
Study design
This is a randomized, double-blind, placebo-controlled study to determine the safety and 
efficacy of ZS in patients with hyperkalemia and on stable hemodialysis. This study consists 
of a screening period, an 8 week randomized treatment period, and a follow-up period. Stable 
hemodialysis patients with persistent pre-dialysis hyperkalemia will be enrolled in the study 
across research sites in US, EU and Japan
Objectives
Primary Objective:
Outcome Measure:
Evaluate the efficacy of ZS in the treatment of 
hyperkalemia in patients on hemodialysis
Proportion of patients who maintain a pre-dialysis 
serum K between 4.0-5.0 mmol/L on 3 out of 4 
dialysis treatments following the long interdialytic 
interval during the evaluation period (last 4 weeks) 
and who do not receive rescue therapy during the 
evaluation period
Secondary Objective:
Outcome Measure:
Evaluate the need for rescue therapy
Frequency and proportion of patients requiring any 
urgent intervention consistent with local practice 
patterns to reduce serum K including insulin/glucose, 
beta adrenergic agonists, sodium bicarbonate, K 
binders or any form of renal replacement therapy

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Evaluate safety of ZS in hemodialysis
Adverse events (AEs), changes in laboratory values, 
physical examination, vital signs, ECG
Exploratory Objective:
Outcome Measure:
Evaluate if treatment of hyperkalemia with ZS 
in hemodialysis patients allows for an increase 
in the dialysate K concentration prescription   
Proportion of patients who are able to increase 
dialysate K concentration
Target patient population
Approximately 180 patients with ESRD receiving maintenance hemodialysis treatments 3 
times per week with an indication for treatment of hyperkalemia. Patients must have 
hemodialysis access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) 
catheter which is expected to remain in place for the entire duration of the study.   
Duration of treatment
1-week screening period, 8-week treatment period, 2-week follow-up
Study period
The study is expected to start in 4Q 2017 and to end by 4Q 2018.
For Japan: the study is expected to start in1Q 2018 and to end by 4Q 2018.
Investigational product, dosage and mode of administration
Sodium zirconium cyclosilicate (ZS), powder for oral suspension, starting dose 5 g on non-
dialysis days, adjusted during the study
Statistical methods
The primary efficacy endpoint will be analysed using Fisher’s exact test applied to the Full 
Analysis Set to assess the proportion difference between ZS and Placebo. Sensitivity analysis 
for the primary efficacy endpoint will be carried out to account for the influence of missing 
data. 
Safety endpoints will be analysed using the Safety Analysis Set.

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................1
VERSION HISTORY...............................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS .........................................................3
TABLE OF CONTENTS..........................................................................................5
1.
INTRODUCTION ..................................................................................12
1.1
Background and rationale for conducting this study ................................12
1.2
Rationale for study design, doses and control groups...............................13
1.2.1
Rationale for study design and control group...........................................13
1.2.2
Rationale for doses..................................................................................14
1.3
Benefit/risk and ethical assessment .........................................................14
1.4
Study design ...........................................................................................15
1.4.1
Treatment duration and dosing ................................................................15
1.5
Study governance and oversight..............................................................17
2.
STUDY OBJECTIVES...........................................................................17
2.1
Primary objective....................................................................................17
2.2
Secondary objectives...............................................................................17
2.3
Exploratory objectives ............................................................................17
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..........18
3.1
Inclusion criteria .....................................................................................18
3.2
Exclusion criteria ....................................................................................19
3.3
Patient enrolment and randomization ......................................................20
3.4
Procedures for handling incorrectly enrolled or randomized patients.......21
3.5
Methods for assigning treatment groups..................................................21
3.6
Methods for ensuring blinding ................................................................21
3.7
Methods for unblinding...........................................................................22
3.8
Restrictions.............................................................................................22
3.9
Discontinuation of investigational product ..............................................24
3.9.1
Procedures for discontinuation of a patient from investigational product .25
3.10
Criteria for withdrawal............................................................................25
3.10.1
Screen failures ........................................................................................26

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Study Code D9480C00006
Version 4.0
Date 05 February 2018
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3.10.2
Withdrawal of the informed consent........................................................26
3.11
Discontinuation of the study....................................................................27
4.
STUDY PLAN AND TIMING OF PROCEDURES................................28
4.1
Screening period .....................................................................................28
4.2
Treatment and follow-up.........................................................................29
4.3
Screening/Enrolment period....................................................................31
4.4
Treatment period and follow-up ..............................................................31
4.4.1
Description of visits (order of assessments etc.) ......................................31
5.
STUDY ASSESSMENTS.......................................................................32
5.1
Efficacy assessments...............................................................................32
5.1.1
Serum potassium measurements..............................................................32
5.1.2
Dialysate potassium concentration prescription and potassium levels......32
5.2
Safety assessments..................................................................................32
5.2.1
Laboratory safety assessments.................................................................33
5.2.2
Physical examination ..............................................................................35
5.2.3
ECG........................................................................................................35
5.2.3.1
Resting 12-lead ECG ..............................................................................35
5.2.4
Vital signs and blood pressure.................................................................35
5.3
Other assessments...................................................................................36
5.3.1
Dialysis prescription ...............................................................................36
5.3.2
Dialysis adequacy ...................................................................................36
5.3.3
Interdialytic weight gain..........................................................................36
5.4
Pharmacokinetics ....................................................................................36
5.5
Pharmacodynamics .................................................................................36
5.6
Genetics..................................................................................................37
5.7
Biomarker analysis..................................................................................37
5.8
Storage, re-use and destruction of biological samples..............................37
5.9
Labelling and shipment of biological samples .........................................37
5.10
Volume of blood.....................................................................................37
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT..................38
6.1
Definition of adverse events....................................................................38
6.2
Definitions of serious adverse event ........................................................38
6.3
Recording of adverse events....................................................................38
6.3.1
Time period for collection of adverse events ...........................................38
6.3.2
Follow-up of unresolved adverse events..................................................39
6.3.3
Variables.................................................................................................39

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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6.3.4
Causality collection.................................................................................40
6.3.5
Adverse events based on signs and symptoms.........................................40
6.3.6
Adverse events based on examinations and tests .....................................40
6.3.7
Hy’s Law ................................................................................................41
6.4
Reporting of serious adverse events ........................................................41
6.5
Overdose.................................................................................................41
6.6
Pregnancy ...............................................................................................42
6.6.1
Maternal exposure...................................................................................42
6.7
Medication Error.....................................................................................43
6.8
Independent Data Monitoring Committee................................................44
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ........45
7.1
Identity of investigational product(s).......................................................45
7.2
Dose and treatment regimens ..................................................................45
7.2.1
Rescue therapy........................................................................................46
7.3
Labelling.................................................................................................46
7.4
Storage....................................................................................................47
7.5
Compliance.............................................................................................47
7.6
Accountability.........................................................................................47
7.7
Concomitant and other treatments ...........................................................47
7.7.1
Oral medications with gastric pH-dependent bioavailability....................48
7.7.2
Other concomitant treatment ...................................................................49
7.8
Post Study Access to Study Treatment ....................................................49
8.
STATISTICAL ANALYSES BY ASTRAZENECA...............................50
8.1
Statistical considerations .........................................................................50
8.2
Sample size estimate ...............................................................................50
8.3
Definitions of analysis sets......................................................................50
8.3.1
Efficacy analysis set................................................................................50
8.3.2
Safety analysis set...................................................................................50
8.3.3
PK analysis set........................................................................................50
8.3.4
Other analysis sets...................................................................................50
8.4
Outcome measures for analyses...............................................................50
8.5
Methods for statistical analyses...............................................................51
8.5.1
Analysis of the primary variable (s).........................................................51
8.5.2
Analysis of the secondary variable(s) ......................................................51
8.5.3
Analysis of the safety variables ...............................................................51
8.5.4
Subgroup analysis (if applicable) ............................................................52
8.5.5
Interim analysis.......................................................................................52

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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8.5.6
Sensitivity analysis (if applicable)...........................................................52
8.5.7
Exploratory analysis (if applicable).........................................................52
8.5.8
Handling of Missing Data .......................................................................52
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA..............53
9.1
Training of study site staff.......................................................................53
9.2
Monitoring of the study...........................................................................53
9.2.1
Source data .............................................................................................54
9.2.2
Study agreements....................................................................................54
9.2.3
Archiving of study documents.................................................................54
9.3
Study timetable and end of study.............................................................54
9.4
Data management by AstraZeneca ..........................................................54
10.
ETHICAL AND REGULATORY REQUIREMENTS............................56
10.1
Ethical conduct of the study ....................................................................56
10.2
Patient data protection.............................................................................56
10.3
Ethics and regulatory review ...................................................................56
10.4
Informed consent ....................................................................................57
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.......58
10.6
Audits and inspections ............................................................................58
11.
LIST OF REFERENCES ........................................................................60
LIST OF TABLES
Table 1
Schedule of assessments - screening...........................................28
Table 2
Schedule of assessments – treatment and follow-up phase..........29
Table 3
Laboratory Safety Variables.......................................................34
Table 4
Volume of blood to be drawn from patient during study.............37
Table 5
Gastric pH-dependent bioavailability drugs................................48
LIST OF FIGURES
Figure 1
Study flowchart..........................................................................16
16

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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LIST OF APPENDICES
Appendix A
Additional Safety Information....................................................62
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document...................................................................64
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .............................................................65

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADR
Adverse Drug Reaction
AE
Adverse Event
AV
Arterio-vascular
BUN
Blood urea nitrogen
c-lab
Central laboratory
CKD
Chronic Kidney Disease
CPS
Calcium polystyrene sulfonate
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
DMP
Data Monitoring Plan 
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
EOS
End of study
EOT
End of treatment
ESRD
End-Stage Renal Disease
FAS
Full analysis set
GCP
Good Clinical Practice
Unless otherwise noted, ‘GCP’ shall mean ‘the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice’ (ICH 
GCP) and the Japanese ‘Good Clinical Practice for Trials on Drugs 
(Ministry of Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 
March 1997, partially revised by MHLW Ordinance and their related 
notifications’ (GCP Ordinance).
GMP
Good Manufacturing Practice
HF
Heart failure
IB
Investigators’ Brochure
ICF
Informed Consent Form

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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Abbreviation or 
special term
Explanation
ICH
International Conference on Harmonisation
ICI
International Co-ordinating Investigator 
IDMC
Independent Data Monitoring Committee 
IDWG
Interdialytic Weight Gain 
IP
Investigational Product 
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LSLV
Last Subject Last Visit
LIDI
Long Inter-Dialytic Interval
LIMS
Laboratory Information Management System
MWF
Monday-Wednesday-Friday (dialysis scheme)
PI
Principal Investigator 
Qb
Blood flow (dialysis)
Qd
Dialysate flow rate
PTDV
Premature Treatment Discontinuation Visit
RAASi
Renin-Angiotensin-Aldosterone inhibitors
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SAS
Safety Analysis Set
SCD
Sudden Cardiac Death
SIDI
Short Inter-Dialytic Interval
SPS
sodium polystyrene sulfonate
S-K
Serum potassium
TTS
Tuesday-Thursday-Saturday (dialysis scheme)
URR
Urea Reduction Ratio
USRDS
United States Renal Data System
WBDC
Web Based Data Capture
WOCBP
Woman of childbearing potential
ZS
Sodium Zirconium Cyclosilicate

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Serum potassium (K) is tightly regulated, typically between 3.5 and 5.0 mmol/L. Homeostatic
maintenance of serum potassium is important for many physiologic processes, such as cardiac 
conduction and inotropy, smooth muscle tone, and neuronal signaling. 
Hyperkalemia is defined as an abnormally high serum potassium (S-K) concentration, usually 
greater than 5.0 mmol/L, and with an incidence of up to 10% of hospitalized patients, and 2-
3% in the general population (Mahoney 2005, Kovesdy 2014).  Potassium homeostasis is 
essential for maintaining the cellular membrane potential and proper neuromuscular 
functioning, and hyperkalemia impairs neuromuscular, cardiac, and gastrointestinal function.  
Hyperkalemia often presents without symptoms or with non-specific symptoms including 
malaise, confusion, muscle weakness or signs of cardiac arrhythmias (Henneman 2016).  The 
risk of fatal cardiac arrhythmias is increased, especially at S-K levels above 6.0 mmol/L, and 
the mortality risk is increased also with modest elevations of S-K (Collins 2014, Nakhoul 
2015).
Potassium homeostasis is essential for maintaining the cellular membrane potential and 
hyperkalemia causes electrophysiological disturbance which impairs neuromuscular, cardiac 
and gastrointestinal function.  The most common underlying cause of hyperkalemia is 
decreased urinary potassium excretion due to reduced kidney function, as in patients 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 hyperkalemia are often chronic conditions that 
worsen over time, there is a need for treatments not only for the correction of hyperkalemia 
into the normal range (S-K 3.5-5.0 mmol/L) but also for chronic treatment to maintain S-K 
within the normal range.
Sodium zirconium cyclosilicate (ZS) 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.  A global clinical 
programme including more than 1800 patients with hyperkalemia demonstrated effective 
correction of hyperkalemia with ZS compared with placebo, where 88% of patients reached 
normal S-K after 48 hours of treatment with ZS 10 g three times a day [TID]).  Maintenance 
of normokalemia was also demonstrated, with lower mean S-K and increased number of 
normokalemic days with ZS 5 g or 10 g once daily (QD) compared with placebo, and a lasting 
maintenance effect for up to 12 months.  
 
The kidney plays a major role in eliminating potassium. Patients with end-stage renal disease 
(ESRD) have reduced renal potassium excretion ability which frequently leads to 
hyperkalemia (K > 5.1 mmol/L). These patients depend on the administration of renal 
replacement therapies (e.g. hemodialysis including low K dialysates as necessary), dietary 

Clinical Study Protocol
Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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potassium restriction, and occasionally the use of oral potassium binding resins to maintain 
serum potassium levels in a physiologic range (Luo 2016, Kovesdy 2007).
High serum potassium can lead to ventricular arrhythmias and cardiac death. Recent studies 
have shown that among patients with ESRD on hemodialysis therapy, serum K > 5.6 mmol/L 
is associated with increased mortality, both all-cause and cardiovascular, compared to a 
referent category of K levels between 4.6 to 4.99 mmol/L (Kovesdy 2007, Yusuf 2016). In 
addition, sudden cardiac death (SCD) is the leading cause of death in hemodialysis patients. In 
the United States Renal Data System (USRDS) database, 26.9% of all-cause mortalities in 
prevalent dialysis patients between 2009 and 2011 were attributed to cardiac arrest or 
arrhythmias. The incidence of SCD in hemodialysis patients was 49.2 per 1000 patient-years 
in 2011, which is much higher than that of the general population (Huang 2015). 
Hyperkalemia is considered an important risk factor for arrhythmias and SCD. This condition 
is also independently associated with greater short-term risk of hospitalization and emergency 
department visits, and with greater hospital costs (Brunelli 2017). Hence prevention and 
treatment of hyperkalemia in hemodialysis patients are of paramount importance.
Previous studies with ZS have demonstrated efficacy and safety in the treatment of 
hyperkalemia, but hemodialysis patients were excluded. The study is designed to evaluate the 
efficacy and safety of ZS in hyperkalemic ESRD patients on hemodialysis and to determine 
the appropriate ZS dosing regimen in this patient population.
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design and control group  
Currently the only universally accepted option for the treatment of hyperkalemia in patients 
with ESRD is dialysis including low K dialysates as necessary (hemo- or peritoneal dialysis, 
and hemodiafiltration). Despite dialysis the prevalence of hyperkalemia remains high in this 
population with a prevalence as high as 62.9 per 100 patient-months at the end of the long 
interdialytic interval (Yusuf 2016 AJN). In this latter study hyperkalemia was defined as a 
pre-dialysis serum potassium greater than 5.5 mmol/L and its presence was associated with 
increased all-cause mortality. Although potassium-binding resins are used in some instances 
to treat hyperkalemia in dialysis patients, these agents have not been systematically studied, 
are not universally used, and have no specific indications in this population.
The study is designed to provide efficacy data for the ZS clinical development program and 
provide information relevant to the efficacy of ZS in the treatment of hyperkalemia in 
hemodialysis patients. The study is a randomized, double-blind study with two treatment 
groups, ZS or placebo, and includes hemodialysis patients 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 hyperkalemia will be withheld in study patients. Rescue therapy will be available 
according to local practice patterns. Thus, placebo is deemed to be the appropriate comparator 
in this study.

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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1.2.2
Rationale for doses 
Initial (hyperkalemia correction) and maintenance doses of ZS 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 normokalemia in the non-dialysis population. Dose 
adjustments were allowed in these studies according to pre-specified rules in order to 
normalize serum potassium levels and minimize hypokalemia. Dose adjustment rules are also 
adopted in this study with appropriate modifications. 
The starting dose of ZS will be 5g once daily on non-dialysis day and may be adjusted to a 
maximum of 15g per non-dialysis day to maintain a pre-dialysis serum K between 4-5 
mmol/L. ZS or placebo will be administered orally on non-dialysis days for a treatment period 
of eight weeks. 
1.3
Benefit/risk and ethical assessment
The primary benefit for patients randomized to ZS is expected to be the maintenance of 
normokalemia during the long interdialytic interval, potentially including the relief of 
associated signs and symptoms and an improved quality of life. ZS is expected to be at least as 
safe as it has been shown to be in the non-dialysis population.
Patients treated with placebo may not obtain any benefit in terms of hyperkalemia correction, 
but may benefit from the closer follow-up and will receive alternative therapies whenever 
clinically indicated. 
An established dose adjustment algorithm will be used during the study to titrate ZS doses to 
enable patients to achieve and maintain pre-dialysis normokalemia after the Long Inter-
Dialytic Interval (LIDI), while evaluating any changes in prescribed dialysate potassium 
concentrations, and the rate of reduction of serum potassium during dialysis based on the 
difference between pre- and post-dialysis potassium levels. 
ZS doses may be reduced in the event that pre-dialysis serum potassium levels after the LIDI 
fall below 4 mmol/L and no further adjustment on prescribed dialysate potassium 
concentration is feasible. 
Five clinical studies including a long-term safety study (ZS-002, ZS-003, ZS-004, ZS-004E 
and ZS-005) have been completed with ZS in subjects with hyperkalemia. Despite the potency 
of ZS in reducing S-K levels, the reductions have not been associated with adverse events of 
severe hypokalemia or other clinically significant changes in electrolytes, including serum 
calcium and magnesium. Dose related increases in bicarbonate and reductions in BUN have 
been observed in ZS treated subjects. There were no clinically important changes in other 
clinical laboratory tests. ZS treatment was well tolerated at all dose levels administered. 
The most commonly reported ADRs were edema-related events, which were reported in 5.7% 
of ZS-treated subjects; 1.7%, 2.7%, 5.2%, and 14.3% of subjects randomized to placebo, ZS 
5g, 10g or 15g QD for up to 1 month, respectively. Fifty-three percent of edema-related events 

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Study Code D9480C00006
Version 4.0
Date 05 February 2018
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were managed by initiating a diuretic or adjusting the diuretic dose; the remainder did not 
require treatment.
In clinical studies, 2.3% of subjects developed hypokalemia with S-K value of <3.5 mmol/L, 
which was resolved with dose adjustment or discontinuation of ZS. One subject reported an S-
K value <2.8 mmol/L. No cases of hypokalemia were reported as serious.
No potential risks based on mechanism of action, nonclinical or clinical data have been 
identified for ZS.
1.4
Study design
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of ZS in the treatment of hyperkalemia in patients with ESRD on stable hemodialysis. 
Approximately 180 patients with ESRD receiving maintenance hemodialysis treatments 
3 times per week will be enrolled in the study across research sites in the US, Europe and 
Japan.
1.4.1
Treatment duration and dosing 
The study will consist of three study periods as follows:

Screening Period: one week

Treatment Period: Patients will be randomized (1:1) to double-blind treatment with 
either ZS or placebo, started at 5g once daily on non-dialysis days, and titrated during 
a period of 4 weeks to achieve and maintain a pre-dialysis serum potassium between 4 
and 5 mmol/L after the LIDI. Maximum ZS dose is 15g once daily on non-dialysis 
days. Treatment will be continued unchanged for an additional 4 week evaluation 
period to complete a total of 8 weeks.

Post-Treatment Follow-Up Period: 2 weeks (14 +/- 3 days to match dialysis schedule)

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Version 4.0
Date 05 February 2018
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Figure 1
Study flowchart 
1
2
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5
6
7
7.5
8
9
9.5
10
10.5
11
11.5
12
12.5
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14.5
15
16
-1
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-7
-5
-3
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36
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71 
+/- 3
Screening
Treatment period
Follow-up
Visit
Day
R
ZS
Placebo
Week

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Drug Substance Sodium Zirconium Cyclosilicate (ZS)
Study Code D9480C00006
Version 4.0
Date 05 February 2018
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1.5
Study governance and oversight
An Independent Data Monitoring Committee will be appointed in the study (See section 6.8).
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
Evaluate the efficacy of ZS in the treatment of 
hyperkalemia in patients on hemodialysis
Proportion of patients who maintain a pre-dialysis 
serum K between 4.0-5.0 mmol/L on 3 out of 4 
dialysis treatments following the long interdialytic 
interval during the evaluation period (last 4 weeks)
and who do not receive rescue therapy during the 
evaluation period
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
Evaluate the need for rescue therapy
Frequency and proportion of patients requiring any 
urgent intervention consistent with local practice 
patterns to reduce serum K including insulin/glucose, 
beta adrenergic agonists, sodium bicarbonate, K 
binders or any form of renal replacement therapy
Evaluate safety of ZS in hemodialysis
Adverse events (AEs), changes in laboratory values, 
physical examination, vital signs, ECG
2.3
Exploratory objectives  
Exploratory Objective:
Outcome Measure:
Evaluate if treatment of hyperkalemia with ZS 
in hemodialysis patients allows for an increase 
in the dialysate K concentration prescription
Proportion of patients who are able to increase 
dialysate K concentration 

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3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures 
2.
Female or male aged ≥ 18 years at screening Visit 1. For patients aged <20 years 
and enrolled in Japan, a written informed consent should be obtained from the 
patient and his or her legally acceptable representative.
3.
Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of end-
stage renal disease (ESRD) for at least 3 months before randomization.
4.
Patients must have hemodialysis access consisting of an arteriovenous fistula, AV 
graft, or tunneled (permanent) catheter which is expected to remain in place for the 
entire duration of the study.
5.
Pre-dialysis serum K >5.4 mmol/L after long inter-dialytic interval and 
>5.0 mmol/L after 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 
hemodialysis/hemodiafltration prescription during screening with prescription 
(time, dialyzer, blood flow [Qb], dialysate flow rate [Qd] and bicarbonate 
concentration) expected to remain unchanged during study
8.
Heparin dose (if used) must be stable during screening and expected to be stable 
during the study
9.
Subjects must be receiving dietary counseling appropriate for ESRD patients treated 
with hemodialysis/hemodiafiltration as per local guidelines, which includes dietary 
potassium restriction

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3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca, including ZS Pharma staff and/or staff at the study site)
2.
Hemoglobin <9 g/dL on screening (as assessed on Visit 1)
3.
Lack of compliance with hemodialysis prescription (both number and duration of 
treatments) during the two-week period preceding screening (100% compliance 
required)
4.
Patients treated with sodium polystyrene sulfonate (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 
5.
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  
6.
Laboratory diagnosis of hypokalemia (K < 3.5 mmol/L), hypocalcemia 
(Ca < 8.2 mg/d; for Japan hypocalcemia is defined as albumin-corrected
Ca < 8.0 mg/dL), hypomagnesemia (Mg < 1.7 mg/dL) or severe acidosis (serum 
bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization
7.
Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not 
considered screening failure, sampling or full screening can be postponed to a later 
time as applicable)
8.
Severe leukocytosis (>20× 109/L) or thrombocytosis (≥450 × 109/L) during 
screening
9.
Polycythemia (Hb >14 g/dL) during screening
10.
Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization
11.
Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics 
for hyperammonemia within 7 days prior to the first dose of study drug
12.
Patients unable to take oral ZS drug mix
13.
Scheduled date for living donor kidney transplant
14.
Patients with a life expectancy of less than 6 months

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15.
Female patients who are pregnant or breastfeeding
16.
Females of childbearing potential, unless using contraception as detailed in the 
protocol or sexual abstinence (see Section 3.8)
17.
Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
18.
Participation in another clinical study with an investigational product during the last 
1 month before screening
19.
Any medical condition, including active, clinically significant infection, that in the 
opinion of the investigator or Sponsor may pose a safety risk to a patient in this 
study, which may confound safety or efficacy assessment and jeopardize the quality 
of the data, or may interfere with study participation
20.
Presence of cardiac arrhythmias or conduction defects that require immediate 
treatment
21.
History of alcohol or drug abuse within 2 years prior to randomization
22.
Previous randomization in the present study
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
2.
Assign the potential patient a unique enrolment number, beginning with ‘E#’, via 
IWRS/IVRS.
3.
Determine patient eligibility. See Section 3.1 and 3.2.
4.
Assign eligible patient unique randomization code via IWRS/IVRS
Screening should begin on a hemodialysis day following the long interdialytic interval (D -7) 
and be completed by the third hemodialysis session of the same week (D -3). 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code (E-code) cannot be reused.

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Patients will remain associated with the same enrolment number throughout the entire study, 
and patients should NOT receive any new E-code if re-screened. If a patient signs the ICF but 
does not meet the inclusion/exclusion criteria the patient will be marked as a screen failure on 
the Screening and Enrolment Log provided by the Sponsor and will be entered in WBDC as a 
screen failure.
A screen-fail patient may be re-screened if deemed appropriate by the investigator. A 
maximum of one re-screening period is allowed (for a total of two screenings) and these 
screening periods should be performed within 60 days.
A new ICF does not need to be signed before re-screening if the original ICF was signed 
within 60 days and the ICF has not been revised.
Randomization codes will be assigned strictly sequentially within each centre as patients 
become eligible for randomization. Randomization of qualified patients must take place on 
Visit 4 (Day 1), which corresponds to the hemodialysis day that follows the long interdialytic 
interval immediately after completion of screening. The randomization visit should be 
scheduled at a time that ensures that study drug has arrived to the study site. 
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule. Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
The randomization codes will be computer generated using the AstraZeneca global 
randomization system (AZRand) and loaded into the IVRS/IWRS database. Randomization 
codes will be generated in blocks to ensure approximate balance (1:1) between the 2 treatment 
arms. Randomization will be stratified by country.
3.6
Methods for ensuring blinding
The randomized treatment phase will have a double blind design. Patients will take by mouth 
assigned dose from the sachet(s) containing either ZS or placebo. Individual sachets are 
enclosed in a carton with a tamper evident seal intended to be broken exclusively by patients 
just before taking the study drug.

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3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS in case of 
unblinding situation. Routines for this will be described in the IVRS/IWRS user manual that 
will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient 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. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.
3.8
Restrictions
The following restrictions apply in the study:
Women of childbearing potential must have a negative pregnancy test during screening 
(before first dose of IP). 
Sexually active women of childbearing potential must be using a highly effective medically
acceptable contraception method such as:

Combined hormonal contraception associated with inhibition of ovulation

Progesterone only hormonal contraception, associated with inhibition of 
ovulation

IUD (intrauterine device)

IUS (intrauterine hormone-releasing system)

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence (true abstinence in line with the subjects preferred and 
usual lifestyle. 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),

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should they become sexually active during the course of study 
participation).
Women who are surgically sterile or those who are postmenopausal for at least 2 years are not 
considered to be of childbearing potential.
Contraceptive methods must be practiced upon being randomized to the study and through 12 
weeks after the last dose of study treatment. If a patient discontinues prematurely, the 
contraceptive method must be practiced for 12 weeks following final administration of study
drug.
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be 
reported (see Section 6.6).
The following must remain unchanged during the study:

Hemodialysis prescription including treatment time and frequency 
(3/week MWF or TTS), 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)

Heparin dose (if used)

Hemodialysis access consisting of an arteriovenous fistula, AV graft, or 
tunneled (permanent) catheter 

Patient compliance with hemodialysis prescription (both number and 
duration of treatments)

Patient dietary counseling and compliance with diet: Dialysis clinics 
included in the study should provide patients dietary advice compiled 
from clinical sources and local Nephrology societies’ recommendations 
that are consistent with the KDOQI (US) and KDIGO (global) guidelines. 
Patients 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 2.5g or as described by local 
guidelines.  
Although details may vary across countries and sites (from general advice 
to detailed instructions), the overall approach should be to give patients 
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 patients is encouraged.

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The study physician should be informed if the investigator deems that changes in any of these 
parameters is necessary or patient is noncompliant with hemodialysis prescription. Any 
changes should be recorded in the eCRF.
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:

Patient decision.  The patient is at any time free to discontinue treatment, 
without prejudice to further treatment

Incorrectly randomized patient in whom the inclusion/exclusion criteria 
violation would put the patient at undue risk

Adverse Event for which the investigator judges continued treatment may 
put the patient at undue risk

Severe non-compliance with the Clinical Study Protocol

Pregnancy 

Renal transplant

Development of any study specific criteria for discontinuation:

Severe hypokalemia - if a patient develops severe hypokalemia (as 
defined by potassium values <2.7 mmol/l, confirmed by a second 
potassium measurement after a 10 ± 2- minute interval) on non-
dialysis days or pre-dialysis the patient should immediately receive 
appropriate medical intervention and be discontinued from the study. 
Post-dialysis hypokalemia should be managed as per established 
dialysis clinic protocols and if severe and persistent beyond the 
immediate post-dialysis period (2 hours) should also lead to study 
discontinuation. Patients considered for discontinuation from study 
due to post-dialysis hypokalemia should be discussed with the study 
physician

QT prolongation - if an absolute QTc >550msec, or an increase in 
QTc interval > 60msec from baseline to more than 500msec is 
reached the patient should immediately receive appropriate medical 
intervention and be discontinued from the study treatment. The 
QTcF algorithm is recommended. All patients meeting the 
QTc>500ms 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

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3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  
Discontinuation from study medication is not the same as complete withdrawal from the study 
(withdrawal of consent), which has a direct impact on the potential validity of all study data, 
and should be avoided wherever possible. It is essential to collect as much data as possible for 
all patients throughout the study and especially all potential endpoint events. All discontinued 
patients will be followed up during entire visit schedule.
A patient that decides to discontinue investigational product will always be asked about the 
reason(s) and the presence of any adverse events.  If possible, they will be seen and assessed 
by an Investigator(s), and a Premature Treatment Discontinuation Visit (PTDV) should be 
performed at the earliest possible dialysis visit after last dose of ZS. The reason for permanent 
discontinuation of treatment with the study medication and the date of the last intake of the 
study medication must also be documented in the eCRF. The PTDV includes the same 
assessments as the EOT visit in addition to any other assessments scheduled for that day, if 
any. Any patient who is withdrawn from the study medication prior to study completion will 
have 3 options:

Option 1: this is the preferred option, the patient continues to undergo all 
scheduled visits and assessments until EOS

Option 2: applies if a patient rejects Option 1. In this case the patient will 
at a minimum return to the clinic for an EOS visit 2 weeks (14 +/- 3 days 
to match dialysis schedule) after a PTDV. All assessments stipulated for 
EOS visit will be collected and recorded at this time

Option 3: applies if the patient refuses Options 1 and 2. In this case 
PTDV and EOS visits will occur simultaneously at the earliest possible 
dialysis visit after last dose of ZS, and all assessments stipulated for these 
visits will be collected and recorded.
Any study related materials and all study drugs should be returned by the patient. Adverse 
events will be followed up (See Section 6).
If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
Patients are at any time free to withdraw from the study (i.e., discontinue study medication
permanently and withdraw from visit assessments), without prejudice to further treatment 
(withdrawal of consent). 

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Withdrawal of consent from the study must be ascertained and documented by the investigator 
and recorded in the appropriate electronic Case Report Form (eCRF). Such patients will 
always be asked about the reason(s) and the presence of any AEs. The date and reason for 
patient withdrawal must be recorded in the eCRF. Every attempt should be made to contact 
any patient considered lost to follow-up.
To ensure validity of study data, it is very important to collect as much data as possible 
throughout the scheduled study visits.
It is understood by all concerned that an excessive rate of withdrawals can render the study 
un-interpretable; therefore, unnecessary withdrawal of patients should be avoided.
The term withdrawal from the study refers to discontinuation from both study medication and 
study assessments.
Specific reasons for withdrawal from study are:

Voluntary discontinuation by the patient who is at any time free to 
discontinue his/her participation in the study, without prejudice to further 
treatment (see Section 3.10.2)

Severe non-compliance to protocol as judged by the Investigator and/or 
Sponsor

Patient lost to follow-up

Death
3.10.1
Screen failures 
Screening failures are patients who are enrolled in the study but do not fulfil the eligibility 
criteria for randomization in the study, and therefore must not be randomized (see Section 3.2, 
Exclusion criteria #8 for special case). These patients should have the reason for study 
withdrawal recorded as ‘Screen failure’ (the potential patient who does not meet one or more 
criteria required for participation in a trial, this reason for study withdrawal is only valid for 
not randomized patients). ‘Failure to meet randomization criteria’ should be selected for an 
indication that the patient has been unable to fulfil/satisfy the criteria required for assignment 
into a randomized group.In the case of a hemolyzed sample yielding an invalid serum K value, 
a repeat sample can be obtained during the screening period, or if this is not possible, the 
screening process can be repeated at a later time without a need to re-consent the patient.
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.

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A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment and 
randomisation code cannot be reused. Withdrawn patients will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:

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 patient at the time of 
discontinuation of the study must be recorded in the eCRF. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.

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4.
STUDY PLAN AND TIMING OF PROCEDURES 
4.1
Screening period
Table 1
Schedule of assessments - screening
Visit
1
2
3
For details 
see Section
Day
-7
-5
-3
Day of the week
M/T
W/Th
F/S
Informed consent
X
4.3
Inclusion /exclusion criteria
X
X
X
3.1, 3.2
Demographics 
X
4.3
Medical/surgical history
X
Physical examination
X
5.2.2
Vital signs and BPa
X
5.2.4
Weightb
X
X
X
Height
X
Safety lab assessments
X
5.2.1
Serum hCG pregnancy testc
X
12-lead ECG
X
5.2.3
Serum Kd
X
X
X
5.1.1
Concomitant medication 
X
X
X
Dialysate K prescription
X
X
X
5.1.2
Dialysis prescriptione
X
5.3.1
Dialysis adequacyf
X
5.3.2
Interdialytic weight gaing
X
X
X
5.3.3
AE review
X
X
X
6
a: BP should be measured prior to the hemodialysis 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
b: Dry weight and pre-dialysis weight on Visit 1; pre-dialysis weight on all other visits
c: Collect from female patients of childbearing potential only
d: Serum K sampling: pre-dialysis c-Lab during screening
e: Blood flow (Qb, ml/min), time on dialysis (minutes)
f: spKt/V and/or urea reduction ratio (URR); record the most recent value but this should be no older than 5 
weeks
g: Interdialytic weight gain: current pre-dialysis weight minus previous post-dialysis weight in Kg 

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4.2
Treatment and follow-up
Table 2
Schedule of assessments – treatment and follow-up phase
Visit description
Randomi
zation
EOT EOS For 
details 
see 
Section
Visit
4
5
6
7
7.5
8
9
9.5
10
10.5
11
11.5 12
12.5
13
13.5
14
14.5
15
16
Day
1
3
5
8
10
12
15
17
22
24
29
31
36
38
43
45
50
52
57
71
+/- 3 
Day of the week
M/T
W/
Th
F/
S
M/
T
W/
Th
F/
S
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
Physical exam
X
Xi
Xi
Xi
Xi
X
5.2.2
Vital signs and BPa
X
X
X
X
X
X
X
X
X
5.2.4
Weightb
X
X
X
X
X
X
X
X
X
Safety lab 
assessments
X
X
X
X
X
X
X
5.2.1
Serum hCG 
pregnancy testc
X
X
X
12-lead ECG
X
X
X
5.2.3
Serum Kd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.1.1
Inclusion/Exclusion 
criteria
X
3.1 ; 3.2
Randomization
X
3.3
Dialysate K 
prescription
X
X
X
X
X
X
X
X
X
X
X
X
X
5.1.2
Dialysis prescriptione
X
X
X
5.3.1
Dialysis adequacyf
X
X 
5.3.2
Interdialytic weight 
gaing
X
X
X 
5.3.3

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Visit description
Randomi
zation
EOT EOS For 
details 
see 
Section
Visit
4
5
6
7
7.5
8
9
9.5
10
10.5
11
11.5 12
12.5
13
13.5
14
14.5
15
16
Day
1
3
5
8
10
12
15
17
22
24
29
31
36
38
43
45
50
52
57
71
+/- 3 
Day of the week
M/T
W/
Th
F/
S
M/
T
W/
Th
F/
S
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
W/
Th
M/
T
Drug 
dispensation/Drug 
accountability
Xj
X
X
X
X
X
X
X
Xk
7.2
Dose adjustment 
reviewh
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
AE review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6
a: BP should be measured prior to the hemodialysis 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
b: Dry weight and pre-dialysis weight on Visit 1; pre-dialysis weight on all other visits
c: Collect from female patients of childbearing potential only
d: Serum K sampling: pre- and post-dialysis c-Lab is measured after LIDI (M/T) throughout the study; pre-dialysis i-STAT is measured during treatment 
phase after LIDI (M/T) on V4 and subsequent dose review visits; only pre-dialysis c-Lab is measured after SIDI (W/Th or F/S) throughout the study on 
visits as indicated in the table
e: Blood flow (Qb, ml/min), time on dialysis (minutes)
f: spKt/V and/or urea reduction ratio (URR); record the most recent value but this should be no older than 5 weeks
g: Interdialytic weight gain: current pre-dialysis weight minus previous post-dialysis weight (measured at immediate dialysis session prior to the study visit) 
in Kg
h: Dose adjustment review will be done weekly during the first 4 weeks of the treatment period based on the pre-dialysis iStat serum K level measured 
following the long interdialytic interval
i: Targeted physical examination only
j: Drug accountability will not be assessed on Visit 4, only dispensation will take place
k: No drug dispensation will take place on the End of Treatment Visit, only drug accountability will be assessed

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4.3
Screening/Enrolment period
Procedures will be performed according to the Study Plan (Table 1). 
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.
Patients can be re-screened once during the clinical trial period. A new ICF does not need to 
be signed before re-screening if the original ICF was signed within 60 days and has not been 
revised.
After a patient has signed the ICF at Visit 1 the site investigator will use the IVRS/IWRS to 
obtain a unique patient enrolment number after collecting the demographic parameters from 
the patient (including sex, date of birth, race, ethnic group).
4.4
Treatment period and follow-up
Table 2 provide an overview of the procedures performed at each visit during the treatment 
period, and further details are provided below. In general, order of the procedures during the 
visit should match site’s practice of handling dialysis patients, for specific requirements please 
refer to the Table 2 and paragraphs below. AZ Study Physician should be contacted if for any 
reason site needs to deviate from the requirements. 
4.4.1
Description of visits (order of assessments etc.)
Procedures will be performed according to the Study Plan (Table 1 and Table 2).
Pre-dialysis c-lab serum K samples will be obtained during the screening phase and will 
determine eligibility of patients to enter the study.
During the treatment phase i-STAT serum K samples will be obtained to determine the need 
for adjustments in ZS dose or in dialysate K concentration. In addition, both pre- and post-
dialysis c-lab samples will be obtained during the treatment phase for final analysis. All 
adjustments in study drug dose and dialysate K concentration prescription will be based on 
pre-dialysis i-STAT serum K values.
After the treatment period (ending with the EOT visit), patients will proceed to the 2-week 
post-treatment follow up period (ending with EOS visit).  Pre- and post-dialysis c-Lab serum 
K samples will be obtained during follow up.

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5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the Clinical Study Protocol and in accordance with the 
instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms eCRF. An electronic copy 
of the completed eCRF will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Serum potassium measurements
Serum potassium levels (Serum K) will be measured using i-STAT device (Point-Of-Care 
analyser) and central laboratory (c-Lab).
Blood samples for determination of potassium will be taken at the times indicated in the Study 
Plan (see Table 1 and Table 2). Potassium samples will be analysed locally using i-STAT 
devices for the purpose of dose titration and treatment control. At the same time 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 hemolyzed samples MUST be redrawn. In the event that hemolysis or 
other artefacts are suspected based on the reported i-STAT result the sample may be re-drawn 
to confirm the result. Only the confirmatory sample result needs to be reported in the eCRF.
5.1.2
Dialysate potassium concentration prescription and potassium levels
The dialysate K concentration prescription should be recorded at the times indicated in the 
Study Plan (see Table 1 and Table 2).
For pre-dialysis serum potassium concentrations <4 mmol/L, subsequent adjustments will be 
made in accordance to locally accepted clinical practice patterns and guided by the 
investigator’s clinical judgment.
For centers that adopt the clinical practice of modifying the prescribed dialysate potassium 
concentration when the pre-dialysis serum potassium concentration decreases, if pre-dialysis 
serum K is below 4 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 1K to 1.5 or 2K, from 
2K to 2.5 or 3K, or from 3K to 3.5 or 4K.
5.2
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. Particular 
emphasis should be placed on identifying signs and symptoms of worsening volume retention 

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Study Code D9480C00006
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such as increases in IDWG, rising blood pressure, uncontrolled hypertension, and excessive 
edema.
Adverse events (AE), serious adverse events (SAEs) and ongoing concomitant medication 
usage will be monitored and recorded throughout the study. SAE reports will be evaluated 
individually to assess for the impact of the event, if any, on the overall safety of the product 
and on the study itself. Cumulative AEs will be monitored throughout the study. SAEs and 
AEs will be followed until resolved, stable, or until the patient’s EOS visit. See Section 6 for 
details on AE and SAE reporting.
Safety will be assessed through:

Adverse events

Laboratory parameters

Vital signs (blood pressure, heart rate, ECG)

Physical Examination
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
times indicated in the Study Plan (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry 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:

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Table 3
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatise (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
S/P-Gamma-glutamyl transferase (GGT)
S/P-Albumin
S/P-Potassium
S/P-Calcium, total
S/P-Sodium
S/P-Chloride
S/P-Creatine kinase (CK)
S/P-Bicarbonate
S/P-Phosphorus
S/P-Glucose
S/P-Blood urea nitrogen
S/P-Magnesium
S/P-Lactate dehydrogenase
S/P-Total protein
S/P Pregnancy test (serum hCG)
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 6.3.
NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer 
to Appendix C ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.

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5.2.2
Physical examination
A physical examination will be performed as specified in Study Plan and include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal 
(including spine and extremities) and neurological systems. Particular attention must be given 
to any signs and symptoms of worsening volume retention such as increases in IDWG, rising 
blood pressure, uncontrolled hypertension and excessive edema.
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 Study Plan.
The complete physical examination includes the following: general appearance, skin, height 
(Day -7 only) and weight, head and neck, 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. 
5.2.3
ECG
ECG will be performed as safety measurement pre-dialysis at timepoints as per schedule of 
assessments. ECG will be assessed by Investigators according to local practice.
5.2.3.1
Resting 12-lead ECG
Standard 12-lead ECGs will be performed on all patients at specific time points as described 
in the Study Plan, Table 1 and Table 2, as to local routines. A single ECG will be taken after 
the patient has been resting in the supine position for 5 minutes. Any abnormalities must be 
evaluated in clinical context (based on patient’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, heart rate (HR), P and QRS durations and PR and QT intervals (if
available), overall interpretation and relevant comments will be recorded in the eCRF. ECG 
recordings will be kept as source documents. 
5.2.4
Vital signs and blood pressure
Vital signs will be assessed at visits as specified in schedule of assessments. Any clinically 
significant changes in vital signs should be investigated and reported as AEs (see section 
6.3.6). Particular attention must be given to evidence of worsening volume retention as 
reflected by rising blood pressure or uncontrolled hypertension.
On specific visits indicated in Table 1 and Table 2, HR and BP will be measured in triplicate 
after the patient has been comfortably at rest in either supine or seated position for at least 5 

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min. The position of the patient 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 patient 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 patient during the course of the study and in the same arm. 
Blood pressure will be measured in triplicate with at least one minute intervals between 
measurements. In HD patients BP and HR will be assessed prior to initiation of the dialysis 
procedures. 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.
Blood pressure measurements are to be obtained prior to initiation of each dialysis procedure
5.3
Other assessments
5.3.1
Dialysis prescription
Dialysis prescription parameters including blood flow (Qb, ml/min) and time on dialysis 
(minutes) should be recorded at the times specified in Tables 1 and 2.
5.3.2
Dialysis adequacy
Dialysis adequacy indices including spKt/V and/or urea reduction ratio (URR) should be 
recorded at the times specified in Tables 1 and 2. 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 visit. Sites 
should consistently use either spKt/V or URR in determining dialysis adequacy. A 
combination of both is not acceptable.
5.3.3
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) in kilograms. In order to obtain all required measurements of IDWG the 
investigators must make sure that a post-dialysis weight is available for the immediate dialysis 
session (as per usual schedule) prior to the visit.
5.4
Pharmacokinetics
Pharmacokinetic samples will not be taken during the study
5.5
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study

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5.6
Genetics
Genetic samples will not be taken during the study
5.7
Biomarker analysis 
Biomarker samples will not be taken or analysed during the study
5.8
Storage, re-use and destruction of biological samples 
After the analyses are complete the samples will be either completely consumed during that 
analytical process or disposed of after the analysis.
5.9
Labelling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are labelled and shipped in accordance 
with the Laboratory Manual and appropriate IATA regulations (see Appendix B)
5.10
Volume of blood
The maximum total volume of blood that will be drawn from each patient for this study is 
listed in Table 4 below. The collection of additional samples is performed locally at the 
discretion of the investigator and recorded in the eCRF as appropriate, thus will require 
additional sample volumes.
Table 4
Volume of blood to be drawn from patient during study
Assessment
Sample 
volume
(mL)
Number of 
samples 
taken
Total 
volume:
(mL)
Hematology
2
8
16
Clinical chemistry
2.5
8
20
Serum potassium 
(central lab)a
2.5
25
62.5
Serum potassium 
(I-Stat)
1
8
8
Serum potassium 
(i-Stat) - Japan
2
8
16
Total
-
-
106.5
Total - Japan
114.5
a: only on timepoints when no clinical chemistry sample is taken. If taken, clinical chemistry panel includes 
serum potassium measurement
b: WOCBP only
Note: if any of above mentioned samples need to be repeated (eg. due to sample hemolysis), 
total blood volume may exceed the total volume provided in Table 4.

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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study patient 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.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase that fulfils one or more of 
the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing 
hospitalization 

Results in persistent or significant disability or incapacity 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of randomization throughout the treatment period 
and including the follow-up period (until Visit 16 or the last patient visit in the study)
SAEs will be recorded from the time of informed consent.

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6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up 
by the Investigator for as long as medically indicated, but without further 
recording in the CRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes/no) 
no)

Action taken with regard to investigational product

AE caused patient’s withdrawal from 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 hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

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
Causality assessment to other medication

Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
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 A to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider (if applicable) or reported in 
response to the open question from the study site staff: (‘Have you had any health problems 
since the previous visit/you were last asked?’) or revealed by observation will be collected and 
recorded in the CRF. 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.
6.3.6
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 
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).

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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
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.4
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 CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 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. 
 
6.5
Overdose
ZS has been given to patients at doses of up to 30 g per day for 1 to 3 days and up to 15 g per 
day for 12 months. An overdose is defined as more than 30g per day. 

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
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.

An overdose without associated symptoms is only reported on the 
Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel 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.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any 
study drug
6.6.1
Maternal exposure
If a patient 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 patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 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 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.

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The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.7
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 patient or 
has the potential to cause harm to the patient. 
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 patient.
Medication error includes situations where an error: 

occurred

was identified and intercepted before the patient received the drug

did not occur, but circumstances were recognized that could have led to 
an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not 
actually given to the patient

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 patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (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 

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
Patient accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient 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.  
If an medication error occurs in the course of the study, then the Investigator or other site 
personnel informs 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 works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
6.8
Independent Data Monitoring Committee
The IDMC will be responsible for monitoring the safety of the study participants, ensuring 
that the study is being conducted with the highest scientific and ethical standards and making 
appropriate recommendations based on the available data. The IDMC will review safety and 
efficacy data. 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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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational 
product
Dosage form 
Dosing instructions
Manufacturer
Sodium Zirconium
Cyclosilicate (ZS) 5g
Powder for oral 
suspension in a sachet
Single dose contains 1 
to 3 sachets that should 
be suspended in 45 mL 
of water by patient and 
administered on non-
dialysis days 
AstraZeneca
Placebo
Powder for oral 
suspension in a sachet
Single dose contains 1 
to 3 sachets that should 
be suspended in 45 mL 
of water by patient and 
administered on non-
dialysis days
AstraZeneca
7.2
Dose and treatment regimens
ZS 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 ZS dose will be 5g once daily and may 
be adjusted to a maximum of 15g per non-dialysis day to maintain a pre-dialysis serum K 
between 4-5 mmol/L. 
All dose adjustments will be based on pre-dialysis serum K values measured by i-STAT. 
Management of dialysis prescription will be according to local clinical pattern practices.
During the first 4 weeks of the treatment period, the ZS dose should be adjusted if the pre-
dialysis potassium value after the long inter-dialytic interval is > 5.0 mmol/L (one weekly 
dose adjustment). For patients taking 5 g on non-dialysis days, the dose should be increased to 
10 g on non-dialysis days. For patients taking 10 g, the dose should be increased to 15 g on 
non-dialysis days. 
During the first 4 weeks of the treatment period, both pre- and post-dialysis serum potassium 
concentrations should be evaluated. 
For pre-dialysis serum potassium concentrations < 4 mmol/L, subsequent adjustments will be 
made in accordance to locally accepted clinical practice patterns and guided by the 
investigator’s clinical judgment.
For sites that adopt the clinical practice of modifying the prescribed dialysate potassium 
concentration when the pre-dialysis serum potassium concentration decreases, if pre-dialysis 
serum K is below 4 mmol/L the dialysate K concentration should be increased by 0.5 or 1 

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mmol/L according to standard of care, e.g. increase dialysate K from 1K to 1.5 or 2K, from 
2K to 2.5 or 3K, or from 3K to 3.5 or 4K. If dialysate K concentration cannot be increased 
further (e.g. patient already using 4K dialysate bath), the dose of ZS can be decreased by 5g or 
held if the patient is already taking the minimum dose (5g).
For sites where local clinical practice does not include increasing the dialysate K 
concentration when pre-dialysis serum K falls, the dose of ZS can be decreased by 5g or held 
if the patient is already taking the minimum dose (5g). 
If during the treatment phase (initial 4 weeks) the dose of ZS has been reduced or held 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 5g or restart ZS 5g if it was held.
After the first 4 weeks, no additional adjustments of ZS dose or dialysate potassium 
concentration should be made unless in the judgement of the principal investigator there is a 
compelling medical need to treat an abnormal serum potassium concentration, i.e. severe 
hyperkalemia or hypokalemia with clinical manifestations. If such an event were to occur the 
appropriate ZS dose adjustment (increase or reduction) can be made with documentation of 
the event. In the case of hyperkalemia with clinical manifestations deemed to require urgent 
treatment, rescue therapy defined as any intervention consistent with local practice patterns to 
reduce serum K can be administered followed by the appropriate ZS dose adjustment and 
proper documentation of the event. During the last 4 weeks of the treatment period, both pre-
and post-dialysis serum potassium concentrations will continue to be evaluated.
It is recommended that the dietary regimen is maintained unchanged during the duration of the 
study.
7.2.1
Rescue therapy
Rescue therapy is defined as any therapeutic intervention considered necessary in accordance 
to local practice patterns to reduce serum K in the setting of severe hyperkalemia 
(>6 mmol/L). Treatments considered rescue include the potassium binders: sodium 
polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, 
Resonium calcium) and patiromer (Veltassa), as well as beta-adrenergic agonists, sodium 
bicarbonate, insulin/glucose and any additional dialysis or other forms of renal replacement 
treatments when used specifically for the treatment of severe hyperkalemia. In addition, any 
reduction in the dialysate K concentration that is prescribed for the treatment of severe 
hyperkalemia during the study is also considered rescue therapy. Rescue therapy should be 
followed by the appropriate ZS dose adjustment if appropriate and proper documentation of 
the event.
7.3
Labelling
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.

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For Japan:  Labels will be prepared in accordance with GCP Ordinance. Details are specified 
in the document explaining the reconstitution procedures and other handling procedures for 
the investigational products
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.
The study site staff will account for all study drugs dispensed to and returned from the patient.
Study site staff or the AZ monitor (as applicable) will account for all study drugs received at 
the site, unused study drugs and for appropriate destruction.  Certificates of delivery and 
destruction should be signed. 
For Japan: Study drug will not be distributed to the study site until the contract is concluded 
between the study site and AstraZeneca. The designated individual (e.g. pharmacist) is 
responsible for managing the study drug from receipt by the study site until the return of all 
unused study drug to AstraZeneca. AstraZeneca will provide the study documents ‘Procedures 
for drug accountability’ and ‘Procedures for drug storage’ which describes the specific 
requirements. The Investigator(s) is responsible for ensuring that the patient has returned all 
unused study drug. 
7.7
Concomitant and other treatments 
Concomitant medications are any prescription or over-the-counter preparations, including 
herbal products and “natural remedies”, used by a patient while participating in this clinical 
study. 
For all concomitant medications, an indication for its use should be provided. If the stated
indication is a non-specific condition, eg. ”rash”, documentation of the condition, as specific 
as possible, should be maintained in the patient’s clinical study records as source 
documentation.

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Restricted Medication/Class of drug:
Usage:
Sodium polystyrene sulfonate (SPS, 
Kayexalate, Resonium), calcium polystyrene 
sulfonate (CPS, Resonium calcium) or 
patiromer (Veltassa) 
Patients taking these drugs within the past 7 days 
before screening or anticipated to require them during 
the study should be excluded. These drugs should be 
avoided during the study and can only be used as 
rescue therapy. 
Heparin (if used)
Patients taking heparin should be on stable dose from 
screening throughout study
Diuretics
Changes to diuretics (including adding a new, 
changing the dose or discontinuation or switching of 
diuretics) during the study are prohibited. If clinically 
indicated to change the diuretics, the patients should 
discontinue study medication
7.7.1
Oral medications with gastric pH-dependent bioavailability 
When co-administered with ZS, some oral medications with gastric pH-dependent 
bioavailability may exhibit a clinically meaningful increase or decrease in their 
bioavailability. 
Therefore, these drugs should be administered at least 2 hours before or 2 hours after study 
drug to mitigate the risk of drug interactions. Drugs that should be taken 2 hours before or 
after study drug to avoid a possible raised gastric pH drug interaction are listed below:
Table 5
Gastric pH-dependent bioavailability drugs
Class of drug
Drugs
Azole antifungals
Ketoconazole, Itraconazole, Posaconazole or 
Voriconazole
Anti-HIV drugs
Amprenavir, Atazanavir, Delavirdine, 
Fosamprenavir, Nelfinavir, Indinavir, Ritonavir, 
Saquinavir, Raltegravir, Ledipasvir, Rilpivirine,
Antibiotics
Cefditoren, Clarithromycin
Antiepileptics
Gabapentin, Phenytoin
Bisphophonates
Risedronic acid
Cardiac glycosides
Digoxin
Immunosuppressants
Methotrexate, mycophenolate mofetil,
mycophenolic acid, tacrolimus
Intestinal anti-inflammatory agents
Mesalazine
Iron preparations
Iron salts
Tyrosine kinase inhibitors
Acalabrutinib, Gefitinib, Pazopanib, Erlotinib, 
Dasatinib, Nilotinib

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7.7.2
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.
7.8
Post Study Access to Study Treatment
Not applicable

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8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations

All personnel involved with the analysis of the study will remain blinded 
until database lock and Clinical Study Protocol violators identified.

Analyses will be performed by AstraZeneca or its representatives.   

A comprehensive Statistical Analysis Plan (SAP) will be prepared and 
signed off before enrollment of the first patient
8.2
Sample size estimate
For the primary efficacy endpoint, 90 patients per treatment group (180 patients in total) will 
yield power at least 90%, assuming a placebo proportion of at most 0.3, a difference in 
proportions (ZS – placebo) of 0.25, using a 2-sided Fisher’s exact test at significance level 
5%.
8.3
Definitions of analysis sets
8.3.1
Efficacy analysis set
The full analysis set (FAS) will be the primary analysis set for the efficacy analysis and will 
include all randomized patients. Patients will be analysed according to their randomised 
investigational product.
8.3.2
Safety analysis set
The safety analysis set (SAS) will comprise all randomized patients who took at least one dose 
of study drug. Patients will be analysed according to the treatment actually received.
8.3.3
PK analysis set
Not applicable
8.3.4
Other analysis sets
Not applicable
8.4
Outcome measures for analyses
The primary efficacy outcome measure is the proportion of patients with 3 out of 4 pre-
dialysis K measurements following the LIDI within 4.0-5.0 during the last 4 weeks of the 
treatment period and that do not receive rescue therapy during the evaluation period. 
The safety outcome measures are frequencies of AEs, serious adverse events (SAEs), physical 
examination findings and vital signs, descriptive measures for laboratory values.

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The first exploratory efficacy outcome measure is the proportion of patients who are able to 
increase dialysate K concentration at the end of the study compared to baseline. 
The secondary outcome measure is the frequency and proportion of patients requiring any 
urgent intervention consistent with local practice patterns to reduce serum K. 
Further details will be provided in the SAP. 
8.5
Methods for statistical analyses
Descriptive statistics will be used to summarize all reported laboratory values, vital signs, and 
ECGs for the changes from baseline to each subsequent visit.  Selected shift tables will be 
created to compare baseline classification to follow up classification.  Additionally, 
individuals with abnormal serum laboratory values, vital signs, ECGs, and physical 
examinations will also be summarized and listed. 
Demographic and baseline characteristics will be summarized and listed.  
Duration of exposure to ZS and compliance rate will be summarized.  Duration of exposure 
will be summarized overall, by study phase, and by treatment.
8.5.1
Analysis of the primary variable (s)
The primary efficacy endpoint of proportion of patients with maintained K 4.0-5.0 on at least 
3 out of 4 pre-dialysis days following the LIDI and that do not receive rescue therapy during 
the evaluation period will be analysed using Fisher’s exact test at the significance level 5% (2-
sided). This analysis will be based on the FAS.
All randomized patients will be classified as either a responder or a non-responder regardless 
of premature discontinuation of IP, premature discontinuation of study or recieving treatments 
other than rescue. Patients with more than one missing K measurement during the evaluation 
period will be classified as a non-responder.
8.5.2
Analysis of the secondary variable(s)
The secondary endpoints will be presented using a frequency table based on the FAS.
8.5.3
Analysis of the safety variables
For safety analyses, adverse events will be listed. Frequency of patients with any adverse 
events will be summarized by SOC and preferred term for the following categories: all 
adverse events, adverse events by intensity, and adverse events by causality as assessed by the 
Investigator. All adverse events will be summarized by decreasing frequency for all patients 
within SOC. Treatment discontinuations due to any adverse event will be summarized. The 
number of days from the initial study administration date to adverse event onset date will be 
computed. Serious adverse events or deaths will be listed and summarized.
Safety analyses will be based on the SAF.

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8.5.4
Subgroup analysis (if applicable)
To facilitate a benefit-risk assessment for the purpose of regulatory submission in Japan, 
subgroup of patients from Japan will be analysed separately, with respect to selected efficacy 
and safety variables of the study. More details will be presented in the SAP.
8.5.5
Interim analysis
N/A
8.5.6
Sensitivity analysis (if applicable)
For the primary efficacy endpoint, sensitivity analysis will be performed to evaluate the 
impact of missing data, again using the Fisher’s exact test. Details will be presented in the 
SAP.
8.5.7
Exploratory analysis (if applicable)
The exploratory endpoint of proportion of patients who are able to increase dialysate K 
concentration will be analysed using Fisher’s exact test at the significance level 5% (2-sided). 
This analysis will be based on the FAS. There will be no adjustments for multiplicity and 
hence the p-value from the analysis is descriptive.
8.5.8
Handling of Missing Data
Patients with at least 3 pre-dialysis K measurements within 4.0-5.0 mmol/L and who do not 
receive rescue therapy during the evaluation period will be defined as responders and all other 
patients will be defined as non-responders. The impact of patients being classified as non-
responders due to missing potassium data will be assessed through sensitivity analyses to be 
presented in the SAP. 

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9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and system(s) 
utilised, including, but not limited to, Rave WBDC.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including both face to face and remote visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study 
Protocol, that data are being accurately and timely recorded in the CRFs, 
that biological samples are handled in accordance with the Laboratory 
Manual and that study drug accountability checks are being performed

Perform source data verification and review (a comparison of the data in 
the CRFs with the patient’s medical records at the hospital or practice, 
and other records relevant to the study) including verification of informed 
consent of participating patient s. This will require direct access to all 
original records for each patient (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.

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9.2.1
Source data
Source data composition and location will be described in detail in Clinical Study Agreement 
for each site.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patient s and in all other respects, not relating to study conduct or treatment of 
patient s, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patient s are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with Sodium Zirconium Cyclosilicate (ZS)
For Japan: The study is expected to start in 1Q 2018 and to end by 4Q 2018.
9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Center staff or other 
party, according to the Data Management Plan (DMP).  
Data will be entered into the eCRF at the study site. Trained site staff will be entering the data 
as specified in the protocol and according to the eCRF instructions. Data entered into the 
eCRF will be immediately saved to a central database and changes tracked to provide an audit 
trail. The data will then undergo quality control and be validated as described in the DMP.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the WHODRUG. Classification coding will be performed by the 
Medical Coding Team at the AZ Data Management Center.
The data collected through third party sources will be obtained and reconciled against study 
data.

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Data queries will be raised for inconsistent, impossible or missing data as defined in the DMP. 
All entries to the study database will be available in an audit trail.
The PI is responsible for signing the eCRF and this may be delegated to a trained Investigator.
For Japan: The PI is responsible for eCRF signature, and it can not be delegated.
Quality control procedures will be applied to each stage of data handling to ensure that all data 
are reliable and have been processed correctly. The DMP will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
Any treatment revealing data in the data base will be inaccessible for all individuals before 
data base lock. With the exception of those who need this information for data cleaning and/or 
patient safety reasons. A person with access to any treatment revealing data must not take part 
in any decisions made regarding the analysis sets or patient populations. 
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be released and the final database will be locked. An 
electronic copy of the eCRF will be archived at the study site when the study is completed.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of genotype data
Not Applicable
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to the clinical database. Data Management will assure that the 
data collection tools for IVRS are tested and validated. External data reconciliation will be 
done with the clinical database as defined in the DMP.

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final Clinical Study Protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to 
be provided to the patients.  The Investigator will ensure the distribution of these documents 
to the applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
For countries where it is applicable, each Principal Investigator is responsible for providing 
the Ethics Committees/IRB with reports of any serious and unexpected adverse drug reactions 
from any other study conducted with the investigational product.  AstraZeneca will provide 
this information to the Principal Investigator so that he/she can meet these reporting 
requirements.

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For Japan: An IRB should approve the final Clinical Study Protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to 
be provided to the patients. The head of the study site will ensure the distribution of these 
documents to the applicable IRB, and the Principal Investigator to the Investigator and study 
site staff.
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the Principal Investigator before enrolment of any patient should into the study.
The IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the Clinical Study Protocol re-approval.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the ICF, should be approved by the national regulatory authority with 
notification provided, according to local regulations.  AstraZeneca will handle the distribution 
of any of these documents to the national regulatory authorities.
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study

Ensure each patient is notified that they are free to discontinue from the 
study at any time

Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided

Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study

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
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the 
patient

Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the informed consent form that is approved 
by an Ethics Committee.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International Co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 
implementation.  Local requirements are to be followed for new versions of Clinical Study 
Protocols.
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a centre’s Informed Consent 
Form, AstraZeneca and the centre’s Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
For Japan: Study procedures will not be changed without the mutual agreement of the 
Principal Investigator and AstraZeneca.  If it is necessary for the Clinical Study Protocol to be 
amended, the new version of the Clinical Study Protocol should be submitted to the Head of 
the Study Site and be approved by its IRB.  If applicable, AstraZeneca should submit a 
notification to the regulatory authority before it is implemented.  If a Clinical Study Protocol 
amendment requires a change to a particular centre's Informed Consent Form, then 
AstraZeneca and the centre's IRB should be notified by the Principal Investigator.  Approval 
of the revised Informed Consent Form by AstraZeneca and by the IRB is required before the 
revised form is used. 
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-

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related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the Clinical Study 
Protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre.

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11.
LIST OF REFERENCES
Brunelli et al 2017
Brunelli SM, MSCE, Du Mond C, Oestreicher N, Rakov V, MD, Spiegel DM. Serum 
Potassium and Short-term Clinical Outcomes Among Hemodialysis Patients: Impact of the 
Long Interdialytic Interval. Am J Kidney Dis 70:21-29 2017
Huang et al 2015
Huang CW, Lee MJ, Lee PT, Hsu CY, Huang WC, Chen CL, Chou KJ, Fang HC. Low 
Potassium Dialysate as a Protective Factor of Sudden Cardiac Death in Hemodialysis Patients 
with Hyperkalemia. PLoS One. 2015 Oct 6;10(10): e0139886. 
doi:10.1371/journal.pone.0139886. 
Kovesdy et al 2007
Kovesdy CP, Regidor DL, Mehrotra R, Jing J, McAllister CJ, Greenland S, Kopple JD, 
Kalantar-Zadeh K. Serum and Dialysate Potassium Concentrations and Survival in 
Hemodialysis Patients. Clin J Am Soc Nephrol 2: 999-1007, 2007
Luo et al 2016
Luo J, Brunelli SM, Jensen, DE, Yang A. Association between Serum Potassium and 
Outcomes in Patients with Reduced Kidney Function. Clin J Am Soc Nephrol 11: 90–100, 
2016
Yusuf et al 2016
Yusuf AA, Hu Y, Singh B, Menoyo JA,Wetmore JB. Serum Potassium Levels and Mortality 
in Hemodialysis Patients: A Retrospective Cohort Study. Am J Nephrol 44:179–186, 2016
Einhorn et al 2009
Einhorn, L. M., et al. (2009). "The frequency of hyperkalemia 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. 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 
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. 

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Henneman et al 2016
Henneman, A., et al. (2016). "Emerging therapies for the management of chronic 
hyperkalemia in the ambulatory care setting." Am J Health Syst Pharm 73(2): 33-44. 
Kovesdy 2015
Kovesdy, C. P. (2015). "Management of Hyperkalemia: An Update for the Internist." Am J 
Med 128(12): 1281-1287.

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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the patient 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 patient’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).
Hospitalization
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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
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, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical intervention 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 hospitalization
Development of drug dependency or drug abuse
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.

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
Time Course.  Exposure to suspect drug.  Has the patient 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.
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.

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Appendix B
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.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) 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 (HIV) 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

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

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 C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1. Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2. Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3. Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

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
AST ≥ 3xULN

TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Section 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
4. Follow-up
4.1 Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2 Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment)

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

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
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which the tests available in the Hy’s 
law lab kit should be used.

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
5. Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other patient matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.

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If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’