Conditions: Hyperkalemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
To assess efficacy of 5 g three times daily (TID) and 10 g TID ZS versus placebo in Japanese patients with hyperkalemia (serum potassium \[S-K\] ≥ 5.1 mmol/L and ≤ 6.5 mmol/L).

Detailed description:
Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled and randomized 1:1:1 to receive ZS 5 g, ZS 10 g, or placebo TID for 48 hours.

Throughout the study most potassium values will be measured at fasting before taking study drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 hours. Potassium level should be determined by both i-STAT and the Central Laboratory on all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT potassium values, as these provide clinical sites with a real-time measurement. Statistical analyses on the study data will in principle be based on S-K values as measured by the central laboratory.

Safety and tolerability will be assessed on an ongoing basis. Standard study assessments including blood potassium, clinical chemistry (including calcium, magnesium, sodium, phosphate, creatinine, bicarbonate, and blood urea nitrogen \[BUN\]) and hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will be assessed during the study at the time points specified in the assessments schedule. All women of childbearing potential will have a urine pregnancy test prior to enrollment and at their End of Study (EOS) visit.

Stopping rules will be implemented to ensure subjects discontinue the study treatment and receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant cardiac arrhythmias.

Arms:
arm 1: Suspension administered 5g orally three times daily for 48 hours. arm 2: Suspension administered 10g orally three times daily for 48 hours. arm 3: Placebo suspension administered orally placebo three times daily for 48 hours.

Interventions: intervention 1: Sodium Zirconium Cyclosilicate (ZS) 5g intervention 2: Sodium Zirconium Cyclosilicate (ZS) 10g intervention 3: Placebo
Intervention descriptions: intervention 1: Suspension administered 5g orally three times daily for 48 hours. intervention 2: Suspension administered 10g orally three times daily for 48 hours. intervention 3: Placebo suspension administered orally placebo three times daily for 48 hours.

Protocol document:
Prot_000.pdf: 
A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and 
Safety of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With 
Hyperkalemia
Sponsor:  AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan
Clinical Study Protocol
Drug Substance
ZS
Study Code
D9482C00002
Version
3.0
Date
26 September 2017


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
2 (61)
VERSION HISTORY
Version 3.0, 26 Sep 2017
Changes to Clinical Study Protocol version 2.0 [14 June 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
CLINICAL STUDY 
PROTOCOL 
SYNOPSIS
Study 
period
9.3
Study 
timetable and end 
of study
Estimated date of last patient completed was updated. 
Changed by study 
progress.
7.7.1
Oral 
medications with 
gastric pH-dependent 
bioavailability
This section was included.
Updated 
information was 
added.
9.4
Data 
management by 
AstraZeneca or 
delegate
“The PI is responsible for signing the eCRF and 
this may be delegated to a trained Investigator.” 
was deleted.
This procedure is 
not applicable in 
Japan. Correction 
of error.
Version 2.0, 14 June 2017
Changes to Clinical Study Protocol version 1.0 [13 February 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
4
STUDY 
PLAN AND 
TIMING OF 
PROCEDURES
4.1 
Screening/Enrolment 
period (Visit 1)
It was added that “If eGFR assessments are 
performed within 1 month prior to Visit 1, the latest 
one can be used for Visit 1 data.”
To decrease burden 
for patients.
4.2.1
Day 1 (Visit 
2)
4.2.2
Day 2 (Visit 
“from 11:00 pm (2300) on the previous day” was 
corrected to “for a minimum of 8 hours”
Correction of error


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
3 (61)
Version 2.0, 14 June 2017
Changes to Clinical Study Protocol version 1.0 [13 February 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
3)
4.2.3
Day 3 (Visit
4)
4.3
Follow-up 
period (EOS)
Version 1.0, 13 February 2017
Initial creation
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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CLINICAL STUDY PROTOCOL SYNOPSIS
A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and 
Safety of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With 
Hyperkalemia
Principal Investigator(s)
See Addendum.
Study site(s) and number of patients planned
A total of approximately 102 subjects with mild to moderate hyperkalemia at screening 
(potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L) will be randomized in the study at 
approximately 20 investigational sites in Japan. 
Study period
Phase of development
Estimated date of first patient enrolled
Q2 2017
Phase II/III
Estimated date of last patient completed
Q1 2018
Study design
Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT (A 
portable blood analyser) potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled 
and randomized 1:1:1 to receive ZS 5 g, ZS 10 g, or placebo TID for 48 hours.
Throughout the study most potassium values will be measured at fasting before taking study 
drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 
hours. Potassium level should be determined by both i-STAT and the Central Laboratory on 
all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT 
potassium values, as these provide clinical sites with a real-time measurement. Statistical 
analyses on the study data will in principle be based on serum potassium (S-K) values as 
measured by the central laboratory.
Safety and tolerability will be assessed on an ongoing basis. Standard study assessments 
including blood potassium, clinical chemistry (including calcium, magnesium, sodium, 
phosphate, creatinine, bicarbonate, and blood urea nitrogen [BUN]) and hematology 
parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will 
be assessed during the study at the time points specified in the assessments schedule. All
women of childbearing potential will have a urine pregnancy test prior to enrollment and at 
their End of Study (EOS) visit.


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Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
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Stopping rules will be implemented to ensure subjects discontinue the study treatment and 
receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant 
cardiac arrhythmias.
Objectives
Primary Objective:
Outcome Measure:
To assess efficacy of 5 g three times daily 
(TID) and 10 g TID ZS versus placebo in 
Japanese patients with hyperkalemia (serum 
potassium [S-K] ≥ 5.1 mmol/L and ≤ 6.5 
mmol/L).
exponential rate of change in S-K values during the 
initial 48 hours of study drug treatment.
Secondary Objectives:
Outcome Measures:
Key secondary objective
To evaluate the proportion of subjects who 
achieved normokalemia at 48 hours after start 
of dosing in ZS 5 g TID and 10 g TID groups 
when compared with placebo. 
Key secondary variable
proportion of patients who achieved normokalemia at 
48 hours after start of dosing
Other secondary objective
To evaluate the efficacy of ZS 5 g TID and 
10 g TID compared with placebo from 
various aspects.
Other secondary variables
!
exponential rate of change in S-K values during 
the initial 24 hours of study drug treatment 
!
proportion of patients who achieved 
normokalemia at 24 hours after start of dosing
!
proportion of patients who achieved 
normokalemia at each scheduled potassium 
assessment time-point after start of dosing
!
mean change and mean percent change from 
baseline in S-K values at all measured time 
intervals post dose
!
time to normalization in S-K values 
(normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
Safety Objective:
Outcome Measures:
To assess safety and tolerability of 5 g TID 
and 10 g TID ZS versus placebo in Japanese 
patients with hyperkalemia (serum potassium 
[S-K] ≥ 5.1 mmol/L and ≤ 6.5 mmol/L).
Safety and tolerability as measured by adverse event 
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.


Clinical Study Protocol Synopsis
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
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Target patient population
The target patient population consists of male and female patients aged ≥ 18 years with 
hyperkalemia, defined as two consecutive i-STAT potassium values, measured 60-minutes 
apart, both ≥ 5.1 mmol/L and ≤ 6.5 mmol/L within 1 day before the first dose of study drug on 
Study Day 1.
Duration of treatment
The treatment duration is 48 hours per subject post-randomization with a subsequent final 
follow up visit 7 days later after the last study treatment administration for all subjects.
Investigational product, dosage and mode of administration
Sodium Zirconium Cyclosilicate should be administered orally as a suspension in water.
Subjects were randomized to receive either ZS 5 g, 10 g or placebo, administered TID for 48 
hours (total 6 doses).
If i-STAT potassium levels are > 6.5 mmol/L as determined by the i-STAT, the patient will be 
discontinued from the study.
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 
3.4 mmol/L, inclusive at any time point on the Day 1 the subject will be directed to not take 
any more study drug for the remainder of the day and return the next day to evaluate whether 
to continue dosing in Day 2.
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 
mmol/L, inclusive at any timepoint on the Day 2, the subject will be directed to not take any 
more study drug for the remainder of the day and return the next day for evaluation.
Patients with confirmed i-STAT potassium <3.0 mmol/L should discontinue from therapy.
Statistical methods
All efficacy analyses will be performed using the full analysis set (FAS) based on the Intent-
to-Treat (ITT) principle. The FAS includes all randomized patients, and patients will be 
analyzed according to their randomized treatment assignment.  Patients without any post 
randomization data will not be used in any of the inferential analyses, but will be accounted 
for in summary statistics tables.
Primary analysis for primary efficacy variable of exponential rate of change in S-K will be 
based on a random slope model. All available S-K measurements from baseline through to 48-
hr post initial dose (Day 3, 0-hour) will be included as the response variables after log-
transformation. The model will include time and time x treatment interaction as fixed 
continuous effects and intercept and time as patient-level random effect with unstructured 
covariance matrix. In addition, baseline estimated glomerular filtration rate (eGFR) category 
(<60, ≥ 60 mL/min/1.73m2) will be included as a factor in the model.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
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Baseline will be established by taking the mean of 2 different S-K values, recorded 60 minutes 
apart (to confirm qualification for randomization) and then averaged with the last S-K value 
taken just before administration of the first dose (0-hr) on Study Day 1.
To protect study wise error rate at 5%, hierarchical testing strategy will be employed. 
Confirmatory testing will proceed with the sequential order as specified below. Each 
individual statistical comparison will be conducted with two-sided significance level of 0.05. 
Step 1: Compare exponential rate change through 48 hours between ZS 10g TID vs. Placebo, 
Step 2: Compare exponential rate change through 48 hours between ZS 5g TID vs. Placebo.
Proportion of normokalemic patients at 48 hours post initial dose will be analyzed by logistic 
regression model. The model will include treatment and stratification factor of baseline 
estimated glomerular filtration rate (eGFR) category (<60, ≥ 60 mL/min/1.73m2) as factors 
and baseline S-K value as a covariate.
Safety endpoints will include adverse events (including incidence of oedema-related events), 
vital signs, and other relevant clinical chemistry (specifically, the incidence of hypokalemia, 
hypomagnesemia, hypophosphatemia, and hypocalcemia), hematology, and urinalysis 
parameters. All safety analyses will be conducted for Safety analysis set, which will include 
all patients who took at least one dose of investigational product (IP) during the study. Safety 
variables will be summarized by treatment group and descriptively evaluated.
Sample size
Approximately 102 patients will be randomized to ZS 5g TID, ZS 10g TID, and Placebo with 
1:1:1 ratio. 
Sample size for the exponential rate of change during the study is calculated based on a 
random slope model, with parameters estimates based on the ZS-003 data, and here it is 
assumed that K measurement schedule is same as that in study 003 correction phase, i.e. K is 
measured at Baseline(0),1,2,4,24,25,28 and 48 hours post first dose. 
 
 
 
respectively.
 
 
Here it was assumed that proportion of normokalemic patients 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
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, 
respectively.


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................4
TABLE OF CONTENTS.....................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................14
1.
INTRODUCTION ............................................................................................. 17
1.1
Background and rationale for conducting this study ...........................................17
1.2
Rationale for study design, doses and control groups..........................................20
1.3
Benefit/risk and ethical assessment ....................................................................21
1.3.1
Clinical benefits.................................................................................................21
1.3.2
Clinical risks......................................................................................................22
1.3.3
Clinical benefit-risk balance...............................................................................23
1.3.4
Conclusions ....................................................................................................... 23
1.4
Study Design...................................................................................................... 24
2.
STUDY OBJECTIVES...................................................................................... 25
2.1
Primary objective...............................................................................................25
2.2
Secondary objectives..........................................................................................25
2.3
Safety objectives................................................................................................25
2.4
Exploratory objectives (Not applicable) .............................................................26
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL.....................26
3.1
Inclusion criteria ................................................................................................26
3.2
Exclusion criteria ...............................................................................................26
3.3
Patient enrolment and randomization .................................................................27
3.4
Procedures for handling incorrectly enrolled or randomized patients..................28
3.5
Methods for assigning treatment groups.............................................................28
3.6
Methods for ensuring blinding ...........................................................................28
3.7
Methods for unblinding......................................................................................29
3.8
Restrictions........................................................................................................29
3.9
Discontinuation of investigational product .........................................................29
3.9.1
Procedures for discontinuation of a subject from investigational product............30


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3.10
Criteria for withdrawal....................................................................................... 31
3.10.1
Screen failures ...................................................................................................31
3.10.2
Withdrawal of the informed consent...................................................................31
3.11
Discontinuation of the study............................................................................... 32
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................33
4.1
Screening/Enrolment period (Visit 1).................................................................34
4.2
Treatment period................................................................................................ 34
4.2.1
Day 1 (Visit 2) ................................................................................................... 34
4.2.2
Day 2 (Visit 3) ................................................................................................... 36
4.2.3
Day 3 (Visit 4) ................................................................................................... 36
4.3
Follow-up period (EOS)..................................................................................... 37
5.
STUDY ASSESSMENTS..................................................................................37
5.1
Efficacy assessments..........................................................................................37
5.1.1
Potassium...........................................................................................................37
5.2
Safety assessments.............................................................................................38
5.2.1
Laboratory safety assessments............................................................................ 38
5.2.2
Physical examination .........................................................................................40
5.2.3
ECG...................................................................................................................40
5.2.3.1
Resting 12-lead ECG .........................................................................................40
5.2.4
Vital signs.......................................................................................................... 40
5.2.4.1
Pulse rate and blood pressure .............................................................................40
5.3
Other assessments (Not applicable)....................................................................41
5.4
Pharmacokinetics (Not applicable).....................................................................41
5.5
Pharmacodynamics (Not applicable) ..................................................................41
5.6
Genetics (Not applicable)...................................................................................41
5.7
Biomarker analysis (Not applicable)...................................................................41
5.8
Storage, re-use and destruction of biological samples......................................... 41
5.9
Labeling and shipment of biological samples ..................................................... 41
5.10
Volume of blood................................................................................................ 41
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 42
6.1
Definition of adverse events............................................................................... 42
6.2
Definitions of serious adverse event ................................................................... 42
6.3
Recording of adverse events............................................................................... 43
6.3.1
Time period for collection of adverse events ......................................................43
6.3.2
Follow-up of unresolved adverse events.............................................................43
6.3.3
Variables............................................................................................................ 43
6.3.4
Causality collection............................................................................................44


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6.3.5
Adverse events based on signs and symptoms .................................................... 44
6.3.6
Adverse events based on examinations and tests ................................................45
6.4
Reporting of serious adverse events ................................................................... 45
6.5
Overdose............................................................................................................46
6.6
Pregnancy .......................................................................................................... 46
6.6.1
Maternal exposure..............................................................................................46
6.6.2
Paternal exposure...............................................................................................47
6.7
Medication Error................................................................................................47
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................48
7.1
Identity of investigational product(s)..................................................................48
7.2
Dose and treatment regimens .............................................................................48
7.3
Labelling............................................................................................................49
7.4
Storage............................................................................................................... 49
7.5
Compliance........................................................................................................49
7.6
Accountability....................................................................................................49
7.7
Concomitant and other treatments ...................................................................... 50
7.7.1
Oral medications with gastric pH-dependent bioavailability...............................50
7.8
Post Study Access to Study Treatment (Not Applicable) .................................... 51
8.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................51
8.1
Statistical considerations....................................................................................51
8.2
Sample size estimate ..........................................................................................51
8.3
Definitions of analysis sets................................................................................. 51
8.3.1
Full analysis set..................................................................................................51
8.3.2
Safety analysis set..............................................................................................52
8.4
Outcome measures for analyses..........................................................................52
8.4.1
Efficacy variables (Primary)...............................................................................52
8.4.2
Efficacy variables (Key Secondary) ................................................................... 52
8.4.3
Efficacy variables (Secondary)...........................................................................52
8.4.4
Safety Variables.................................................................................................52
8.5
Methods for statistical analyses..........................................................................52
8.5.1
Analyses of efficacy variables............................................................................52
8.5.1.1
Analysis of Primary efficacy variable.................................................................52
8.5.1.2
Confirmatory testing strategy.............................................................................53
8.5.1.3
Analysis of Key secondary efficacy variable ......................................................53
8.5.2
Analysis of Safety data....................................................................................... 53
8.5.3
Interim analysis.................................................................................................. 53
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.........................54


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Study Code D9482C00002
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Date 26 September 2017
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9.1
Training of study site staff.................................................................................. 54
9.2
Monitoring of the study...................................................................................... 54
9.2.1
Source data ........................................................................................................ 54
9.2.2
Study agreements............................................................................................... 54
9.2.3
Archiving of study documents............................................................................ 55
9.3
Study timetable and end of study........................................................................55
9.4
Data management by AstraZeneca or delegate ................................................... 55
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 ...................................................................................58
LIST OF TABLES
Table 1
Study Plan.............................................................................................33
Table 2
Summary of Serum Potassium Collection Times...................................38
Table 3
Laboratory Safety Variables..................................................................39
Table 4
Volume of blood to be withdrawn from each patient .............................41
LIST OF FIGURES
Figure 1
Multivariable-adjusted mortality by serum potassium level in a 
cohort of 55,266 patients with eGFR <60 ml/min per 1.73 m2
during median follow up 2.76 years (Luo J et al 2016) ..........................21
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g..........23
Figure 3
Study flow chart....................................................................................24


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Study Code D9482C00002
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LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................59
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................61


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Study Code D9482C00002
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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
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AZ
AstraZeneca
AZRand
AZ global Randomization System
BP
Blood pressure
BUN
Blood Urea Nitrogen
CI
Confidence Interval 
CKD
Chronic Kidney Disease
CPS
Calcium Polystyrene Sulfonate
CRF
Case Report Form
CRO
Clinical Research Organization
CSA
Clinical Study Agreement
CSR
Clinical Study Report
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
eGFR
estimated Glomerular Filtration Rate
EOS
End of Study
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).
GGT
Gamma-glutamyl transferase


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Study Code D9482C00002
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Abbreviation or 
special term
Explanation
GMP
Good Manufacturing Practice
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
i-STAT
A portable blood analyser
ITT
Intent-to-Treat 
Hb
Haemoglobin
HCG
Human chorionic gonadotropin
HF
Heart Failure
IB
Investigators Brochure
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator 
qd
once daily
qod
every other day 
RAAS
Renin-angiotensin-aldosterone system 
RAASi
Renin angiotensin aldosterone system inhibitors
RBC
Red Blood Cell
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
S-Ca
Serum calcium
S-HCO3
Serum bicarbonate 
S-K
Serum potassium
S-Mg
Serum magnesium 
S-Na
Serum sodium 
S-PO4
Serum phosphate 
SPS
Sodium Polystyrene Sulfonate
TEAE
Treatment Emergent Adverse Event
tid
three times daily
WBC
White Blood Cell


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Study Code D9482C00002
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Abbreviation or 
special term
Explanation
WBDC
Web Based Data Capture
ZS
sodium zirconium cyclosilicate


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Study Code D9482C00002
Version 3.0
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Potassium is a ubiquitous ion, involved in numerous processes in the human body. It is the 
most abundant intracellular cation and is critically important for numerous physiological 
processes, including maintenance of cellular membrane potential, homeostasis of cell volume, 
and transmission of action potentials. The normal potassium values in serum are between 3.5 
and 5.0 mmol/L, with the kidney being the main regulator of potassium values. 
Hyperkalemia develops when there is excessive intake or insufficient elimination of 
potassium. Insufficient elimination can be hormonal, pharmacologic or due to reduced kidney 
function. Increased extracellular potassium leads to impairment of the neuromuscular, cardiac, 
and gastrointestinal organ systems. Impairment of cardiac conduction can lead to fatal cardiac 
arrhythmias. Severe hyperkalemia must therefore be immediately corrected.
There is a close correlation between the degree of kidney failure and serum potassium (S-K) 
values. In addition, a number of different commonly used drugs can cause hyperkalemia, as 
can advanced degrees of heart failure (HF), massive injuries, burns, intravascular hemolysis, 
or metabolic acidosis, most often as part of diabetic ketoacidosis.
Symptoms of hyperkalemia are non-specific and include malaise and muscle weakness or
signs of cardiac arrhythmias, such as palpitations, bradycardia, or tachycardia.
Diagnosis is established by S-K or plasma potassium measurements. Serum potassium values
are most commonly used for diagnosis and to evaluate treatment response. 
Treatment of hyperkalemia depends on the S-K values. In mild to moderate hyperkalemia 
acute treatment with a potassium-binding resin, combined with dietary advice (low potassium 
diet) and possibly modification of drug treatment (if treated with drugs causing hyperkalemia) 
will be standard of care. In severe hyperkalemia, or if arrhythmias are present, emergency 
lowering of potassium and close monitoring in a hospital setting are mandated. Potassium 
lowering therapies used in the emergency setting include intravenous, calcium, insulin, 
glucose, inhaled beta receptor agonists and dialysis.
The only pharmacologic therapies increasing elimination of potassium from the body are the 
potassium binding resins sodium polystyrene sulfonate (SPS) and calcium polystyrene 
sulfonate (CPS). Due to constipation, SPS and CPS cannot be administered on a chronic basis 
in many patients. Hence there is a significant medical need for new and better treatment for 
acute and chronic treatment of hyperkalemia.
Sodium zirconium cyclosilicate (ZS) has a crystal geometry conferring a high and selective 
exchange capacity for potassium and ammonium ions, and is being developed for the 
treatment of hyperkalemia.


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The potassium-binding capacity of ZS has been shown in vitro to be approximately 10 times 
that of SPS in the presence of calcium and magnesium cations, which represents a significant 
therapeutic advantage over SPS. In vivo studies in dogs and rats demonstrated significant 
dose-related reductions in the fractional excretion of urinary potassium up to 95%. Toxicology 
studies have shown ZS to be well tolerated. ZS is not systemically absorbed, but exerts its 
effects locally in the gastrointestinal tract, significantly reducing the risk of systemic toxicity.
Four clinical studies of ZS have been completed (ZS-002, ZS-003, ZS-004, and ZS-004E) in 
patients with hyperkalemia.
In addition a phase 1 pharmacodynamic study (Study ZS-006) was conducted to characterize 
the potential effect of ZS on sodium and potassium excretion.
Completed Phase 2 and 3 Studies 
ZS-002 was a proof-of-concept phase 2 study to assess the safety and efficacy of acute dosing 
in patients with chronic kidney disease (CKD) and hyperkalemia. ZS-003 and ZS-004 were 
phase 3 studies to assess the safety and efficacy of acute and extended dosing with ZS in 
patients with hyperkalemia. ZS-004E was an open-label, long-term extension (11 months) of 
Study ZS-004. The studies are described in detail in the Investigator Brochure, and have been 
published. (Packham DK et al 2015, Luo J et al 2016, Kosiborod M et al 2014).
ZS at doses of 3 g and 10 g tid in Study ZS-002, 2.5 g, 5 g, and 10 g tid in Study ZS-003, and 
10 g tid in Study ZS-004 demonstrated highly statistically significant and clinically 
meaningful dose-dependent decreases in S-K within 48 hours of treatment. Following S-K 
normalization via acute tid administration, extended dosing maintained normokalemia for up 
to 12 days with ZS qd doses of 5 g and 10 g in Study ZS-003, and for up to 28 days with ZS 
qd doses of 5 g, 10 g, and 15 g in Study ZS-004. The effectiveness of acute and extended 
dosing with ZS was evident across all predefined subpopulations (diabetes mellitus, heart 
failure [HF], CKD, and concurrent use of renin-angiotensin-aldosterone system [RAAS] 
inhibitor medication). Importantly, there was a close correlation between starting S-K and 
effect so that the higher starting S-K, the greater the effect. For example, in Study ZS-003, 
patients with a starting S-K > 5.5 mmol/L demonstrated a mean reduction in S-K of -1.1 
mmol/L at 48 hours versus a reduction of -0.57 mmol/L at 48 hours in patients with a starting 
S-K ≤ 5.3 mmol/L. This effect was also observed in Study ZS-004 with the mean reductions 
in S-K at 48 hours increasing with higher baseline S-K values (S-K ≥ 6.0: -1.49 mmol/L; S-K 
≥ 5.5 to < 6.0: -1.19 mmol/L; S-K < 5.5: -0.78 mmol/L). (Kosiborod M et al 2014, Packham 
DK et al 2015, Luo J et al 2016)
In Study ZS-004E, extended dosing with ZS for up to 11 months was effective in maintaining 
normokalemia. Across Study Days 8 to 337, 88.3% (95% Confidence Interval [CI]: 81.2%, 
93.5%) of patients had average S-K values ≤ 5.1 mmol/L. The least squares mean from a 
logistic regression analysis, which adjusted for baseline covariates, was 92.8% (95% CI: 
84.7%, 96.8%). Results were consistent across subgroups defined by age and baseline 
presence of CKD, HF, diabetes mellitus, and RAAS inhibitor use. 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
19 (61)
In the previous studies, the reductions of S-K by ZS were not associated with events of 
significant hypokalemia or other clinically significant changes in electrolytes. Dose-related 
increases in bicarbonate and reductions in blood urea nitrogen (BUN) were consistently 
observed in ZS-treated patients. There were no clinically important changes in other clinical 
laboratory tests, including no dose-related changes in serum magnesium, sodium, or calcium. 
ZS treatment was well tolerated at all dose levels administered in Studies ZS-002, ZS-003, 
ZS-004, as well as the long-term Study ZS-004E. In these studies, commonly reported 
treatment-emergent adverse events among patients who received ZS or placebo were 
gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and dyspepsia). The 
majority of the treatment-emergent adverse events reported were mild or moderate in severity 
and most were considered unrelated to study drug. In Study ZS-004, an increased incidence of 
events associated with peripheral edema was reported with the ZS 15 g qd dose during 
extended dosing; however, this might be explained by more severe disease at baseline in the 
ZS 15 g group as compared to placebo (greater proportions of patients with HF [45% versus 
31%]). Edema was also monitored in long-term Study ZS-004E and the exposure-corrected 
edema rate (taken into consideration total exposure days) was comparable to the placebo rate 
in Study ZS-004. Furthermore, peripheral edema did not increase with duration of treatment 
with ZS, indicating that edema is unlikely to be related to ZS. No dose-response relationship 
has been observed for the occurrence of any other specific treatment-emergent adverse event. 
No clinically significant dose-related changes in vital signs have been observed in ZS-treated 
patients. Consistent with the decrease in S-K, a small dose-related increase in QTc interval has 
been observed in patients during treatment with ZS. The level of increase in QTc is considered 
clinically insignificant and no increase in cardiac arrhythmias has been observed. 
Ongoing Clinical Studies 
One open-label phase 3 study (ZS-005) is currently ongoing, evaluating the long-term (up to 1 
year) safety and efficacy of ZS in maintaining normokalemia. The study contains an Acute 
Phase, in which patients are dosed with ZS 10 g tid for 24 to 72 hours, followed by a long-
term Extended Dosing period in which patients are dosed with ZS starting at 5 g qd, which 
may be increased or decreased in increments/decrements of 5 g qd up to a maximum of 15 g 
qd or a minimum of 5 g qod based on i-STAT potassium measurements. A total of 751 
patients have been included in the Acute Phase, of whom 746 patients entered Extended 
Dosing.
In the Acute Phase of the study, 99.3% of patients achieved normokalemia. Of the 746 
patients who entered Extended Dosing, 526 have completed ≥ 3 months of therapy, 364 have 
completed ≥ 6 months, 247 have completed ≥ 9 months, and 145 have completed 12 months. 
The vast majority of patients maintained normal serum potassium on ZS, with 87.9% and 
98.8% of patients reporting mean serum potassium ≤5.1 and ≤5.5 mmol/L throughout months 
3-12. Similar results were observed in pre-specified subgroups of patients with CKD, HF, 
diabetes mellitus, and those receiving RAAS inhibitor therapy. Mean S-K levels were 
maintained at 4.6 mmol/L. Safety data were consistent with other ZS studies.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
20 (61)
Two double-blind phase 3 studies (HARMONIZE Asia, D9480C00001 and HARMONIZE 
Global, D9480C00002) are currently under set up. Both studies are multicenter, prospective, 
randomized, placebo-controlled, double-blind, dose-ranging maintenance studies to 
investigate the safety and efficacy of ZS in patients with hyperkalemia (i-STAT potassium 
values ≥ 5.1 mmol/L). 
1.2
Rationale for study design, doses and control groups
The dosage and administration to be evaluated in the Japan dose response study was decided 
referring to the Study ZS-003 data. 
In Study ZS-003, the primary efficacy outcome variable of the proportion of patients who 
achieve normokalemia after 48 hours of initial treatment showed statistical significance in all 
the groups of ZS 10 g TID, 5 g TID and 2.5 g TID as compared with placebo group, and 
numerically, the proportion of patients with normokalemia increased dose-dependently, with 
86.4% patients in 10 g TID group achieving normokalemia after 48 hours.  Regarding safety, 
in the 2 days treatment at doses between ZS 10 g TID and 1.25 g TID, ZS was safe and well 
tolerated with no dose-dependent increase of adverse events.  Based on this result, the dosage 
and administration of 10 g TID was recommended for the correction phase in foreign 
countries.  
During the correction phase of Study ZS-004, patients received ZS 10 g TID for 2 days. Based 
on Kaplan-Meier estimates, 84.28% of subjects had normalized S-K values at 24 hours after 
the first dose ZS, and 97.62% of subjects had normalized S-K values at 48 hours after the first 
dose ZS. The treatment was safe and well tolerated. 
Because it is necessary to normalize serum potassium within 48 hours of dosing in as many 
patients as possible, the most beneficial regimen for Japanese patients with hyperkalemia was 
considered to be 10 g TID for 2 days which achieved normokalemia in approximately 86-88% 
of non-Japanese patients. In Study ZS-003, clear dose response was observed in the 4 groups 
of 1.25 g TID, 2.5 g TID, 5 g TID and 10 g TID.  Although a certain level of efficacy is 
expected with 2.5 g TID, it was judged that comparison of the 2 doses of ZS 5 g TID and ZS 
10 g TID with placebo is sufficient to evaluate dose response.
Specific exclusion criteria ensure that appropriate patients, who are not at excess risk from 
treatment with ZS or placebo, will be enrolled. The multicenter design enhance the external 
validity, reproducibility, and generalizability of the results observed.
The patient selection criteria allows for the assessment of both efficacy and safety of ZS in a 
relevant population of patients with hyperkalemia. Since hyperkalemia affects both men and 
women, the inclusion criteria allows equal access to the protocol for both sexes. Exclusion 
criteria are developed based on consideration of safety concerns and to prevent enrollment of 
patients who are unsuitable for the study. In order to ensure the study population reflect ‘real 
life’, the exclusion criteria are not extensive, as the Sponsor want to ensure that the patient
population enrolled is representative of the patient population receiving the drug post-approval. 
Hence, a large number of concomitant diseases and concomitant treatments are allowed, 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
21 (61)
recognizing that many patients with hyperkalemia would also suffer from a range of 
concomitant diseases. This approach was further justified by the favorable safety and 
tolerability profile observed in Study ZS-003 and Study ZS-004, combined with the fact that 
ZS is not systemically absorbed.
1.3
Benefit/risk and ethical assessment
Hyperkalemia is common in patients with chronic kidney disease or heart failure, particularly 
when treated with renin angiotensin aldosterone system inhibitors (RAASi). Mortality risk 
with hyperkalemia parallels the magnitude of potassium elevation.
Figure 1
Multivariable-adjusted mortality by serum potassium level in a cohort 
of 55,266 patients with eGFR <60 ml/min per 1.73 m2 during median 
follow up 2.76 years (Luo J et al 2016) 
0
1
2
3
4
5
<3.5
3.5-3.9
4.0-4.4
4.5-4.9
5.0-5.4
5.5-5.9
>6.0
Mortality- Adjusted IRR ± 95% CI
Serum K+ (mEq/L) 
1.49
[1.34, 1.65]
3.05
[2.53, 3.68]
1.06
[0.98, 1.14]
1.14
[1.04, 1.26]
1.60
[1.37, 1.88]
3.31
[2.52, 4.34]
Reference
For acute treatment, intravenous glucose/insulin and inhaled beta-adrenergic agonists drive 
potassium into cells. Potassium can be removed from the body by dialysis or with non-
absorbed polymers which non-selectively bind potassium and are excreted. Polymers do not 
lower potassium rapidly and cause significant gastrointestinal (GI) side effects (colonic 
necrosis, bowel obstruction, GI bleeding, ischemic colitis, perforation), bind to many oral 
medications and to other cations, lowering magnesium and calcium levels. Thus, an unmet 
need remains for safe, rapid, and an effective treatment for hyperkalemia.
Sodium zirconium cyclosilicate (ZS) is a non-absorbed, inorganic crystal that selectively 
exchanges hydrogen and sodium cations for potassium in a dynamic process throughout the 
upper and lower gastrointestinal tract. Bound potassium ions are excreted from the body. ZS is 
a white, insoluble, powder provided in 5g and 10g sachets to be suspended in water for oral 
administration.
1.3.1
Clinical benefits
In randomized, double-blind, placebo-controlled trials, ZS rapidly corrected potassium levels 
and maintained normokalemia in patients with hyperkalemia including those with chronic 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
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kidney disease, heart failure, diabetes mellitus and RAASi use. ZS was effective regardless of 
the underlying cause of hyperkalemia, age, sex, race or baseline potassium level. 
ZS acts rapidly, statistically significantly reducing potassium within one hour (study ZS-003). 
With ZS10g TID, 77% of patients achieved normokalemia within 24 hours and 86% within 48 
hours. Median time to normokalaemia was 2.2 hours (ZS-004). 
Potassium fell 0.8, 1.2 and 1.5 mmol/L at 48 hours among patients with baseline potassium 
<5.5, 5.5-5.9 and ≥6.0 mmol/L, respectively (ZS-004). This physiologic effect reduces the risk 
of hypokalemia and reflects the mechanism of action; as potassium levels normalize, less 
potassium is excreted into the GI tract and fewer cations are exchanged. 
ZS maintains normokalemia. Patients who achieved normokalemia with TID dosing were 
randomized to maintenance therapy with once daily ZS or placebo for 12 days (ZS-003) or 28 
days (ZS-004). ZS-003 met predefined efficacy endpoints at the 5 and 10g doses when 
compared with placebo. In ZS-004, ZS 5, 10 or 15g increased the number of normokalemic 
days (p ≤0.0001 for each dose vs placebo) and maintained potassium at lower levels than 
placebo (p ≤0.0001 for all doses). ZS maintained normokalemia for up to 12 months in the 
open label extension; when ZS was stopped, potassium rose to near baseline levels (ZS-004E).
Co-administration of ZS with clopidogrel, dabigatran, glipizide, losartan, furosemide, 
atorvastatin, amlodipine, warfarin, and levothyroxine identified no clinically meaningful drug-
drug interactions (ZS-009).
1.3.2
Clinical risks
In double-blind, placebo-controlled trials 1009 patients received ZS. Subjects were 22 to 93 
years of age, 42% female, 86% white, 12% black and nearly all had chronic kidney disease, 
heart failure and/or diabetes mellitus. 
Hypokalemia: During treatment up to 12 months at doses titrated to maintain normokalemia, 
hypokalemia was identified in 5.7% (7/123) of subjects in ZS-004E. Only 1 of 7 patients 
developed K+ <3.0 mmol/L. In ZS-004, one case of hypokalemia (3.4 mmol per liter in a 
patient receiving the 10-g dose) was reported in the 48 hours initial phase. This case was 
transient and resolved without potassium repletion.
Edema: Among subjects randomized to placebo, ZS 5, 10 or 15g QD, edema was reported by 
1.7, 0.9, 4.4 and 14.3%, respectively (ZS-003 & -004). Edema was untreated in 47% (7/15) of 
ZS-treated subjects and managed with diuretic initiation or dose adjustment and/or 
discontinuation of calcium channel blocker in the remainder. Although ZS exchanges protons 
and sodium for potassium, ZS did not increase urine sodium excretion in study ZS-002, -004 
or -006 indicating no increase in sodium absorption; the mechanism underlying edema 
remains uncertain.


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
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1.3.3
Clinical benefit-risk balance
Based on available oversea data, for correction of hyperkalemia, ZS 10g TID is recommended 
for up to 3 days until normokalemia is achieved. Thereafter, maintenance therapy is initiated 
with 5g QD and dose adjusted from 10g daily to 5g every other day to maintain normokalemia. 
Benefits and risks for ZS are summarized below:
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g
10g
15g
10g
15g
10g
15g
10g
Hyperkalemia increases the risk of mortality; potassium lowering reduces this risk even if 
normokalemia is not achieved (Figure 1). Benefits of ZS over placebo in patients with 
hyperkalemia include rapidly reducing serum potassium to achieve normokalemia and 
maintenance of normokalemia. Advantages over currently available therapies include rapidity 
of potassium lowering, no clinically meaningful drug-drug interactions, no increase in 
gastrointestinal adverse events or hypomagnesemia. 
No serious safety risks have so far been identified. Serum potassium should be periodically 
monitored.
1.3.4
Conclusions
Based on oversea available data, the benefit-risk assessment for sodium zirconium 
cyclosilicate is favourable for correction of hyperkalemia (10g TID for up to 3 days) and for 
maintenance treatment of patients with hyperkalemia across the dose range 15g daily to 5g 
every other day.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
24 (61)
1.4
Study Design 
Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT potassium 
values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled and randomized 1:1:1 to receive 
ZS 5 g, ZS 10 g, or placebo TID for 48 hours.
Throughout the study most potassium values will be measured at fasting before taking study 
drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 
hours. Potassium level should be determined by both i-STAT and the Central Laboratory on 
all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT 
potassium values, as these provide clinical sites with a real-time measurement. Statistical 
analyses on the study data will in principle be based on S-K values as measured by the central 
laboratory.
Safety and tolerability will be assessed on an ongoing basis. Standard study assessments 
including blood potassium, clinical chemistry (including calcium, magnesium, sodium, 
phosphate, creatinine, bicarbonate, and blood urea nitrogen [BUN]) and hematology 
parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will 
be assessed during the study at the time points specified in the assessments schedule. All 
women of childbearing potential will have a urine pregnancy test prior to enrollment and at 
their End of Study (EOS) visit.
Stopping rules will be implemented to ensure subjects discontinue the study treatment and 
receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant 
cardiac arrhythmias.
Figure 3
Study flow chart
Placebo TID
10 g TID
Patients with K+ between
5.1 and 6.5 mmol/L, inclusive
Double blind（2days）
5 g TID
R
Follow up
(Day9)
TID: Three times per day


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
25 (61)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess efficacy of 5 g three times daily 
(TID) and 10 g TID ZS versus placebo in 
Japanese patients with hyperkalemia (serum 
potassium [S-K] ≥ 5.1 mmol/L and ≤ 6.5 
mmol/L).
exponential rate of change in S-K values during the 
initial 48 hours of study drug treatment.
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
Key secondary objective
To evaluate the proportion of subjects who 
achieved normokalemia at 48 hours after start 
of dosing in ZS 5 g TID and 10 g TID groups 
when compared with placebo. 
Key secondary variable
proportion of patients who achieved normokalemia at 
48 hours after start of dosing
Other secondary objective
To evaluate the efficacy of ZS 5 g TID and 
10 g TID compared with placebo from 
various aspects.
Other secondary variables
!
exponential rate of change in S-K values during 
the initial 24 hours of study drug treatment 
!
proportion of patients who achieved 
normokalemia at 24 hours after start of dosing
!
proportion of patients who achieved 
normokalemia at each scheduled potassium 
assessment time-point after start of dosing
!
mean change and mean percent change from 
baseline in S-K values at all measured time 
intervals post dose
!
time to normalization in S-K values 
(normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
2.3
Safety objectives
Safety Objective:
Outcome Measures:
To assess safety and tolerability of 5 g TID 
and 10 g TID ZS versus placebo in Japanese 
patients with hyperkalemia (serum potassium 
[S-K] ≥ 5.1 mmol/L and ≤ 6.5 mmol/L).
Safety and tolerability as measured by adverse event 
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.


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Study Code D9482C00002
Version 3.0
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2.4
Exploratory objectives (Not applicable)
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.
Patients aged ≥18.  For patients aged <20 years, a written informed consent should 
be obtained from the patient and his or her legally acceptable representative.
3.
Two consecutive i-STAT potassium values, measured 60 (± 10) minutes apart, both 
values should be ≥ 5.1 mmol/L and ≤ 6.5 mmol/L and measured within 1 day before 
the first dose of study drug on Study Day 1.
4.
Ability to have repeated blood draws or effective venous catheterization.
5.
Female patients must be 1 year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (an acceptable method of contraception is 
defined as a barrier method in conjunction with a spermicide) for the duration of the 
study (from the time they sign consent) and for 3 months after the last dose of 
ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, 
approved contraceptive implant, long-term injectable contraception, intrauterine 
device, or tubal ligation are allowed. Oral contraception alone is not acceptable; 
additional barrier methods in conjunction with spermicide must be used.
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 staff and/or staff at the study site)
2.
Cause or symptoms of pseudohyperkalemia, such as
1)
hemolyzed blood specimen due to excessive fist clenching to make veins 
prominent
2)
hemolyzed blood specimen due to difficult or traumatic venepuncture


Clinical Study Protocol
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Study Code D9482C00002
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3)
history of severe leukocytosis or thrombocytosis
3.
Patients treated with lactulose, rifaximin, or other non-absorbed antibiotics for 
hyperammonemia within 7 days prior to first dose of study drug on Study Day 1.
4.
Patients treated with resins (such as sevelamer hydrochloride, sodium polystyrene 
sulfonate [SPS; e.g. Kayexalate®] or calcium polystyrene sulfonate [CPS]), calcium 
acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first 
dose of study drug.
5.
Patients with a life expectancy of less than 3 months
6.
Patients who are severely physically or mentally incapacitated and who, in the 
opinion of investigator, are unable to perform the patients’ tasks associated with the 
protocol.
7.
Female patients who are pregnant, lactating, or planning to become pregnant
8.
Patients who have an active or history of diabetic ketoacidosis 
9.
Presence of any condition which, in the opinion of the investigator, places the 
patient at undue risk or potentially jeopardizes the quality of the data to be 
generated.
10.
Known hypersensitivity or previous anaphylaxis to ZS or to components thereof.
11.
Treatment with a drug or device within the last 30 days that has not received 
regulatory approval at the time of study entry.
12.
Patients with cardiac arrhythmias that require immediate treatment.
13.
Patients on dialysis.
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 or their guardian/legal 
representative before any study specific procedures are performed. Patient is 
considered enrolled in the study after she/he has signed the informed consent form 
(ICF).


Clinical Study Protocol
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Study Code D9482C00002
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2.
Assign potential patient a unique enrolment number via Interactive Voice Response 
System (IVRS) / Interactive Web Response System (IWRS), beginning with ‘E#’.
3.
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 the Web Based Data Capture (WBDC) as a 
screen failure. Patients can be re-screened once. A new ICF does not need to be 
signed before re-screening if the original ICF was signed within 30 days and the 
ICF has not been revised.
If a patient withdraws from participation in the study, then his/her enrolment/randomisation
code cannot be reused.
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, and must be withdrawn from the study.
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 AZ global randomization 
system (AZRand) and loaded into the IVRS/IWRS database. Randomization codes will be 
generated in blocks to ensure approximate balance (1:1:1) between the three treatment arms 
(ZS 5g or ZS 10g or placebo three times per day). Randomization will be stratified by eGFR 
(<60, >= 60 mL/min/1.73m2) measured at each study centre during the screening period, so 
that proportion of subjects with eGFR >=60 mL/min/1.73m2 will not exceed 25% of the entire 
randomized subjects.
3.6
Methods for ensuring blinding
This study will have a double blind design. Patients will take by mouth the entire contents of a 
single sachet containing either ZS 5g, ZS 10g or placebo three times per day. The exterior 
appearance of the sachets are identical, but the volume of study drug will differ depending 
upon the randomized treatment group.  Individual sachets are enclosed in a carton with a 


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
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tamper evident seal intended to be broken exclusively by patients just before taking the study 
drug.
A designated individual (e.g. pharmacist) at each study site will be responsible for performing 
study drug accountability and if required, this person will answer questions from patients 
related to the investigational product (IP). The designated individual will not participate in 
patient management or patient assessments.
No member of the study team at AZ, or representative, personnel at study centers, or any 
clinical research organization (CRO) handling data will have access to the randomization 
scheme during the conduct of the study, with the exception of the AZ personnel generating the 
randomization scheme as well as AZ Supply Chain, and the CRO companies providing the 
IVRS/IWRS and carrying out the packaging and labeling of study medication. This 
documentation will be kept in a secure location until the end of the study.
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 randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.
AstraZeneca representatives who are independent to the study evaluation at the Patient Safety 
Department retains the right to break the code for Serious Adverse Event (SAE) 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
For concomitant medications which are restricted during the study, please see Section 7.7.
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:
!
Patient’s decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment
!
Adverse Event
!
Severe non-compliance with the Clinical Study Protocol


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
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!
Risk to patient as judged by investigator
!
Pregnancy
!
Require treatment with medications prohibited or contraindicated for use due to 
safety concerns with ZS
!
Patient unblinded due to emergency
!
Patient develops potassium values > 6.5 mmol/L or <3.0 mmol/L (confirmed by 
taking a second potassium measurement after a 10 ± 2-minute interval, and both i-
STAT values meet the study drug discontinuation rule). Patients discontinuing due 
to this criterion must immediately receive appropriate medical treatment to manage 
their hypo- or hyperkalemia.
!
Patient develops clinically significant cardiac condition (see below). The patient 
should immediately receive appropriate medical treatment and be discontinued from 
study drug.
∀
Serious cardiac arrhythmias (ventricular tachycardia or ventricular fibrillation, 
new atrial fibrillation or atrial flutter, new paroxysmal supraventricular 
tachycardia [other than sinus tachycardia], new 2nd or 3rd degree AV block 
or significant bradycardia [HR < 40 bpm])
∀
Acute heart failure
∀
Significant increase in PR interval (> 250 msec in the absence of pre-existing 
atrioventricular block) or widening of the QRS complex (>140 msec in the 
absence of pre-existing bundle branch block). If an ECG shows peaked T-
wave, the serum potassium must be checked immediately and decide whether 
to continue the IP based on the criteria described in Section 3.9.
∀
An absolute QTc >550msec, or an increase in QTc interval > 60msec from 
baseline to more than 500msec. 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
Patients who discontinue from study medication but agree to remain in the study should 
continue to follow protocol-specified procedures and assessments except for dispensing of 
study medication for the study.
Note: Discontinuation of investigational product does not necessarily imply discontinuation of 
follow-up or termination of all study participation.
3.9.1
Procedures for discontinuation of a subject 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.  A patient that decides to discontinue investigational product will always be 


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asked about the reason(s) and the presence of any adverse events.  If possible, they will be 
seen and assessed by an Investigator(s).  Adverse events will be followed up; and all study 
drugs should be returned by the patient.
If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
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
!
Lost of patient to follow-up
!
Death
Any patient who is withdrawn from the study medication prior to study completion will return 
to the clinic 7 (± 1) days after the last IP administration for an EOS visit. Dosing schedule 
cards and all study drugs should be returned by the patient.
The date and reason for patient withdrawal must be recorded on the appropriate electronic 
Case Report Form (eCRF). Every attempt should be made to contact any patient considered 
lost to follow-up.
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. 
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These patients should have the reason for study withdrawal
recorded as ‘Screen failure’(the potential subject 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).
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.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events. The Investigator will follow up AEs outside of the clinical study. 


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Study Code D9482C00002
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If a patient withdraws from participation in the study, then his/her enrolment/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 and 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 follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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Study Code D9482C00002
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4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan
Study Visit
Visit 1
Visit 26
Visit 3
Visit 4
EOS5
Study Day
Screening
Day 16
Day 2
Day 3
Day 95
Written informed consent
X
Eligibility criteria
X
Demographics
X
Medical History
X
Physical exam including weight
X
X
Randomization
X
Access IVRS/IWRS
X
X
Study drug (IP) dispensation
X
Study drug (IP) administration
X
X
ECG
X
X
X
Vital signs
X
X
X
Concomitant medications
X
X
X
X
Adverse events
X7
X
X
X
eGFR8
X
Potassium1
X2
X3
X
X
Serum Chemistry1
X
X
X
Hematology1
X
X
X
Urinalysis1
X
X
X
Urine HCG
X4
X4
IP Reconciliation
X
1.
All blood potassium samples are analyzed by i-STAT and by the Central Laboratories on all occasions. 
Serum clinical chemistry, including S-K, hematology and urinalysis will be measured fasting and before 
administration of study drug. For diabetic patients all blood potassium samples should be collected prior to 
insulin administration whenever possible
2.
Potassium will be measured twice 60 (±10) minutes apart within 1 day prior to first dose administration, 
and  prior to, 1, 2 and 4 hours (±15 min) after administration of the first dose of study drug on Day 1. 
Potassium will be measured again at 90 minutes after taking the second dose for patients with i-STAT 
potassium ≥6.1 mmol/L or <4.0 mmol/L 4 hours after the first dose
3.
Potassium will be measured predose (0 hour), 1 and 4 hour (±15 min) after the first dose on Day 2 (Visit 3)
4.
U-HCG will be performed exclusively for women of childbearing potential. Samples will be analysed 
locally, and the data will not need to be collected in the database. Pregnant women are excluded from the 
study. 
5.
The End of Study (EOS) visit will occur 7±2 day after the last administration of IP.


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6.
Baseline parameters should be measured/collected no earlier than 1 day prior to administration of the 1st 
dose of study drug on Day 1 (Visit 2). Visits 1 and 2 may be combined into a single visit on the same day. 
7.
AEs will be collected after the patient has signed informed consent, so during  the Day 1 (Visit 2), 
investigator need to check if any AE happened since from inform consent
8.
If eGFR assessments are performed within 1 month prior to Visit 1, the latest one can be used for Visit 1 
data.
4.1
Screening/Enrolment period (Visit 1)
Procedures will be performed according to the Study Plan in 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 entered 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 30 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).
S-creatinine (local laboratory) will be measured for stratification (based on eGFR value) prior 
to randomization. If eGFR assessments are performed within 1 month prior to Visit 1, the 
latest one can be used for Visit 1 data.
The GFR was estimated using the following equation generated by the Japanese Society of 
Nephrology: GFR (mL/min/1.73 m2) = 194 × serum creatinine−1.094 × Age−0.287 (× 0.739 if 
female) (Matsuo S et al 2009).
4.2
Treatment period
An overview of the procedures for this period are included in the Study Plan (see Table 1). 
The specific procedure(s) to be performed at each visit are detailed below.
4.2.1
Day 1 (Visit 2)
Subject will arrive fasting (nothing by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications only prior to the blood collection for a minimum of 8 
hours) at or before 8:00 am (0800 ± 120 minutes). Then, the following steps will be taken:
!
All eligibility criteria will be assessed. This includes 2 consecutive S-K 
measurements at 60 (± 10) - minute intervals by using both i-STAT and the Central 
Laboratory. If both i-STAT values are ≥ 5.1 mmol/L and ≤ 6.5 mmol/L the 
following samples will be collected: a standard assessment of clinical chemistry, 
hematology and urinalysis, a pregnancy test if the subject is a woman of 


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childbearing potential, vital signs, an ECG and a full physical including weight, 
performed by the Principal Investigator (PI)/sub PI. The standard clinical chemistry 
and hematology assessments are analyzed by the central laboratory. Patient medical 
and surgical history including co-morbidities will be obtained with the review of 
selection criteria. Review and record the concomitant medications and AEs/SAEs.
Note: The above procedures should be performed within 1 day of the first 
administration of study drug and before any IP administration.
!
S-K samples (i-STAT and central laboratory) will be taken prior to administration 
of Dose 1 and at 1, 2 and 4 hours (± 15 min) post Dose 1 (prior to administration of 
Dose 2).
!
The first two (2) doses of study IP will be administered at the clinic at as a 
suspension in water.
!
The first doses of study IP will be administered at ~ 9.00 am (0900 ± 120 minutes) 
followed by a light breakfast. At dose administrations the subject will be instructed 
on how to mix and administer the IP. 
!
1 hour (± 15 min) after dose administration a potassium sample (i-STAT and 
Central Laboratory) will be collected.
!
The second dose (Dose 2) will be administered 4 hours after Dose 1, after the 4 
hour post Dose 1 blood sample will be drawn, before lunch.
!
Patients with i-STAT potassium levels < 6.1 and ≥4.0 mmol/L at the 4 hour (± 15 
minutes) post Dose 1 blood draw will be sent home after the second dose with 
instructions on how to take the IP. They will be requested to fill out a dosing 
schedule card indicating when they took the IP; The patient will return to the clinic 
the following morning of Day 2 (Visit3).
!
Patients with i-STAT potassium ≥6.1 or <4.0 mmol/L at the 4 hour post Dose 1 
blood draw will stay in the clinic and take the second dose of study drug 
approximately 4-hours after the first dose. They will then remain in the clinic an 
extra 90 minutes (±15 minutes) after taking the second dose when another blood 
sample for potassium determination (i-STAT and Central Laboratory will be 
collected and an ECG will be recorded).
∀
If i-STAT potassium levels are > 6.5 mmol/L as determined by the i-STAT at 
the 90-minute post Dose 2 blood draw, the patient will be discontinued from 
the study. Patients will return to the clinic 7 (±1) days later for an EOS visit.
∀
If i-STAT potassium levels are ≤ 6.5 mmol/L as determined by i-STAT, and 
the ECG does not show any of the ECG withdrawal criteria, the patient will 
be sent home with the 3rd dose of study drug and the dosing card and return to 
the clinic in the morning of Day 2 (Visit 3).
!
All other activities will take place as outlined in the Study Plan (see Table 1).


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Study Code D9482C00002
Version 3.0
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!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L. 
4.2.2
Day 2 (Visit 3)
Subjects will arrive at the clinic at or before 8:00 am (0800 ± 120 minutes) with any 
remaining IP and empty sachets and IP boxes from the previous day and completed dosing 
schedule card. Subjects will arrive fasting (nothing by mouth except water, coffee or tea, with 
or without milk and/or sugar, and essential medications only prior to the blood collection for a 
minimum of 8 hours). 
!
The clinic staff will solicit any AEs, and will note any unused IP on the eCRF and 
source documents. 
!
Potassium levels will be evaluated prior to administration of the first daily dose 
(Dose 1; 0 hour) and then at 1 and 4 hour (± 15min) post Dose 1. Samples will be 
evaluated by i-STAT and the central laboratory.
!
If the predose potassium level is > 6.5 mmol/L as determined by i-STAT, subjects 
will be considered treatment failures and will be withdrawn from the study and will 
receive standard of care. Subjects will return to the clinic on Study Day 9 for an 
EOS visit.
!
The first two doses of IP on day 2 will be administered in the clinic. Dose 1 will be 
administered as a suspension in water before breakfast. The second dose (Dose 2) 
will be administered ~ 4 hours after Dose 1, and after the 4 hour post Dose 1 blood 
draw.
!
If the 4-hour post Dose 1 potassium level is > 6.5 mmol/L as determined by i-
STAT, subjects will be considered treatment failures and will be withdrawn from 
the study and will receive standard of care. Subjects will return to the clinic on Day 
9 for an EOS visit.
!
After receiving the second dose subjects will be sent home with instructions on how 
to take the IP at dinnertime. They will be requested to fill out a dosing schedule 
card indicating when they took the IP.
!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L.
4.2.3
Day 3 (Visit 4)
Subjects will arrive at the clinic at or before 8:00 am (0800 ± 120 minutes) with any 
remaining IP and empty sachets and IP boxes from the previous day and completed dosing 
schedule card. Subjects will arrive fasting (nothing by mouth except water, coffee or tea, with 
or without milk and/or sugar, and essential medications only prior to the blood collection for a 
minimum of 8 hours).
The clinic staff will solicit any AEs, and will note any unused IP on the eCRF and source 
documents.
A standard assessment of blood chemistry, hematology and urinalysis assessment, an ECG 
and vital signs will be performed. In addition S-K will also be determined by i-STAT.


Clinical Study Protocol
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Study Code D9482C00002
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4.3
Follow-up period (EOS)
Subjects will arrive at the clinic at 8:00 am (0800 ± 120 minutes). Subjects will arrive at the 
clinic fasting (nothing by mouth except water, coffee or tea, with or without milk and/or 
sugar, and essential medications only prior to the blood collection for a minimum of 8 hours).
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, and if the subject has visited a doctor or emergency room since the last 
visit. A final accounting of all study drug dosing supplies will be performed.
!
Blood samples for i-STAT potassium and assessment of hematology and clinical 
chemistry including S-K will be collected.
!
Assessment of urinalysis parameters.
!
A urine pregnancy test will be performed if the subject is a woman of childbearing 
potential.
!
An ECG will be performed (Section 5.2.3).
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4)
!
Perform a complete physical examination including weight, see Section 5.2.2
!
A full clinical supply inventory for each subject will be conducted and reconciled. 
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.  A copy of the completed 
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Potassium
Blood samples for determination of potassium will be taken at the times indicated in the Study 
Plan (see Table 1). Potassium samples will be analyzed locally using i-STAT devices, and 
serum samples will be prepared and shipped to the Central Laboratory. All serum samples 
should be examined and any hemolyzed samples MUST be redrawn. In the event that 
hemolyzis 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.


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
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Table 2
Summary of Serum Potassium Collection Times
Study Day
Time
Central Laboratory
i-STAT
-1 ~ 1
1st assessment to confirm 
qualification (within 1 day of 
the first administration of study 
drug)
1 hour post 1st assessment
X
X1
X
X
1
0 hour (pre-dose)
1 hour post Dose 1
2 hours post Dose 1
4 hours post Dose 1
90 minutes post Dose 2
X
X
X
X
X2
X
X
X
X
X2
2
0 hour (pre-dose)
1 hour post Dose 1
4 hours post Dose 1
X
X
X
X
X
X
3
0 hour
X1
X
EOS
0 hour
X1
X
1
S-K analyzed as part of the serum chemistry assessment.
2
Sample only collected if i-STAT potassium value at the 4-hour post Dose 1 time point was ≥6.1 or <4.0 
mmol/L.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Table 1). 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 in the appropriate 
eCRF module.
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory.


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
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Table 3
Laboratory Safety Variables
Haematology
Clinical Chemistry (serum)
B-Hemoglobin (Hb)
S-Total Protein
B-Hematocrit
S-Albumin
B-Erythocyte count (RBC)
S-Bicarbonate
B-Total leukocyte count (WBC)
S-Blood Urea Nitrogen
B-Platelet count
S-Creatinine (including eGFR assessment1)
S-Bilirubin, total
Urinalysis
S-Alkaline phosphatise (ALP)
U-PH
S-Glucose
U-Specific gravity
S-Sodium
U-Glucose 
S-Potassium2
U-Ketones
S-Inorganic phosphate
U-Bilirubin
S-Calcium, total
U-Urobilinogen
S-Magnesium
U-Blood
S-Gamma-glutamyl transferase (GGT)
U-Albumin
S-Aspartate aminotransferase (AST)
U-Creatinine
S-Alanine aminotransferase (ALT)
U- Human chorionic gonadotropin (HCG) (only 
for females of childbearing potential) 3
1.
eGFR will be measured at each study site during at Visit 1 only.
2.
Blood potassium will be tested by i-STAT and Central Laboratory
3.
Urine-HCG will be measured at clinic, using the tube provided by Central Laboratory
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 
center as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
Blood chemistry and hematology parameters will be evaluated fasting, by the Central 
Laboratory, at Visit 2, 4 and EOS.
The Visit 2 urine pregnancy test for women of childbearing potential is performed as part of 
the screening procedure prior to any IP administration and at EOS visit.
Urinalysis, will be performed by the Central Laboratory at Visit 2, 4 and EOS.
Note: Whenever possible, all blood draws collected prior to meals should be collected prior to 


Clinical Study Protocol
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insulin/insulin analog treatment.
5.2.2
Physical examination
A complete physical examination should be performed no earlier than 1 day before 
administration of the first dose of study drug on Visit 2 and EOS visit.
The complete physical examination includes the following: general appearance including skin,
height and weight, lymph nodes, thyroid, musculoskeletal/extremities, cardiovascular 
including assessment of signs of heart failure, lungs, abdomen, and neurological systems. 
5.2.3
ECG
5.2.3.1
Resting 12-lead ECG
A 12-lead ECG will be performed after the patient has been lying down for 5 minutes at the
times indicated in the Study Plan in Table 1. Heart rate, P and QRS durations, PR and QT 
intervals will be recorded from standard lead of the computerized quantitative 12-lead ECG.
ECGs will be recorded at Visits 2, 4 and EOS. In addition, for patients who have i-STAT 
potassium levels ≥ 6.1 mmol/L at the 4 hour post 1st dose time point on the Day 1(Visit 2), an 
additional ECG will be recorded 90 minutes post 2nd dose.
5.2.4
Vital signs
5.2.4.1
Pulse rate and blood pressure
Pulse rate and systolic and diastolic blood pressure (BP) will be assessed using non-invasive 
equipment by an adequately trained health care professional. Measurements with a calibrated 
sphygmomanometer are preferred. If not available, another device calibrated carefully in 
proportion to a mercury sphygmomanometer is preferred. Use of aneroid manometers should 
be avoided. Appropriate cuff size must be used to ensure accurate measurement.
The disappearance of sound (Korotkov phase V) should be used for the diastolic reading. 
Three (3) readings separated by 2 minutes should be averaged, and the average result will be 
recorded in the eCRF. If the first two readings of SBP differ by more than 5 mmHg, additional 
readings should be obtained.
Blood pressure should be checked in both arms at the first visit. Subsequent blood pressure
measurements should be recorded in the arm with the higher pressure. Blood pressure should 
be measured in either supine or sitting position. No shift from one position to another should 
be made during the study. Supine or sitting posture should be adopted for at least 5 minutes 
before measurement. The patient should be relaxed and with the arm outstretched and 
supported. Blood pressure should be measured under standardized conditions, as nearly as 
possible at the same time each visit, on the same arm, by the same personnel, and with the 
same apparatus.


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Study Code D9482C00002
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5.3
Other assessments (Not applicable)
5.4
Pharmacokinetics (Not applicable)
5.5
Pharmacodynamics (Not applicable)
5.6
Genetics (Not applicable)
5.7
Biomarker analysis (Not applicable)
5.8
Storage, re-use and destruction of biological samples
After the analyses are complete the samples will be either completely consumed during the 
analytical process or disposed of after the analysis.
5.9
Labeling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are labeled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A
criteria), see Appendix B.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labeling, shipment and containment provisions are approved.
5.10
Volume of blood
The total volume of blood that will be drawn from each patient for this study is listed in Table 
4 as below. The collection of additional samples is performed locally at the discretion of the 
investigator and recorded in the eCRF as appropriate, thus requiring additional sample 
volumes.
Table 4
Volume of blood to be withdrawn from each patient
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume 
Total (mL)
V 1
(Screening)
V 2
(D 1)
V 3
(D 2)
V 4
(D 3)
EOS
(D 9)
eGFR
2.51
1
2.5
Hematology
2
13
1
1
6
Clinical 
Chemistry
2.5
13
1
1
7.5
Potassium 
(i-STAT and 
Central Lab 
S-K)
4.5
6-72,5
34
15
15
54


Clinical Study Protocol
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Study Code D9482C00002
Version 3.0
Date 26 September 2017
42 (61)
Table 4
Volume of blood to be withdrawn from each patient
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume 
Total (mL)
V 1
(Screening)
V 2
(D 1)
V 3
(D 2)
V 4
(D 3)
EOS
(D 9)
Maximum 
blood volume 
Total (mL)
2.5
36
13.5
9
9
70
V= Visit; D=Day
1
Actual blood volumes in each study centre may be a little different.
2
Potassium will be measured twice 60 (±10) minutes apart within 1 day of first dose administration on Day 
1(Visit 2) and pre dose and at 1, 2 and 4 hours (±15 min) after administration of the first dose of study drug; 
An extra potassium will be measured at 90 minutes (±15 minutes) after taking the second dose for patients 
with i-STAT potassium ≥ 6.1 mmol/L or < 4.0 mmol/L at the 4 hour post Dose 1
3
On Day 1(Visit 2), the Central Laboratory clinical chemistry and hematology samples will be collected at 
the same time as the 60 minutes i-STAT screening potassium sample
4
Potassium will be measured predose (0 hour), 1 and 4 hour (±15 min) post 1st dose on Day 2 (Visit 3)
5
Central laboratory S-K sample collected as part of the clinical chemistry
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 


Clinical Study Protocol
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Study Code D9482C00002
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!
Results in persistent or significant disability or incapacity
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the subject 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 (including SAEs) will be collected from the time of informed consent, 
throughout the treatment period and including the EOS visit.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment (EOS) or other assessment /
visit as appropriate in the study are followed up by the Investigator for as long as medically 
indicated, but without further recording in the eCRF. AstraZeneca retains the right to request 
additional information for any 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 collect 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 or no)
!
Action taken with regard to investigational product
!
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


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!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication
!
Description of AE.
Intensity rating scale:
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3
severe (incapacitating, with inability to perform normal activities)
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 or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 
visit?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.


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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 Clinical Study Report (CSR).  Deterioration as compared to baseline in 
protocol-mandated laboratory values, vital signs 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).
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.
6.4
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 Case Report Form 
(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. 


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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 11 months. For the purpose of this study, an overdose is defined as more than 30 g per day.
!
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 ZS 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 subject 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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When the CRF module is used include the following:  The PREGREP module in the CRF is 
used to report the pregnancy and the PREGOUT is used to report the outcome of the 
pregnancy.
6.6.2
Paternal exposure
Nonclinical data with ZS based on conventional studies of safety pharmacology, repeated dose 
toxicity, genotoxicity, and carcinogenic potential and toxicity to reproduction and 
development did not reveal special hazard effect on libido, fertility, or embryofetal and 
postnatal development (see investigator’s brochure [IB] for further details). Therefore there is 
no restriction on fathering children or donating sperm during the study.
In case of pregnancy of the patient’s partners, an ICF FOR PREGNANT PARTNERS OF STUDY 
PATIENTS the partner’s pregnancy will be sent to the partner to obtain her consent for collection 
of pregnancy information. Such pregnancy report will follow the same timeframe and routing as 
described for any participant’s pregnancy. These pregnancies will be also followed up, and the 
outcome of the pregnancy (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be obtained and documented if possible.
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 recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the 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


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!
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 
!
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.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product and 
strength
Dosage form
Manufacturer
Sodium Zirconium
Cyclosilicate (ZS) 5 g
Powder for Oral Suspension in 
a sachet
AstraZeneca 
Sodium Zirconium
Cyclosilicate (ZS) 10 g
Powder for Oral Suspension in 
a sachet
AstraZeneca 
Placebo
Powder for Oral Suspension in 
a sachet
AstraZeneca
7.2
Dose and treatment regimens
Sodium Zirconium Cyclosilicate should be administered orally as a suspension in water.
Subjects were randomized to receive either ZS 5 g, 10 g or placebo, administered TID for 48 
hours (total 6 doses).


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If i-STAT potassium levels are > 6.5 mmol/L as determined by the i-STAT, the patient will be 
discontinued from the study.
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 
mmol/L, inclusive at any time point on the Day 1 the subject will be directed to not take any 
more study drug for the remainder of the day and return the next day to evaluate whether to 
continue dosing in Day 2. 
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 
mmol/L, inclusive at any timepoint on the Day 2, the subject will be directed to not take any 
more study drug for the remainder of the day and return the next day for evaluation.
Patients with confirmed i-STAT potassium <3.0 mmol/L should discontinue from therapy.
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.
7.4
Storage
All study drug 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.
IP kits will have the unique number identifiers and will be assigned through the study. On 
receipt of IP supplies the Investigator/designee will check the supplies against the shipment 
manifest and will confirm receipt of IP shipments via the IVRS/IWRS. The system will then 
issue an acknowledgement receipt. Sites are required to place all shipment manifests and 
acknowledgement receipts in the site regulatory binder.
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 subject has returned all unused study 
drug.


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7.7
Concomitant and other treatments 
All concomitant medications taken by the patient from 7 days prior to Day 1 until EOS visit, 
or the end of the study (7 ± 1 days after the last dose of IP) for patients, will be recorded. 
While it is expected that patients with diabetes will be enrolled, use of insulin/insulin analog is
not restricted. Whenever possible, all blood draws collected for the study evaluation prior to
meals during the study treatment period should be collected prior to any insulin/insulin analog
treatment.
During the study, the patient cannot receive alternative treatment for hyperkalemia (including 
medication). If dosing with IP is discontinued or the patient has completed dosing, the patient 
may receive alternative treatment for hyperkalemia if clinically indicated prior to completing 
the EOS visit scheduled 7 days after the last dose. Any alternative treatment administered 
during the above period must be recorded in eCRF. 
In addition to therapies for hyperkalemia also other drugs with World Health Organization 
Anatomic Therapeutic Chemical classification code V03AE, i.e. potassium or ion binders 
such as sevelamer, calcium acetate, and lanthanum carbonate, are prohibited to be taken while 
receiving IP, as the effects of potassium binding drugs may effect safety laboratory 
assessments.
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:
Class of Drug
Drugs
Azole antifungals
Ketoconazole, Itraconazole, Posaconazole, 
Voriconazole
Anti-HIV drugs
Atazanavir, Nelfinavir, Indinavir, 
Ritonavir, Saquinavir, Raltegravir, 
Ledipasvir, Rilpivirine
Tyrosine kinase inhibitors
Erlotinib, Dasatinib, Nilotinib


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7.8
Post Study Access to Study Treatment (Not Applicable)
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to database lock/unblinding.
8.2
Sample size estimate
Approximately 102 patients will be randomized to ZS 5g TID, ZS 10g TID, and Placebo with 
1:1:1 ratio. 
Sample size for the exponential rate of change during the study is calculated based on a 
random slope model, with parameters estimates based on the ZS-003 data, and here it is 
assumed that K measurement schedule is same as that in study 003 correction phase, i.e. K is 
measured at Baseline(0),1,2,4,24,25,28 and 48 hours post first dose. When the model is fit to 
the ZS-003 data (for only Placebo, ZS5g TID, ZS10g TID groups), with time measured in 
days, the variance of the slope was 0.001053, the variance of intercept was 0.004237, and 
covariance between intercept and slope was -0.00065, and the residual variance was 0.003980. 
Based on these parameters, 34 patients in each ZS dose and Placebo group would provide 
more than 95% power to detect difference of slopes of 0.055/day (assumed for ZS 10g TID vs. 
Placebo) and approximately 83% power to detect the difference in slopes of 0.030/day 
(assumed for ZS 5g TID vs. Placebo), respectively.
For the proportion of normokalemic patients at the end of dosing, 34 patients in each ZS dose 
and Placebo would provide approximately 90% and 66% power to detect the difference in 10g 
TID vs. Placebo and 5g TID vs. Placebo with nominal significance level of 0.05, respectively, 
according to Fisher’s exact test. Here it was assumed that proportion of normokalemic patients 
at 48 hours are 47.8%, 77.6% and 86.4% for Placebo, ZS 5g TID, and ZS 10g TID, 
respectively.
8.3
Definitions of analysis sets
All efficacy analyses will be performed using the full analysis set (FAS) based on the Intent-
to-Treat (ITT) principle. 
8.3.1
Full analysis set
The FAS includes all patients randomized in the study. Patients will be analysed according to 
their randomized treatment assignment. Patients without any post randomization data will not 
be used in any of the inferential analyses, but will be accounted for in summary statistics 
tables.


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8.3.2
Safety analysis set
The safety analysis set will include all patients who took at least one dose of IP during the
study. Patients will be analysed according to actual treatment they received.  
8.4
Outcome measures for analyses
8.4.1
Efficacy variables (Primary) 
Primary efficacy variable is the exponential rate of change in S-K values during the initial 48 
hours of study drug treatment. 
8.4.2
Efficacy variables (Key Secondary)
Key secondary efficacy variable is the proportion of patients who achieved normokalemia at 
48 hours after start of dosing. 
8.4.3
Efficacy variables (Secondary)
Also, secondary efficacy variables include the followings: 
!
exponential rate of change in S-K values during the initial 24 hours of study drug 
treatment
!
proportion of patients who achieved normokalemia at 24 hours after start of dosing
!
proportion of patients who achieved normokalemia at each scheduled potassium 
assessment time-point after start of dosing
!
mean change and mean percent change from baseline in S-K values at all measured 
time intervals post dose
!
time to normalization in S-K values (normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
8.4.4
Safety Variables
In this study, the following safety data will be collected: adverse events (AEs), vital signs, 
ECGs, physical examinations, clinical laboratory evaluations, and other electrolytes 
(specifically, serum potassium [S-K], serum calcium [S-Ca], serum magnesium [S-Mg], 
serum sodium [S-Na], serum phosphate [S-PO4], serum bicarbonate [S-HCO3], and blood 
urea nitrogen [BUN]).
8.5
Methods for statistical analyses
8.5.1
Analyses of efficacy variables
8.5.1.1
Analysis of Primary efficacy variable
Primary analysis for primary efficacy variable of exponential rate of change in S-K will be 
based on a random slope model. All available S-K measurements from baseline through to 48-
hr post initial dose (Day 3, 0-hour) will be included as the response variables after log-
transformation. The model will include time and time x treatment interaction as fixed 


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continuous effects and intercept and time as patient-level random effect with unstructured 
covariance matrix. In addition, baseline eGFR category (<60, ≥ 60 mL/min/1.73m2) will be 
included as a factor in the model.
Baseline will be established by taking the mean of 2 different S-K values, recorded 60 minutes 
apart (to confirm qualification for randomization) and then averaged with the last S-K value 
taken just before administration of the first dose (0-hr) on Study Day 1.
8.5.1.2
Confirmatory testing strategy
To protect study wise error rate at 5%, hierarchical testing strategy will be employed. 
Confirmatory testing will proceed with the sequential order as specified below. Each 
individual statistical comparison will be conducted with two-sided significance level of 0.05. 
Step 1: Compare exponential rate change through 48 hours between ZS 10g TID vs. Placebo, 
Step 2: Compare exponential rate change through 48 hours between ZS 5g TID vs. Placebo.
8.5.1.3
Analysis of Key secondary efficacy variable
Proportion of normokalemic patients at 48 hours post initial dose will be analyzed by logistic 
regression model. The model will include treatment and baseline eGFR category (<60, 
≥60 mL/min/1.73m2)as factors and baseline S-K as a covariate.
8.5.2
Analysis of Safety data
Safety endpoints will include adverse events (including incidence of Oedema related events, 
defined as Fluid overload, Fluid retention, Generalised oedema, Hypervolaemia, Localised 
oedema, Oedema, Oedema peripheral and Peripheral swelling), vital signs, and other relevant 
clinical chemistry (specifically, the incidence of hypokalemia, hypomagnesemia, 
hypophosphatemia, and hypocalcemia), hematology, and urinalysis parameters.
Treatment emergent AEs (TEAE) will be mainly analyzed.  Adverse events will be classified 
by the Medical Dictionary for Regulatory Activities (MedDRA) to be consistent with other ZS 
studies. Safety data will be collected and analyzed while on study phases and reported until 
treatment-emergent adverse events are resolved. Unresolved adverse event outcomes at the 
end of treatment will be followed for an additional 7 days or until resolution, whichever 
occurs earlier. The type, incidence, timing (onset, duration), relationship, and severity of 
adverse events will be reported for treatment-emergent and serious adverse events. Reasons 
for withdrawal due to adverse events will also be reported. Narratives will be written for every 
adverse event classified as serious or associated with death.
8.5.3
Interim analysis
NOT APPLICABLE.


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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 the WBDC
system(s) utilised.
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 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 (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects. This 
will require direct access to all original records for each subject (e.g., clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the subject.
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.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
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 


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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 subjects and in all other respects, not relating to study conduct or treatment of 
subjects, 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 subjects 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 subject undergoing the study’.
The study is expected to start in Q2 2017 and to end by Q1 2018.
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (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 ZS.
9.4
Data management by AstraZeneca or delegate
Data management will be performed 
 
 according to the Data Management Plan.  
Data will be entered into the WBDC system 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 WBDC system 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 Data Management Plan.
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 AZ Drug Dictionary or WHODRUG. Classification coding will be 
performed by the Medical Coding Team at the AZ Data Management Center or other party.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
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 Data Management Plan will also clarify 


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the roles and responsibilities of the various functions and personnel involved in the data 
management process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked. A 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 associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) 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 Data Management Plan.
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 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 subjects.  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.


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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 subject should into the study.
The IRB should approve all advertising used to recruit subjects 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 subject 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
!
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 subjects harmed as a consequence of study participation are 
described in the informed consent form that is approved by an IRB.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
58 (61)
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
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.  If the changes are of an administrative nature, it is submitted to the IRB.  If the changes 
have a significant impact on the safety of the subjects, the scientific value of the study, the 
conduct and management of the study, and the quality of any investigational product used in 
the study, it should be approved by the 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 IRB 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-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, 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.
11.
LIST OF REFERENCES
Kosiborod M et al 2014
Kosiborod M, Rasmussen HS, Lavin PT, et al. Effect of sodium zirconium cyclosilicate on 
potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE 
randomized clinical trial. JAMA 2014;312:2223-33
Luo J et al 2016
Luo J, Brunelli SM, Jensen DE, et al. Association between serum potassium and outcomes in 
patients with reduced kidney function.  Clin J Am Soc Nephrol 2016;11:90-100.
Matsuo S et al 2009
Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine 
in Japan. Am J Kidney Dis 2009;53:982-92
Packham DK et al 2015
Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in 
hyperkalemia. N Engl J Med 2015;372:222-31.


Clinical Study Protocol Appendix A
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
59 (61)
Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
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, hospitalisation, disability or incapacity but may jeopardize the subject 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 hospitalisation
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.
!
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?


Clinical Study Protocol Appendix A
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
60 (61)
!
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.


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9482C00002
Version 3.0
Date 26 September 2017
61 (61)
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.


               
                 
                                
                                                                                                                                     
                                                                                                                              
                                                                                                                                             
                                                                                                                 
                                                                                  
                  
 
 
 
 
 
 
 
     
            
                                          
              
  

SAP_001.pdf: 
Statistical Analysis Plan, ANGEL
Version number 4.0
Form Doc Number: LDMS_001_00026934
Parent Doc Number: 
Statistical Analysis Plan
Study Code
D9482C00002
Edition Number
2.0
Date
19-Feb-2018
A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and Safety 
of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With 
Hyperkalemia






Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY..................................................................................8
1.
STUDY DETAILS...............................................................................................9
1.1
Study objectives...................................................................................................9
1.2
Study design ...................................................................................................... 10
1.2.1
Study Plan..........................................................................................................11
1.2.2
Assessment schedule of S-K ..............................................................................12
1.3
Number of subjects ............................................................................................13
2.
ANALYSIS SETS .............................................................................................14
2.1
Definition of analysis sets .................................................................................. 14
2.1.1
Enrolled subjects................................................................................................14
2.1.2
Full analysis set (FAS).......................................................................................14
2.1.3
Safety analysis set (SAF) ...................................................................................14
2.2
Protocol deviations............................................................................................. 14
3.
PRIMARY AND SECONDARY VARIABLES.................................................15
3.1
Primary efficacy variable ...................................................................................15
3.2
Key secondary efficacy variable.........................................................................15
3.3
Other secondary efficacy variables.....................................................................15
3.4
Safety variables..................................................................................................15
4.
ANALYSIS METHODS....................................................................................15
4.1
General principles.............................................................................................. 15
4.1.1
Objectives and hypotheses .................................................................................16
4.1.2
Definitions .........................................................................................................17
4.1.2.1
Baseline Value...................................................................................................17
4.1.2.2
Change and Percent Change from Baseline ........................................................17
4.1.3
Visit windows and Time mapping ...................................................................... 17
4.1.4
Handling of drop outs and missing data..............................................................18
4.1.4.1
Missing central lab measurements of S-K...........................................................18


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
5
4.1.4.2
Handling early study discontinuation .................................................................18
4.1.5
Random slope (coefficient) model for log-transformed S-K ...............................19
4.1.6
Logistic regression model for responder analysis................................................20
4.1.7
Kaplan Meier plots............................................................................................. 20
4.1.8
Nonparametric test for time to event variables....................................................20
4.1.9
Descriptive summary of continuous variables.....................................................20
4.1.10
Descriptive summary of categorical variables.....................................................20
4.2
Analysis methods...............................................................................................20
4.2.1
Populations ........................................................................................................ 20
4.2.1.1
Disposition.........................................................................................................20
4.2.1.2
Demographics and baseline characteristics.........................................................20
4.2.1.3
Medical history/Surgical history......................................................................... 22
4.2.2
Extent of Exposure.............................................................................................22
4.2.2.1
Study medication ...............................................................................................22
4.2.2.2
Prior- and concomitant medications ...................................................................22
4.2.2.3
Measurements of Treatment Compliance ...........................................................22
4.2.3
Efficacy .............................................................................................................22
4.2.3.1
Primary efficacy variable ...................................................................................22
4.2.3.2
Key secondary efficacy variables ....................................................................... 24
4.2.3.3
Other secondary efficacy variables.....................................................................25
4.2.4
Safety.................................................................................................................26
4.2.4.1
Adverse events...................................................................................................26
4.2.4.2
Safety laboratory parameters..............................................................................27
4.2.4.3
Vital signs.......................................................................................................... 28
4.2.4.4
ECGs .................................................................................................................29
5.
INTERIM ANALYSES (NOT APPLICABLE).................................................. 29
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................29
7.
REFERENCES (NOT APPLICABLE)...............................................................30
8.
APPENDIX (NOT APPLICABLE).................................................................... 30
LIST OF TABLES
Table 1
Study Plan.............................................................................................11
Table 2
Summary of Serum Potassium Collection Times...................................12
Table 3
Time mapping for serial S-K measurements..........................................18
Table 4
Demographics.......................................................................................21
Table 5
Other baseline characteristics ................................................................21
Table 6
Potentially Clinically Significant Abnormalities for Laboratory 
Values...................................................................................................27


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
6
Table 7
Potentially Clinically Significant Abnormalities for Vital Signs ............28
Table 8
Categorical evaluation of QTc prolongation ..........................................29
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................11


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
CI
Confidence Interval 
CKD
Chronic Kidney Disease
DM
Diabetes mellitus 
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
eGFR
estimated Glomerular Filtration Rate
EOS
End of Study
FAS
Full Analysis Set
ITT
Intent-to-Treat 
IP
Investigational Product 
RAAS
Renin-angiotensin-aldosterone system 
SAE
Serious Adverse Event
SAF
Safety Analysis Set
S-K
Serum potassium
S-Mg
Serum magnesium 
S-Na
Serum sodium 
S-PO4
Serum phosphate 
TEAEs
Treatment-emergent Adverse Events
TID
Three times a day
ZS
Sodium Zirconium Cyclosilicate


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
8
AMENDMENT HISTORY
Date
Brief description of change
19-February-2018
-
Baseline eGFR category (<60, >=60 mL/min/1.73 m2) is taken out from 
primary and key secondary analysis models and from some subgroup 
analyses since the expected number of subjects in eGFR >= 60 mL/min/1.73 
m2 is quite small.
-
Imputation rule for missing central lab S-K based on non-missing i-STAT 
level is modified to reflect assay change in Central lab. 
-
Sensitivity analysis to check the impact of S-K assay change are added.  
-
Cardiac events and Hypertension are added as the AEs of special interest. 
-
Heart Rate was taken out from vital sign section, as it is evaluated as one of 
the ECG parameters.  


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
9
1.
STUDY DETAILS
1.1
Study objectives
Primary Objective:
Outcome Measure:
To assess efficacy of 5 g three times daily 
(TID) and 10 g TID ZS versus placebo in 
Japanese patients with hyperkalemia (serum 
potassium [S-K] ≥ 5.1 mmol/L and ≤ 6.5 
mmol/L).
Exponential rate of change in S-K values during the 
initial 48 hours of study drug treatment.
Secondary Objectives:
Outcome Measures:
Key secondary objective
To evaluate the proportion of subjects who 
achieved normokalemia at 48 hours after start 
of dosing in ZS 5 g TID and 10 g TID groups 
when compared with placebo. 
Key secondary variable
Proportion of patients who achieved normokalemia at 
48 hours after start of dosing
Other secondary objective
To evaluate the efficacy of ZS 5 g TID and 
10 g TID compared with placebo from 
various aspects.
Other secondary variables
!
Exponential rate of change in S-K values during 
the initial 24 hours of study drug treatment 
!
Proportion of patients who achieved 
normokalemia at 24 hours after start of dosing
!
Proportion of patients who achieved 
normokalemia at each scheduled potassium 
assessment time-point after start of dosing
!
Mean change and mean percent change from 
baseline in S-K values at all measured time 
intervals post dose
!
Time to normalization in S-K values
(normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
Safety Objective:
Outcome Measures:
To assess safety and tolerability of 5 g TID 
and 10 g TID ZS versus placebo in Japanese 
patients with hyperkalemia (serum potassium 
[S-K] ≥5.1 mmol/L and ≤ 6.5 mmol/L).
Safety and tolerability as measured by adverse event 
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
10
1.2
Study design
This is a randomized, double-blind, parallel group, multicentre, Phase 2/3 study to determine 
the efficacy and safety of ZS 5g TID and 10g TID versus placebo for correction of 
hyperkalemina in Japanese patients.
Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT (A 
portable blood analyser) potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled 
and randomized 1:1:1 to receive ZS 5 g, ZS 10 g, or placebo TID for 48 hours. Randomization 
will be stratified by screening eGFR (< 60, >=60 mL/min/1.73m2) so that proportion of 
subjects with eGFR >= 60 mL/min/1.73m2 will not exceed 25% of the entire randomized 
subjects.  
Throughout the study most potassium values will be measured at fasting before taking study 
drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 
hours. Potassium level should be determined by both i-STAT and the Central Laboratory on 
all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT 
potassium values, as these provide clinical sites with a real-time measurement. Statistical 
analyses on the study data will in principle be based on serum potassium (S-K) values as 
measured by the central laboratory.
Safety and tolerability will be assessed on an ongoing basis. Standard study assessments 
including blood potassium, clinical chemistry (including calcium, magnesium, sodium, 
phosphate, creatinine, bicarbonate, and blood urea nitrogen [BUN]) and hematology 
parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will 
be assessed during the study at the time points specified in the assessments schedule. All 
women of childbearing potential will have a urine pregnancy test prior to enrollment and at 
their End of Study (EOS) visit.
Stopping rules will be implemented to ensure subjects discontinue the study treatment and 
receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant 
cardiac arrhythmias.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
11
Figure 1
Study flow chart
Placebo TID
10 g TID
Patients with K+ between
5.1 and 6.5 mmol/L, inclusive
Double blind（2days）
5 g TID
R
Follow up
(Day9)
TID: Three times per day
1.2.1
Study Plan 
Table 1 provides an overview of the procedures at each visit in this study. Further details are 
provided in the protocol. 
Table 1
Study Plan
Study Visit
Visit 1
Visit 26
Visit 3
Visit 4
EOS5
Study Day
Screening
Day 16
Day 2
Day 3
Day 95
Written informed consent
X
Eligibility criteria
X
Demographics
X
Medical History
X
Physical exam including weight
X
X
Randomization
X
Access IVRS/IWRS
X
X
Study drug (IP) dispensation
X
Study drug (IP) administration
X
X
ECG
X
X
X
Vital signs
X
X
X
Concomitant medications
X
X
X
X
Adverse events
X7
X
X
X
eGFR
X
Potassium1
X2
X3
X
X


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
12
Table 1
Study Plan
Study Visit
Visit 1
Visit 26
Visit 3
Visit 4
EOS5
Serum Chemistry1
X
X
X
Hematology1
X
X
X
Urinalysis1
X
X
X
Urine HCG
X4
X4
IP Reconciliation
X
1.
All blood potassium samples are analyzed by i-STAT and by the Central Laboratories on all occasions. 
Serum clinical chemistry, including S-K, hematology and urinalysis will be measured fasting and before 
administration of study drug. For diabetic patients all blood potassium samples should be collected prior to 
insulin administration whenever possible
2.
Potassium will be measured twice 60 (±10) minutes apart within 1 day prior to first dose administration, 
and prior to, 1, 2 and 4 hours (±15 min) after administration of the first dose of study drug on Day 1. 
Potassium will be measured again at 90 minutes after taking the second dose for patients with i-STAT 
potassium ≥6.1 mmol/L or <4.0 mmol/L 4 hours after the first dose
3.
Potassium will be measured predose (0 hour), 1 and 4 hour (±15 min) after the first dose on Day 2 (Visit 3)
4.
U-HCG will be performed exclusively for women of childbearing potential. Samples will be analysed 
locally, and the data will not need to be collected in the database. Pregnant women are excluded from the 
study. 
5.
The End of Study (EOS) visit will occur 7±2 day after the last administration of IP.
6.
Baseline parameters should be measured/collected no earlier than 1 day prior to administration of the 1st 
dose of study drug on Day 1 (Visit 2). Visits 1 and 2 may be combined into a single visit on the same day. 
7.
AEs will be collected after the patient has signed informed consent, so during  the Day 1 (Visit 2), 
investigator need to check if any AE happened since from inform consent
1.2.2
Assessment schedule of S-K
Blood samples for determination of potassium will be taken at the times indicated in the Study 
Plan (see Table 1). Potassium samples will be analyzed locally using i-STAT devices, and 
serum samples will be prepared and shipped to the Central Laboratory. All serum samples 
should be examined and any hemolyzed samples MUST be redrawn. In the event that 
hemolyzis 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. Table 2 shows the collection times of serum Potassium.
Table 2
Summary of Serum Potassium Collection Times
Study Day
Time
Central Laboratory
i-STAT
-1 ~ 1
1st assessment to confirm 
qualification (within 1 day of 
the first administration of study 
drug)
1 hour post 1st assessment
X
X1
X
X


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
13
Table 2
Summary of Serum Potassium Collection Times
Study Day
Time
Central Laboratory
i-STAT
1
0 hour (pre-dose)
1 hour post Dose 1
2 hours post Dose 1
4 hours post Dose 1
90 minutes post Dose 2
X
X
X
X
X2
X
X
X
X
X2
2
0 hour (pre-dose)
1 hour post Dose 1
4 hours post Dose 1
X
X
X
X
X
X
3
0 hour
X1
X
EOS
0 hour
X1
X
1
S-K analyzed as part of the serum chemistry assessment.
2
Sample only collected if i-STAT potassium value at the 4-hour post Dose 1 time point was ≥6.1 or <4.0 
mmol/L.
1.3
Number of subjects
Approximately 102 patients will be randomized to ZS 5g TID, ZS 10g TID, and Placebo with 
1:1:1 ratio. 
Sample size for the exponential rate of change during the study is calculated based on a 
random slope model, with parameters estimates based on the ZS-003 data, and here it is 
assumed that K measurement schedule is same as that in study 003 correction phase, i.e. K is 
measured at Baseline(0),1,2,4,24,25,28 and 48 hours post first dose. When the model is fit to 
the ZS-003 data (for only Placebo, ZS5g TID, ZS10g TID groups), with time measured in 
days, the variance of the slope was 0.001053, the variance of intercept was 0.004237, and 
covariance between intercept and slope was -0.00065, and the residual variance was 0.003980. 
Based on these parameters, 34 patients in each ZS dose and Placebo group would provide 
more than 95% power to detect difference of slopes of 0.055/day (assumed for ZS 10g TID vs. 
Placebo) and approximately 83% power to detect the difference in slopes of 0.030/day 
(assumed for ZS 5g TID vs. Placebo), respectively.
For the proportion of normokalemic patients at the end of dosing, 34 patients in each ZS dose 
and Placebo would provide approximately 90% and 66% power to detect the difference in 10g 
TID vs. Placebo and 5g TID vs. Placebo with nominal significance level of 0.05, respectively, 
according to Fisher’s exact test. Here it was assumed that proportion of normokalemic patients 
at 48 hours are 47.8%, 77.6% and 86.4% for Placebo, ZS 5g TID, and ZS 10g TID, 
respectively.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
14
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Enrolled subjects
All subjects who signed informed consent. 
2.1.2
Full analysis set (FAS)
The FAS includes all patients randomized in the study. Patients will be analysed according to 
their randomized treatment assignment. Patients without any post randomization data will not 
be used in any of the inferential analyses, but will be accounted for in summary statistics 
tables.
All efficacy analyses will be performed using the full analysis set (FAS).
2.1.3
Safety analysis set (SAF) 
The safety analysis set will include all patients who took at least one dose of investigational 
products (IP) during the study. Patients will be analysed according to the actual treatment they 
received.  
2.2
Protocol deviations
Protocol deviations will be identified programmatically or manually and reviewed in a blinded 
fashion and documented prior to the un-blinding the study. Subjects who had any important 
protocol deviations will be summarized by treatment group. Important protocol deviations will 
include but not limited to: 
Important protocol deviations would include but not limited to:
∀
Patients who received study drug but did not meet Inclusion/Exclusion criteria
∀
Patients who received prohibited concomitant medication or non-drug therapy 
∀
Patients who received wrong study drug
∀
Study drug compliance < 80% or > 120%.
No protocol deviations will lead to exclusion of randomized subjects from FAS. All efficacy 
analysis will be carried out with FAS following Intent-to-treat principle.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
15
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary efficacy variable
Primary efficacy variable is the exponential rate of change in S-K values during the initial 48 
hours of study drug treatment. 
3.2
Key secondary efficacy variable
Key secondary efficacy variable is proportion of patients who achieved normokalemia (S-K 
between 3.5 and 5.0, inclusive) at 48 hours after start of dosing. 
3.3
Other secondary efficacy variables 
Following secondary efficacy variables will be evaluated. 
!
Exponential rate of change in S-K values during the initial 24 hours of study drug 
treatment 
!
Proportion of patients who achieved normokalemia at 24 hours after start of dosing
!
Proportion of patients who achieved normokalemia at each scheduled potassium 
assessment time-point after start of dosing
!
Mean change and mean percent change from baseline in S-K values at all measured 
time intervals post dose
!
Time to normalization in S-K values (normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
3.4
Safety variables
Safety evaluation will be done with the following variables. 
!
Adverse events
!
Safety Laboratory parameters
!
ECGs
!
Vital Signs 
4.
ANALYSIS METHODS
4.1
General principles
The SAS® software, version 9.2 or higher, will be used in order to generate all the statistical 
outputs. 


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
16
Unless otherwise specified, all efficacy analyses will be carried out on the FAS and all safety 
analyses will be based on the Safety set. Efficacy summary results during the treatment phase 
will be presented based on randomized treatment group (ZS 10g TID, ZS 5g TID or placebo).  
Safety summary results will be presented based on treatment they actually received. For 
Safety analysis, if a patient receives more than one treatment, they will be analysed according 
to the highest dose of study medication received. 
Continuous variables will be summarized by descriptive statistics, including number of non-
missing observations (n), mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages. Results of 
statistical analyses will be presented using a 95% confidence interval (CI) and two-sided p-
value, unless otherwise stated. 
4.1.1
Objectives and hypotheses 
The primary objective of this study is to demonstrate the superiority of ZS 10g TID and 5g 
TID to placebo in correction of hyperkalemia, as measured by the exponential rate of change 
through to 48 hours. Here, the exponential rate of change refers to the slope coefficient when 
longitudinal S-K measurements in log scale were regressed on time. The detail about model 
specification is provided in section 4.1.5.
The null hypothesis family is composed of two elementary hypotheses. 
H0,L : 
P
L
#
#
∃
H0,H : 
P
H
#
#
∃
The alternative hypotheses are complements of them. 
HA,L : 
P
L
#
#
%
HA,H : 
P
H
#
#
%
, where 
P
#
, 
L
#
, and 
H
#
are exponential rate of change in Placebo, ZS 5g TID group, and 
ZS 10g TID group, respectively. 
To protect family wise error rate (FWER) at 5%, hierarchical testing strategy will be 
employed. Confirmatory testing will proceed with the sequential order as specified below. 
Each individual statistical comparison will be conducted with two-sided significance level of 
0.05. 
Step 1: Compare exponential rate of change through 48 hours between ZS 10g TID vs. 
Placebo, 
Step 2: Compare exponential rate of change through 48 hours between ZS 5g TID vs. Placebo.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
17
4.1.2
Definitions
4.1.2.1
Baseline Value
For S-K, baseline value will be established by taking the mean of 2 different S-K values, 
recorded 60 minutes apart (to confirm qualification for randomization) and then averaged with 
the last S-K value taken just before administration of the first dose (0-hr) on Study Day 1.
For the other variables (excluding S-K), baseline value of a parameter (eg, safety laboratory 
test, ECG or vital signs, etc) is defined as the last assessment of that parameter prior to the 
start date and time of the first dose of the double-blind study medication.
4.1.2.2
Change and Percent Change from Baseline
Change from baseline to any Time t in correction phase double-blind treatment period is 
defined as follows:
CTime t = MTime t - Mbaseline ,
where:
!
CTime t is the change from baseline at Time t,
!
MTime t is the measurement at Time t,
!
Mbaseline is the measurement at baseline.
Percent change from baseline to any Time t in correction phase double-blind treatment period 
is defined as follows:
PTime t =100×(MTime t - Mbaseline) / Mbaseline .
Where PTime t is the percent change from baseline at Time t, and MTime t and Mbaseline are defined 
as above.
4.1.3
Visit windows and Time mapping
In principle, efficacy analyses will be based on nominal scheduled visit/time basis in efficacy 
evaluation. For the safety evaluation of incidence of events (e.g. hypokalemia) any post-
baseline measurements regardless of scheduled or unscheduled will be included in analyses. 
The scheduled S-K time will be mapped to time in hours relative to first dose of ZS to include 
in efficacy analysis model. S-K Measurements taken after Hour 48 (Day 3, 0 hour) will not be 
included in main efficacy analysis, but EOS (Day 9) visit will be separately presented.   


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
18
Table 3
Time mapping for serial S-K measurements
Study Day
Time
Mapped time (Hours) 
for Analysis
-1 ~ 1
1st assessment to confirm qualification (within 1 day of the first 
administration of study drug)
0*
(Baseline) 
-1 ~ 1
1 hour post 1st assessment
1
0 hour (pre-dose)
1
1 hour post Dose 1
1
1
2 hours post Dose 1
2
1
4 hours post Dose 1
4
1
90 minutes post Dose 2
5.5
2
0 hour (pre-dose)
24
2
1 hour post Dose 1
25
2
4 hours post Dose 1
28
3
0 hour
48
*
Baseline S-K will be derived as outlined in section 4.1.2.1
4.1.4
Handling of drop outs and missing data
4.1.4.1
Missing central lab measurements of S-K
In the event of missing S-K data from the central laboratory, the i-STAT data will be used to 
replace missing data by adjusting for the average paired difference between the central and i-
STAT levels collected at the same timepoint. As illustration of the change methodology, if the 
mean difference between central laboratory and i-STAT assessments for all patients with both 
values available at the relevant visit is 0.12 mmol/L higher for the central laboratory 
assessment, then 0.12 mmol/L will be added to the i-STAT level to impute the missing central 
laboratory assessment.
The above imputation procedure for missing central lab S-K based on non-missing i-STAT 
level will be carried out separately for samples tested on or before 3rd-December-2017 and for 
samples tested on or after 4th-December-2017. 
If both central lab S-K and i-STAT are missing, the measurement at that visit/timepoint will 
be left as missing.
4.1.4.2
Handling early study discontinuation
Whether subjects completed or discontinued the study, all available data taken up to Hour 48 
(Day 3, 0 hour) will be included in the efficacy analysis. The EOS visit (Day 9 or last dose + 7 
days) will be additionally displayed in the by-visit summary. 


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
19
4.1.5
Random slope (coefficient) model for log-transformed S-K
Exponential rate of change in S-K through to T (=48 or 24) hours will be analysed with the 
following mixed effect model (random slope model). SAS procedure PROC MIXED will be 
used. 
0
1
2
(
)
(
)
(
)
ijk
ij
i
i
ij
k
ijk
Ln Y
a
L
H
b
t
&
#
#
#
∋
∃
(
(
(
(
(
)
(
Where
!
Yijk is the kth measurement (at Time tk) of subject j in treatment group i 
!
& is the fixed intercept
!
aij is random intercept for subject j in treatment i
!
0
#
is fixed slope on time t for reference group (Placebo)
!
1
#
is fixed slope difference of ZS 5g TID to reference group (Placebo)
!
2
#
is fixed slope difference of ZS 10g TID to reference group (Placebo)
!
Li =1 if subject is in ZS 5g TID and Li=0 otherwise. 
!
Hi = 1 if subject is in ZS 10g TID and Hi=0 otherwise
!
bij is random slope on time t for subject j in treatment i 
!
Discrete Time tk spans as follows, and will be regarded as continuous variable in the 
models. 
∀
from 0 to 48 hours (0, 1, 2, 4, 5.5,24, 25, 28, and 48 hours) in primary analysis 
model,
∀
from 0 to 24 hours (0, 1, 2, 4, 5.5, and 24 hours) in secondary analysis model
Subject-level random effects (aij and bij) are assumed to be bivariate normally distributed with 
mean zeros, independent of random error. An unstructured covariance will be specified in 
MIXED procedure. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. 
The estimate of treatment difference in slopes (coefficients for the time x treatment interaction 
for each dose) with its 95%CI as well as two-sided p-values for pairwise comparison to 
placebo will be presented for both ZS 10g TID and ZS 5g TID groups. 


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
20
4.1.6
Logistic regression model for responder analysis
Dichotomous variables (e.g. proportion of patients who achieved normokalemia at 48 hours 
after start of dosing) will be analysed with logistic regression model, including treatment as a 
factor and baseline S-K as a covariate. Subjects with missing S-K at that time point will be 
counted as non-responders. Odds ratio and its 95%CI as well as nominal two-sided p-values 
will be presented for each pairwise comparison (ZS 10g TID vs. Placebo and ZS 5g TID vs. 
Placebo). 
4.1.7
Kaplan Meier plots
Kaplan-Meier plots of time to event variables (e.g. time to normokalemia) will be displayed 
by treatment group.  
4.1.8
Nonparametric test for time to event variables
Time to event variables (e.g. time to normokalemia) will be analysed with log-rank test and 
nominal p-value will be provided for pairwise comparisons for each ZS dose vs. Placebo. 
4.1.9
Descriptive summary of continuous variables
Descriptive summary of continuous variables includes n, mean, standard deviation (SD), 
median, minimum and maximum. 
4.1.10
Descriptive summary of categorical variables
Descriptive summary of categorical variables will consist of frequencies and percentages. 
4.2
Analysis methods
4.2.1
Populations
4.2.1.1
Disposition
The disposition of subjects for the enrollment period, double-blind treatment period and 
follow-up period will be summarized. The summary of disposition for the enrolment period 
will include all Enrolled subjects (who signed informed consent). 
The summary of disposition for double-blind treatment period will include FAS. This 
summary will include subjects completing and discontinuing the double-blind treatment 
period, broken down by reason for the discontinuation. 
The summary of disposition for follow up period will include FAS. This summary will include 
subjects completing and discontinuing the follow up period, broken down by reason for 
discontinuation. 
4.2.1.2
Demographics and baseline characteristics 
Demographic and other baseline characteristics, including disease-related characteristics will 
be summarized by treatment group and overall, using the FAS.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
21
Demographic and baseline characteristics are listed in Table 4. Other disease related baseline 
characteristics are listed in Table 5.
Table 4
Demographics
Characteristic
Summarized as
Categories
Sex
Categorical
Male, Female
Age
Categorical and Continuous
< 55 years
55-64 years
>= 65 years
Body Weight 
Categorical and Continuous
< 50, >= 50 kg
BMI
Continuous
-
Height
Continuous
-
Race
Categorical
Asian, Other
Table 5
Other baseline characteristics
Characteristic
Summarized as
Categories
Baseline S-K 
Categorical and Continuous
<= 5.3 mmol/L
5.4-5.5 mmol/L
> 5.5 mmol/L 
Baseline eGFR
Categorical and Continuous
< 15 mL/min/1.73 m2
15-<30 mL/min/1.73 m2
30-<60 mL/min/1.73 m2
>= 60 mL/min/1.73 m2
< 60 mL/min/1.73 m2
>= 60 mL/min/1.73 m2
Comorbidity –Heart Failure
Categorical 
Yes, No 
Comorbidity – Diabetes
Categorical
Yes, No
Comorbidity – CKD 
Categorical
Yes, No
RAAS Inhibitor Use 
Categorical
Yes, No
Diuretic Use
Categorical
Yes, No
*eGFR derived by Japan guideline formula; 
∗
+
2
1.094
0.287
eGFR[mL/min/1.73m ]
194 SCr[mg/ dL]
Age[years]
0.739forfemale
∀
∀
∃
,
,
,
All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentages will be calculated out of the total number of subjects in 


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
22
the analysis set (ie, each denominator includes the number of subjects with missing/unknown 
values for the characteristic).
4.2.1.3
Medical history/Surgical history 
The number (%) of subjects with each past and current medical histories as well as surgical 
history will be summarized by system organ class (SOC) and preferred term (PT) using SAF. 
4.2.2
Extent of Exposure 
4.2.2.1
Study medication
Duration of exposure (defined as the last dose date – first dose date + 1), and number of doses 
taken (for overall and for each of Day 1 and 2) will be summarized by categorical/continuous 
descriptive statistics, using SAF. 
4.2.2.2
Prior- and concomitant medications
Prior medications are defined as medications taken within 1 week before the first dose of 
study medication. Concomitant medications are defined as treatments taken during treatment 
period (any medications taken between the first dose of ZS and EOS visit). The medications 
continuing before 1st dose of ZS will be counted both as a prior medication and as a 
concomitant medication. All prior medication and concomitant medications will be coded 
with the WHO Drug Dictionary, and summarized by treatment group by safety set. The 
number and percentage of patients with prior and concomitant medications will be tabulated
by Anatomic Therapeutic Chemical classification system (ATC) Term and Drug Preferred 
Name. 
4.2.2.3
Measurements of Treatment Compliance
Percent treatment compliance is calculated. For each type of medication, percent compliance 
is defined as the number of sachets actually taken divided by the number of sachets that 
should have been taken. A subject is considered compliant if percent compliance is ≥ 80% and 
≤ 120%. 
4.2.3
Efficacy
4.2.3.1
Primary efficacy variable 
The primary efficacy variable in exponential rate of change in S-K through to 48 hours post 
dose. 
The primary efficacy analysis will be carried out for Full Analysis Set. 
The primary efficacy analysis for the exponential rate of change in S-K through to 48 hours 
post dose will be based on the random coefficient model including all the serial S-K 
measurement from baseline to 48 hours as response variable and time and time x treatment 
interaction as fixed continuous effect. In addition, subject-level random effects for intercept 
and time will be included (section 4.1.5).


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
23
The estimates of treatment difference in slopes (coefficients for the time by treatment 
interaction for each dose) with its 95%CI as well as two-sided p-values for pairwise 
comparison to placebo will be presented for both ZS 10g TID and ZS 5g TID groups. The 
confirmatory testing will proceed with a sequential manner (ZS 10g TID first, then ZS 5g 
TID) as specified in section 4.1.1. 
Sensitivity analysis of primary efficacy analysis
Missing mechanism
The primary efficacy model would provide inference based on direct likelihood, which 
implicitly assumes Missing At Random (MAR) for missing mechanisms.
The discontinuation rate is expected to be minimal due to the short treatment duration of the 
treatment period. Hence the following analyses would be carried out only if the early 
discontinuation of treatment period exceeded 10% in any treatment group (in any ZS 
treatment group for the latter one). Depending on the volume of missing data as well as on the 
discontinuation reasons, further sensitivity analyses may be performed.
!
Completer case analysis, where only subjects who completed Day 3 assessment will 
be included. 
!
Multiple imputation with Jump to Reference (Placebo) assumption for ZS treatment 
groups.
Analysis with S-K adjusted for assay change bias
Assay for S-K in 
 was updated during the study, on 4th December 2017.  A sensitivity 
analysis will be performed by subtracting the average bias (0.208 mmol/L) between the old 
and the new assays from all the Central lab S-K measurements analysed by the new assay. 
Primary analysis will be repeated on this new dataset containing all original S-K 
measurements analysed by the old assay and the adjusted measurements analysed by the new 
assay, i.e. 
∀
S-K (adjusted) =S-K (reported) for data measured by old assay
∀
S-K (adjusted) =S-K (reported) – 0.208 mmol/L for data measured by new 
assay 
By doing this, the adjusted measurements will be on the same "level" as the S-K 
measurements analysed by the old assay, and results will reflect what could have been 
observed had the assay not been changed.
Analysis with iSTAT values


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
24
!
The same analysis as primary efficacy analysis using iSTAT potassium values 
instead of S-K measured by Central lab 
Different set of covariates 
!
The same analysis as primary efficacy analysis model using different set of baseline 
covariates. Following fixed effects will be added to the primary model. 
: Age category (<55, 55-64, >= 65 years), baseline eGFR (as continuous), binary 
indicators for DM, CKD, HF and RAASi usage. This is the same model as used in 
the study ZS-003.
Subgroup analysis of primary efficacy variable 
The primary efficacy analysis model will be repeated with the following subgroups.
!
Patients with or without Heart Failure (HF) 
!
Patients with or without Diabetes Mellitus (DM)  
!
Patients with or without Chronic Kidney Disease (CKD)
!
Patients treated or not treated by RAAS inhibitors 
4.2.3.2
Key secondary efficacy variables
Proportion of normokalemic patients at 48 hours post initial dose will be analyzed by logistic 
regression model. The model will include treatment as a factor and baseline S-K as a 
covariate. In this analysis, a subject who did not have S-K measurement at 48 hours are 
treated as a non-responder (not normokalemic).
The estimated odds ratio and its 95%CI as well as nominal two-sided p-values for pairwise 
comparisons for ZS 10g TID vs. Placebo and ZS 5g TID vs. Placebo will be provided from the 
above logistic model. 
Further, the same logistic regression analysis for key secondary variable will be repeated (1) 
with S-K values adjusted for assay change bias as well as (2) with iSTAT potassium 
measurements.
Subgroup analysis of key secondary variable
The logistic regression model will be repeated with the following subgroups.
!
Patients with or without Heart Failure (HF)
!
Patients with or without Diabetes Mellitus (DM)  
!
Patients with or without Chronic Kidney Disease (CKD)


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
25
!
Patients treated or not treated by RAAS inhibitors  
4.2.3.3
Other secondary efficacy variables
!
Exponential rate of change in S-K values during the initial 24 hours of study drug 
treatment
The primary model used for primary efficacy analysis (section 4.1.5) will be repeated for the 
serum Potassium measurements from baseline to 24 hours post dose. Only data up-to 24 hours 
post dose will be included in this analysis. 
!
Proportion of patients who achieved normokalemia at 24 hours after start of dosing
The logistic regression model used for key secondary variable (section 4.1.6) will be repeated 
using the patients with normokalemia at 24 hours as a response variable. Patients with missing 
S-K at 24 hours will be handled as non-responder (not normokalemic). 
!
Proportion of patients who achieved normokalemia at each scheduled potassium 
assessment time-point after start of dosing
Number (%) of subjects who achieved normokalemia at each scheduled time point and EOS 
visit will be provided by treatment group. 
The same descriptive summary will be provided by baseline by baseline eGFR category ( <15, 
15-<30, 30-<60, >= 60 mL/min/1.73m2), by baseline S-K (< 5.3, 5.3-5.5,  > 5.5 mmol/L), and 
by subjects with or without each of comorbidities/mediation use (CKD, HF, DM, RAASi use)
!
Mean change and mean percent change from baseline in S-K values at all measured 
time intervals post dose
Descriptive summary will be provided by time for the values measured at each time point and 
EOS visit, change from baseline as well as percent change from baseline will be displayed. 
The same descriptive summary will be provided by baseline by baseline eGFR category ( <15, 
15-<30, 30-<60, >= 60 mL/min/1.73m2), by baseline S-K (< 5.3, 5.3-5.5,  > 5.5 mmol/L), and 
by subjects with or without each of comorbidities/mediation use (CKD, HF, DM, RAASi use)
!
Time to normalization in S-K values (normalization defined as S-K values between 
3.5 and 5.0 mmol/L, inclusive).
Kaplan-Meier plot for cumulative percentage who achieved normokalemia will be provided. 
The subjects who did not achieve normokalemia until Hour 48 will be censored at the time 
point when the last available S-K measurement was obtained at or before Hour 48. Median 
time to normalization (hours) will be produced. Treatment comparison for each ZS dose vs. 
Placebo is carried out with log rank test and nominal two-sided p-values will be presented.
!
Time to a decrease in S-K levels of 0.5 mmol/l


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
26
Kaplan-Meier plot for cumulative percentage who achieved S-K decrease by 0.5 mmol/l will 
be provided. Median time to S-K decrease by 0.5 mmol/L (hours) will be produced. Treatment 
comparison for each ZS dose vs. Placebo is carried out with log rank test and nominal two-
sided p-values will be presented.
4.2.4
Safety
The Safety set will be used for all safety analyses. Safety data will be presented with 
descriptive summary by treatment group.
4.2.4.1
Adverse events 
Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs 
with an onset date on or after first dose of IP but on or before the Day 3 will be considered as 
treatment-emergent AEs (TEAEs). TEAEs will be analysed and evaluated. AEs starting before 
Day 1 will only be listed. Off-treatment AEs (AEs starting on or after Day 4) will be 
separately summarized as necessary. 
All Adverse events (including SAEs)
Summary of following TEAEs will be presented by SOC and PT. Number and proportion of 
subjects with these events will be provided.
!
Any AEs 
!
Adverse events by preferred term and treatment group 
!
Deaths
!
Serious AEs (SAEs) 
!
AEs leading to drug discontinuation (DAEs)
!
AEs by maximal intensity
!
AEs related to study drug
Off -treatment AEs (AEs starting on or after Day 4) will be analysed by SOC and PT.  
!
Any AEs 
!
AEs related to study drug
Adverse events of special interest (AEOSI)
Oedema-related events


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
27
Oedema related event will be defined as any of the following events (PT): Fluid overload, 
Fluid retention, Generalised oedema, Hypervolaemia, Localised oedema, Oedema, Oedema 
peripheral and Peripheral swelling.
Cardiac Failure 
Cardiac Failure will be searched by SMQ “Cardiac Failure” (narrow). 
Hypertension 
Hypertension will be searched by SMQ “Hypertension” (narrow). 
Treatment-emergent Oedema-related events, Cardiac Failure and Hypertension will be 
summarized by PT using as number (%) of subjects with events.
4.2.4.2
Safety laboratory parameters 
Change from baseline over time
For continuous variables, observed values and changes from baseline to Day 3 and Day 9 
(EOS) will be summarized by descriptive statistics.
For categorical variables, shift table from baseline to Day 3 and Day 9 will be summarized by 
number (%) of subjects with each category. 
Laboratory abnormalities 
The incidence of hypokalemia will be evaluated by tabulating the proportion of subjects with 
a lowest S-K assessment (regardless of scheduled or unscheduled, during Day 1-3 and during 
Day 4-EOS) <3.5 mmol/L and will be repeated for a more severe definition of < 3.0 mmol/L. 
Other potentially clinically significant laboratory abnormalities will also be identified based 
on the most extreme (lowest and/or highest) post-baseline values (during Day 1-3 and during 
Day 4-EOS) and tabulated with number and proportion of subjects meeting each criterion. 
Table 6
Potentially Clinically Significant Abnormalities for Laboratory Values
Variable
Unit
Low
High
Chemistry
Calcium
mg/dL
< 7.0
> 11.0
Inorganic Phosphorus
mg/dL
< 2.0
> 6.5
Albumin
g/dL
< 2.0
> 6.0 
Bicarbonate
mmol/L
< 15
> 35
Glucose
mg/dL
< 60
> 300
Potassium
mmol/L
< 3.0
> 6.0


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
28
Variable
Unit
Low
High
Sodium
mmol/L
< 120
> 160
Total Protein
g/dL
< 4.0
> 10.0
Magnesium
mg/dL
< 0.9
> 4.0
ALP
IU/L
-
> 3xULN
GGT
IU/L
-
> 3xULN
AST
IU/L
-
> 3xULN
ALT
IU/L
-
> 3xULN
Total Bilirubin
mg/dL
-
> 3xULN
Hematology
Hematocrit
%
< 28
> 55
Hemoglobin
g/dL
< 8
> 20
Platelet Count
x 10^9/L
< 50
> 600
WBC
x 10^9/L
< 2.0
> 14
4.2.4.3
Vital signs 
Summary statistics for changes from baseline to Day 3 and Day 9 (EOS) for each parameter 
(SBP, DBP, HR and body weight) by treatment group will be provided.
In addition, potentially clinically significant abnormal changes at any time post-baseline
(during Day 1-3 and during Day 4-EOS) will be summarized with number of subjects and 
proportions. 
Table 7
Potentially Clinically Significant Abnormalities for Vital Signs
Parameter
Direction 
Criterion
SBP
Low
Value <= 90 mmHg and decreased >= 20 mmHg from 
baseline
High
Value >= 180 mmHg and increased >= 20 mmHg from 
baseline
DBP
Low
Value <= 50 mmHg and decreased >= 15 mmHg from 
baseline
High
Value >= 105 mmHg and increased >= 15 mmHg from 
baseline


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
29
4.2.4.4
ECGs 
Number of subjects with clinically significant abnormality (as assessed by investigator) will 
be summarized for baseline and post-baseline visits (Day 3 and Day 9 (EOS)). 
Summary statistics for changes from baseline to Day 3 and Day 9 (EOS) for each parameter 
(heart rate (HR), P, PR, QRS, QT and QTcB and QTcF) will be provided. Here QTcB and 
QTcF will be derived by below formula. 
1/2
1/3
,
(60 / HR)
(60 / HR)
QT
QT
QTcB
QTcF
∃
∃
where, QT is in msec and HR is in bpm. 
Abnormal prolongation of QTc (QTcB and QTcF) will be summarized based on criteria
specified in the table below. The most extreme (highest) value for a subject during treatment
(during Day 1-3 and during Day 4-EOS) will be used in this summary.
Table 8
Categorical evaluation of QTc prolongation
Parameter
Criterion
QTcB, QTcF
>450 msec
>480 msec
>500 msec
Change from baseline in QTcB, QTcF
>30 msec 
>60 msec
5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Additional efficacy variable of “Time to a decrease in S-K levels of 0.5 mmol/l” is added as 
one for the other secondary efficacy variables. 
Baseline eGFR category is taken out from the primary and key secondary analysis models, 
since it was anticipated that extremely small number of subjects would be available in eGFR > 
60 mL/min/1.73 m2 stratum.


Statistical Analysis Plan 
Study Code D9482C00002
Edition Number 2.0
Date 19-Feb-2018
30
7.
REFERENCES (NOT APPLICABLE)
8.
APPENDIX (NOT APPLICABLE)