Clinical trial NCT03172702
Conditions: Hyperkalemia
Sponsor: AstraZeneca
Start date: 2017-09-04; Completion date: 2019-07-06
Enrollment: 150 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The Open-Label Maintenance Study contains an Correction Phase, in which subjects will be dosed with ZS 10 g three times daily (tid) for 24 to 72 hours, followed by a 12-month long-term Maintenance Phase.

Detailed description:
The study will start with the screening period, and all baseline parameters should be measured/collected up to 1 day prior to administration of first dose of study drug on Correction Phase Day 1. Subjects with 2 consecutive i-STAT potassium values ≥ 5.1 mmol/L will enter the Correction Phase and receive ZS 10 g TID for up to 72 hours, depending on potassium values. Once normokalemia (i-STAT potassium between 3.5 and 5.0 mmol/L, inclusive) is restored (whether after 24, 48 or 72 hours), subjects will be entered into the Maintenance Phase to be dosed with ZS at a starting dose of 5 g QD. Potassium (i-STAT and Central Laboratory) will be measured Days 1, 2, 5, 12, 19 and 26 throughout the first month of study and every 4 weeks thereafter until Day 362 (Visit 23) then patients will be required to complete the EOS visit which is 7±1 days after the last administration of study medication. For patients who do not enter the Maintenance Phase the last visit will be 7±1 day after the last treatment dose in the Correction Phase. The total expected study duration for an individual patient is approximately 53-54 weeks.

Arms: arm 1: Correction Phase Dosing: Sodium Zirconium Cyclosilicate 10 g three times daily (TID) from 24 to 72 Extended Dosing: Sodium Zirconium Cyclosilicate 5 g once daily (QD). Sodium Zirconium Cyclosilicate dose increased or decreased in increments/decrements of 5 g QD up to a maximum of 15 g QD or a minimum of 5 g every other day (QOD) (or 2.5 g QD) based on i-STAT potassium measurements up to 12 months.
Interventions: intervention 1: Zirconium Cyclosilicate
Intervention descriptions: intervention 1: Correction Phase Dosing: Sodium Zirconium Cyclosilicate 10 g three times daily (TID) from 24 to 72 Extended Dosing: Sodium Zirconium Cyclosilicate 5 g once daily (QD). Sodium Zirconium Cyclosilicate dose increased or decreased in increments/decrements of 5 g QD up to a maximum of 15 g QD or a minimum of 5 g every other day (QOD) (or 2.5 g QD) based on i-STAT potassium measurements up to 12 months.

Protocol documents:
Prot_001.pdf: 
A Phase 3 Multicenter Open-label Maintenance Study to Investigate the 
Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese 
Subjects With Hyperkalemia
Sponsor:  AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan
Clinical Study Protocol
Drug Substance
ZS
Study Code
D9482C00001
Version
5.0
Date
13 Sep 2018


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
2 (90)
VERSION HISTORY
Version 5.0, 13 September 2018
Changes to Clinical Study Protocol version 4.0 [28 March 2018] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
2.3 Exploratory 
objectives
“To explore change in doses and reasonings of 
the change of RAAS inhibitors during the 
treatment period” was added.
To add a new 
Exploratory objective
3.9 Discontinuation of 
investigational product
Discription about IP discontinuation critera related to 
potassium value was ammended
Clarification
3.9 Discontinuation of 
investigational product
Paragraph indent was ajusted
Clarification
3.9 Discontinuation of 
investigational product
Explanation that visit5 or visit 23 procedure is 
required for patients discontinuing IP was added.
To collect the end 
of treatment data
3.11 Interruption  of 
investigational product  
The section was added
To make it possible 
to interrupt IP when 
necessary
4. STUDY PLAN 
AND TIMING OF 
PROCEDURES
Annotation text #9 in Table 2 was removed.
Pationt questionnaire at EOS visit was removed
To align with the 
change in section 
3.9 (visit5 or visit 
23 procedure for 
patients 
discontinuing IP)
4.2.1 Correction Phase 
Day 1 (Visit 2)
Explanation that hematology and clinical chemistry 
samples can be collected at the same time as iSTAT 
sample collection was added
To reduce 
patioents’ burden 
associated with 
frequent 
needlepick.
4.2.7
Maintenance 
Phase Day 5 (Visit 8)
4.2.8
Maintenance 
Phase Day 12 (Visit 9)
4.2.9
Maintenance 
Phase Day 19 (Visit 
10)
4.2.10
Maintenance 
Phase Day 26- Day 334 
(Visit 11- Visit 22)
IP doses in sentences which describe situations 
requiring a second potassium measurement were 
corrected
Correction of error 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
3 (90)
Version 5.0, 13 September 2018
Changes to Clinical Study Protocol version 4.0 [28 March 2018] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
4.3 Follow-up period 
(EOS)
Paragraph about patient questionnaire was removed
To align with the 
change in section 
3.9 (visit5 or visit 
23 procedure for 
patients 
discontinuing IP)
7.2 Dose and treatment 
regimens
7.7 Concomitant and 
other treatments
Allowed visit window for an extra visit has been 
changed from “±1” to “±2”.
To increase 
flexibility
7.2 Dose and treatment 
regimens
7.7 Concomitant and 
other treatments
Restrictions that patients should follow for an extra 
visit has been added.
To obtain  
appropriate 
investigational 
results
7.7 Concomitant and 
other treatments
Additional data collected related to concomitant 
medication was described. 
To align with 
newly added 
Exploratory 
objectives
Version 4.0, 28 March 2018
Changes to Clinical Study Protocol version 3.0 [26 September 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
3.2 Exclusion criteria
“Washout of SPS and CPS for 7 days (or longer) 
prior to the first dose of ZS is allowed, if termination 
of CPS or SPS is judged to be clinically acceptable 
by the investigator. Documented informed consent 
has to be obtained prior to the washout.” was added 
to exclusion criteria #4.
To clarify that 
SPS/CPS can be 
discontinued before 
study participation 
and IC has to be 
obtained before the 
discontinuation.
4.1
Screening/Enrolment 
period (Visit 1)
“The following rule will be applied for the patient 
who will be ineligible due to the deviation of 
inclusion criteria No. 3. If the patient is expected to 
meet the eligibility criteria based on the patient‘s 
disease condition, the patient can be re-enrolled 
(including one re-screening) only once after 30 days 
To allow inclusion 
of patients showing 
fluctuation of blood 
K+ concentration. 
One re-enrollment 
is not considered to 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
4 (90)
Version 4.0, 28 March 2018
Changes to Clinical Study Protocol version 3.0 [26 September 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
or later from the screening failure. In this case, new 
enrolment number will be allocated to the patient” 
was added.
be a risk to the 
patient's 
opportunity for 
other treatment or 
the purpose of the 
study.
Version 3.0, 26 September 2017
Changes to Clinical Study Protocol version 2.0 [11 May 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
CLINICAL STUDY 
PROTOCOL 
SYNOPSIS 
Objectives
2.3
Exploratory 
objectives
4
STUDY 
PLAN AND 
TIMING OF 
PROCEDURES
4.2.11 Maintenance 
Phase Day 362 (Visit 
23)
4.3
Follow-up 
period (EOS)
Appendix D
Exploratory objective, the adherence questionnaire 
was added.
Exploratory 
objective was 
added.
3.2
Exclusion 
criteria
“Non peritoneal dialysis (PD) patients only” was 
added.
To clarify the study 
procedure.
4
STUDY 
PLAN AND 
TIMING OF 
PROCEDURES
Table 2
Footnote 5 was amended. 
Visit allowance 
was expanded to 
provide flexibility.
4.2.2
Correction 
Phase Day 2 (Visit 3)
“1 hour (± 15 min) after first serum potassium 
measurement a potassium sample (i-STAT and 
Central Laboratory) will be collected. “ was added if 
To align with 
Figure 4.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
5 (90)
Version 3.0, 26 September 2017
Changes to Clinical Study Protocol version 2.0 [11 May 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
the i-STAT potassium value is between 3.0 and 3.4 
mmol/L inclusive.
4.2.6
Maintenance 
Phase Day 2 (Visit 7) 
~ 
4.2.11 Maintenance 
Phase Day 362 (Visit 
23)
‘The time’ was changed to ‘when’ from phrase 
“examine the returned investigational product sachets 
and make note of the time the doses were taken and 
any unused investigational products on the eCRF and 
source documents.”
Correction of error. 
The Dosing time 
will not be 
collected. 
4.2.6
Maintenance 
Phase Day 2 (Visit 7)
4.2.7
Maintenance 
Phase Day 5 (Visit 8)
4.2.9
Maintenance 
Phase Day 19 (Visit 
10)
boxes was deleted from “examine the returned 
investigational product boxes.”
Correction of error 
5.2.3.1 Resting 12-
lead ECG
or <4.0 mmol/L was added.
To align with 
Figure 4.
7.7.1
Oral 
medications with 
gastric pH-dependent 
bioavailability
This section was included.
Updated 
information was 
added.
Version 2.0, 11 May 2017
Changes to Clinical Study Protocol version 1.0 [09 March 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
4
STUDY 
PLAN AND 
TIMING OF 
PROCEDURES
Table 2
Added the assessment of serum chemistry on Visit 6 
and footnote 8.
To clarify the study 
procedure.
4.2.1
Correction 
Phase Day 1 (Visit 2)
Order of SF-36 v2 questionnaire was changed and 
added sentence.
To clarify the study 
procedure.
4.2.5
Maintenance 
Phase Day 1 (Visit 6)
5.2.1
Laboratory 
Added Clinical chemistry.
To align with Table 
2 changes


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
6 (90)
Version 2.0, 11 May 2017
Changes to Clinical Study Protocol version 1.0 [09 March 2017] are summarised below.
Section, Heading
Revision Summary
Reason for 
Revision
safety assessments
4.2.11 Maintenance 
Phase Day 362 (Visit 
23)
Order of SF-36 v2 questionnaire was changed and 
added sentence.
To clarify the study 
procedure.
5.10
Volume of 
blood
Table 5
Number of Samples and Maximum blood volume 
Total (mL) were updated. Added Visit 6 in footnote 
1.
To align with Table 
2 changes
Version 1.0, 9 March 2017
Initial creation


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
7 (90)
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.


8 (90)
CLINICAL STUDY PROTOCOL SYNOPSIS
A Phase 3 Multicenter Open-label Maintenance Study to Investigate the 
Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese 
Subjects With Hyperkalemia
Principal Investigator(s)
See Addendum.
Study site(s) and number of patients planned
This study will be conducted in approximately 30 centers in Japan. The primary objective of 
this Japanese study is to assess the safety and tolerability of long-term treatment of ZS flexible 
dose regimen (initial dose 5g once daily [QD] then up- or down- titrated based on the 
potassium level) for 12 months. In total 150 subjects will be entered into the Correction Phase 
to have approximately 100 subjects treated for 1 year, assuming a drop-out rate of around 
35%. 
Study period
Phase of development
Estimated date of first patient enrolled
Q2 2017
Phase III
Estimated date of last patient completed
Q3 2019
Study design
The study is an open label, single arm study with flexible dose regimen focused on assessing 
long-term safety and tolerability of ZS in Japanese subjects with hyperkalemia.
Correction Phase: If the subject is normokalemic (i-STAT [A portable blood analyser] 
potassium between 3.5 and 5.0 mmol/L, inclusive) on the morning of Correction Phase Study 
Day 2 after 3 doses of ZS 10 g, they will enter the Maintenance Phase. If the subject is not 
normokalemic, they will receive an additional 24 hours of ZS 10 g TID treatment (6 total 
doses). If the subject’s i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, on 
the morning of Correction Phase Study Day 3, the subject will enter the Maintenance Phase. If 
the subject is not normokalemic, they will receive an additional 24 hours of ZS 10 g TID 
treatment (9 total doses). If the subject’s i-STAT potassium value is between 3.5 and 5.0 
mmol/L, inclusive, on the morning of Correction Phase Study Day 4, the subject will enter the 
Maintenance Phase. If the i-STAT potassium value is still < 3.5 mmol/L or ≥ 5.1 mmol/L on 
the morning of Correction Phase Study Day 4, after 72 hours of TID treatment, the subject 
will be withdrawn from the study and referred to their normal health care provider for 
standard of care treatment. Subjects withdrawn from the Correction Phase of the study will 
return to the clinic 7 (± 1) days after their last dose of ZS for an End of Study (EOS) visit.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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Maintenance Phase: Patients will initially be dosed with ZS at a starting dose of 5g QD. 
Potassium (i-STAT and central laboratory) will be measured as indicated in the study schedule 
(Table 2). During the Maintenance Phase, the ZS dose may be increased up to 15 g QD or 
decreased down to 5g QOD (or 2.5 g QD) based on i-STAT potassium measurements as 
outlined in Section 7.2.
Throughout all phases of the study, most potassium values will be measured at fasting before 
taking ZS. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, for a minimum of 8 hours prior to the blood 
collection. Potassium level should be determined by both i-STAT and the Central Laboratory 
on all occasions. Treatment decisions (eg, dose titration, stopping rules) will be made based on 
i-STAT potassium values, as these provide clinical sites with a real-time measurement, 
according to dose modification rules as described in Section 7.2. 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]), aldosterone, renin and 
hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms 
(ECGs) will be assessed during the study at the time points specified in Table 1 and Table 2. 
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, arrhythmias, or 
development of congestive heart failure or end stage renal failure.
Objectives
Primary Objective:
Outcome Measure:
Maintenance Phase
To assess open-label, long-term (12 months) 
safety and tolerability for ZS in Japanese 
subjects with hyperkalemia (serum potassium 
≥ 5.1 mmol/L).
Safety and tolerability as measured by adverse events
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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Secondary Objectives:
Outcome Measures:
Maintenance Phase
!
To evaluate the proportion of ZS-treated 
subjects in whom normokalemia can be 
maintained over prolonged periods of 
time, using an individually titrated dose 
(5 g every other day [or 2.5 g once daily], 
5 g once daily, 10 g once daily or 15 g 
once daily)
!
Proportion of patients who can maintain 
normokalemia (defined as S-K level of ≥ 3.5 and 
≤ 5.0 mmol/L, inclusive) on ZS at each 
Maintenance Phase study visit
!
Proportion of patients with average S-K ≤ 5.1
mmol/L
!
Proportion of patients with average S-K ≤ 5.5 
mmol/L
!
Proportions of patients who were normokalemic 
(S-K ≥ 3.5 and ≤ 5.0 mmol/L), hypokalemic (< 
3.5 mmol/L), or hyperkalemic (> 5.0 mmol/L) at 
each Maintenance Phase visit.
!
Subject-level average S-K over certain period of 
time
!
Observed values at visit and change from 
baseline in S-K over time
!
Number of normokalemic days during 
Maintenance Phase
!
Change in S-K level from the last on-treatment 
Maintenance Phase visit to the End of Study 
(EOS)
!
To explore the time course of S-
Aldosterone and S-Bicarbonate
!
Change from baseline in S-Aldosterone over 
time 
!
Proportion of patients with normal S-
Aldosterone 
!
Change from baseline in S-Bicarbonate 
!
Proportion of patients with normal S-
Bicarbonate
!
To evaluate the health state in the study 
population using SF-36 v2.
!
SF-36 v2 questionnaire
Correction Phase
To assess efficacy, safety and tolerability of 
10 g TID ZS in Japanese patients with 
hyperkalemia (serum potassium [S-K] ≥ 5.1 
mmol/L).
!
Observed values and change from Correction 
Phase baseline in S-K
!
Proportion of patients who achieved 
normokalemia at 24, 48 and 72 hours after start of 
dosing
!
Safety and tolerability as measured by adverse 
events reporting, vital signs, ECGs, physical 
examinations, and safety laboratory 
measurements during Correction Phase


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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Exploratory Objectives:
Outcome Measures:
Maintenance Phase 
Patient reported outcomes:
To evaluate if patients prefer ZS QOD or OD 
using the patient questionnaire.
Patient questionnaire
Treatment period 
To explore change in doses and reasonings of 
the change of RAAS inhibitors during the 
treatment period.
!
Proportion of subjects increased RAASi doses
!
Proportion of subjects who decrease or 
discontinued RAASi doses
!
Proportion of subjects who increased at least 
once RAASi due to each reason
!
Proportion of subjects who 
decreased/discontinued at least once RAASi due 
to each reason
!
Time to first reduction/discontinuation of 
RAASi
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 (± 
15 minutes) apart, both ≥ 5.1 mmol/L within 1 day before the first dose of ZS on Correction 
Phase Study Day 1.
Duration of treatment
The study will start with the screening period, and all baseline parameters should be 
measured/collected up to 1 day prior to administration of first dose of study drug on 
Correction Phase Day 1. Subjects with 2 consecutive i-STAT potassium values ≥ 5.1 mmol/L 
will enter the Correction Phase and receive ZS 10 g TID for up to 72 hours, depending on 
potassium values. Once normokalemia (i-STAT potassium between 3.5 and 5.0 mmol/L, 
inclusive) is restored (whether after 24, 48 or 72 hours), subjects will be entered into the 
Maintenance Phase to be dosed with ZS at a starting dose of 5 g QD. Potassium (i-STAT and 
Central Laboratory) will be measured Days 1, 2, 5, 12, 19 and 26 throughout the first month of 
study and every 4 weeks thereafter until Day 362 (Visit 23) then patients will be required to 
complete the EOS visit which is 7±1 days after the last administration of study medication. 
For patients who do not enter the Maintenance Phase the last visit will be 7±1 day after the 
last treatment dose in the Correction Phase. The total expected study duration for an individual 
patient is approximately 53-54 weeks.
Investigational product, dosage and mode of administration
Sodium Zirconium Cyclosilicate (ZS) should be administered orally as a suspension in water. 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
12 (90)
Correction Phase: ZS 10g TID for 24, 48 or 72 hours (3, 6 or 9 doses). Patients will enter the 
Maintenance phase after 24, 48 or 72h if the morning i-STAT potassium is between 3.5 and 
5.0 mmol/L, inclusive.
If a patient develops i-STAT potassium values between 3.0 mmol/L and 3.4 mmol/L, 
inclusive (confirmed by taking a second potassium measurement after a 10 ± 2 minute 
interval) during the Correction Phase the subject will be directed to not take any more study 
drug for the remainder of the day and return the next day to continue in the study.
Patients with i-STAT potassium <3.0 mmol/L (confirmed by taking a second potassium 
measurement after a 10 ± 2 minute interval) should discontinue from therapy.
Maintenance Phase: The starting dose is ZS 5 g QD. The ZS dose may be increased in 
increments of 5 g up to a maximum of 15 g QD or decreased to a minimum of 5 g QOD (or 
2.5 g QD) dependent upon i-STAT potassium measurements (see Dose modification rules in 
Table 6).
Statistical methods
Separate efficacy and safety analyses will be performed for the correction phase and 
maintenance phase. Separate analysis sets will be defined for each phase. 
For the correction phase, patients will be considered evaluable if 1) they receive the correction 
dose and 2) they have any post-baseline S-K levels after receiving the ZS during the 
correction phase. Then, the full analysis set will include all patients that receive the ZS, and 
have any post-baseline S-K levels. The safety analysis set will include all patients as treated 
with at least one dose of correction phase ZS among those treated and with any post-baseline 
correction phase safety data.
For the subsequent maintenance phase, patients will be considered evaluable if 1) they receive 
the ZS and 2) they have any post-baseline maintenance phase S-K levels after receiving the 
ZS. Then, the full analysis set will include all patients who receive any ZS and have any post-
baseline maintenance phase S-K levels. The safety analysis set will include all patients as 
treated with at least one dose of ZS among those dosed with any post-baseline maintenance 
phase safety data.
All safety and efficacy analyses will be carried out in a descriptive manner. If deemed 
necessary, 95% confidence intervals will also be presented. 
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. Kidney function will be evaluated by assessments of creatinine, estimated 
Glomerular Filtration Rate (eGFR), urine protein-to-creatinine ratio (UPCR) and urine 
albumin-to-creatinine ratio (UACR) over time. Liver function will be evaluated by assessing 
bilirubin, AST and ALT. 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
13 (90)
Sample size of in total 150 subjects to be enrolled to this study was determined so that at least 
safety data of 100 subjects treated by ZS as long as one year will be collected, assuming 35% 
drop out rate.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
14 (90)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................8
TABLE OF CONTENTS...................................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................19
1.
INTRODUCTION ............................................................................................. 21
1.1
Background and rationale for conducting this study ...........................................21
1.2
Rationale for study design, doses and control groups..........................................24
1.3
Benefit/risk and ethical assessment ....................................................................25
1.3.1
Clinical benefits.................................................................................................25
1.3.2
Clinical risks......................................................................................................26
1.3.3
Clinical benefit-risk balance...............................................................................26
1.3.4
Conclusions ....................................................................................................... 27
1.4
Study Design...................................................................................................... 27
2.
STUDY OBJECTIVES...................................................................................... 30
2.1
Primary objective...............................................................................................30
2.2
Secondary objectives..........................................................................................30
2.3
Exploratory objectives ....................................................................................... 31
3.
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL..................................................31
3.1
Inclusion criteria ................................................................................................32
3.2
Exclusion criteria ...............................................................................................32
3.3
Patient enrolment ...............................................................................................33
3.4
Procedures for handling incorrectly enrolled ......................................................34
3.5
Methods for assigning treatment groups (Not Applicable)..................................34
3.6
Methods for ensuring blinding (Not Applicable) ................................................34
3.7
Methods for unblinding (Not Applicable)...........................................................34
3.8
Restrictions........................................................................................................34
3.9
Discontinuation of investigational product .........................................................34
3.9.1
Procedures for discontinuation of a subject from investigational product............36
3.10
Criteria for withdrawal....................................................................................... 36


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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3.10.1
Screen failures ...................................................................................................36
3.10.2
Withdrawal of the informed consent...................................................................36
3.11
Interruption  of investigational product...............................................................37
3.12
Discontinuation of the study............................................................................... 37
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................38
4.1
Screening/Enrolment period (Visit 1).................................................................42
4.2
Treatment period................................................................................................ 42
4.2.1
Correction Phase Day 1 (Visit 2)........................................................................ 42
4.2.2
Correction Phase Day 2 (Visit 3)........................................................................ 44
4.2.3
Correction Phase Day 3 (Visit 4)........................................................................ 45
4.2.4
Correction Phase Day 4 (Visit 5) (Visit 5 is only for patients who needed 
72 hour correction phase.)..................................................................................46
4.2.5
Maintenance Phase Day 1 (Visit 6) ....................................................................49
4.2.6
Maintenance Phase Day 2 (Visit 7) ....................................................................50
4.2.7
Maintenance Phase Day 5 (Visit 8) ....................................................................51
4.2.8
Maintenance Phase Day 12 (Visit 9)................................................................... 51
4.2.9
Maintenance Phase Day 19 (Visit 10)................................................................. 52
4.2.10
Maintenance Phase Day 26- Day 334 (Visit 11- Visit 22)...................................53
4.2.11
Maintenance Phase Day 362 (Visit 23)............................................................... 54
4.3
Follow-up period (EOS)..................................................................................... 54
5.
STUDY ASSESSMENTS..................................................................................55
5.1
Efficacy assessments..........................................................................................55
5.1.1
Potassium...........................................................................................................55
5.1.2
Aldosterone and Renin Samples.........................................................................55
5.2
Safety assessments.............................................................................................55
5.2.1
Laboratory safety assessments............................................................................ 55
5.2.2
Physical examination .........................................................................................57
5.2.3
ECG...................................................................................................................57
5.2.3.1
Resting 12-lead ECG .........................................................................................57
5.2.4
Vital signs.......................................................................................................... 58
5.2.4.1
Pulse rate and blood pressure .............................................................................58
5.3
Other assessments.............................................................................................. 58
5.4
Pharmacokinetics (Not applicable).....................................................................58
5.5
Pharmacodynamics (Not applicable) ..................................................................58
5.6
Genetics (Not applicable)...................................................................................58
5.7
Biomarker analysis (Not applicable)...................................................................58
5.8
Storage, re-use and destruction of biological samples......................................... 58
5.9
Labeling and shipment of biological samples ..................................................... 59


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
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5.10
Volume of blood................................................................................................ 59
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 62
6.1
Definition of adverse events............................................................................... 62
6.2
Definitions of serious adverse event ................................................................... 62
6.3
Recording of adverse events............................................................................... 62
6.3.1
Time period for collection of adverse events ......................................................62
6.3.2
Follow-up of unresolved adverse events.............................................................62
6.3.3
Variables............................................................................................................ 63
6.3.4
Causality collection............................................................................................64
6.3.5
Adverse events based on signs and symptoms....................................................64
6.3.6
Adverse events based on examinations and tests ................................................64
6.4
Reporting of serious adverse events ................................................................... 65
6.5
Overdose............................................................................................................65
6.6
Pregnancy .......................................................................................................... 66
6.6.1
Maternal exposure..............................................................................................66
6.6.2
Paternal exposure...............................................................................................66
6.7
Medication Error................................................................................................67
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................68
7.1
Identity of investigational product(s)..................................................................68
7.2
Dose and treatment regimens .............................................................................68
7.3
Labelling............................................................................................................70
7.4
Storage............................................................................................................... 70
7.5
Compliance........................................................................................................70
7.6
Accountability....................................................................................................70
7.7
Concomitant and other treatments ...................................................................... 71
7.7.1
Oral medications with gastric pH-dependent bioavailability...............................71
7.8
Post Study Access to Study Treatment (Not Applicable) ....................................72
8.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................72
8.1
Statistical considerations....................................................................................72
8.2
Sample size estimate ..........................................................................................72
8.3
Definitions of analysis sets................................................................................. 72
8.3.1
Full analysis sets ................................................................................................ 72
8.3.2
Safety analysis sets ............................................................................................73
8.4
Outcome measures for analyses..........................................................................73
8.4.1
Efficacy variables (Secondary)...........................................................................73
8.4.2
Efficacy variables (Exploratory).........................................................................74


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8.4.3
Safety Variables.................................................................................................74
8.5
Methods for statistical analyses..........................................................................74
8.5.1
Analyses of efficacy variables............................................................................74
8.5.2
Analysis of Safety data....................................................................................... 74
8.5.3
Interim analysis..................................................................................................75
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.........................75
9.1
Training of study site staff.................................................................................. 75
9.2
Monitoring of the study...................................................................................... 75
9.2.1
Source data ........................................................................................................76
9.2.2
Study agreements............................................................................................... 76
9.2.3
Archiving of study documents............................................................................ 76
9.3
Study timetable and end of study........................................................................76
9.4
Data management by AstraZeneca or delegate ................................................... 77
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................78
10.1
Ethical conduct of the study ...............................................................................78
10.2
Patient data protection........................................................................................78
10.3
Ethics and regulatory review ..............................................................................78
10.4
Informed consent ...............................................................................................79
10.5
Changes to the Clinical Study Protocol and Informed Consent Form..................79
10.6
Audits and inspections .......................................................................................79
11.
LIST OF REFERENCES ...................................................................................80
LIST OF TABLES
Table 1
Study Plan for the Correction Phase ......................................................38
Table 2
Study Plan for the Maintenance Phase...................................................40
Table 3
Laboratory Safety Variables..................................................................56
Table 4
Volume of blood to be withdrawn from each patient: Correction 
Phase ....................................................................................................59
Table 5
Volume of blood to be withdrawn from each patient: Maintenance 
Phase ....................................................................................................61
Table 6
Dose modification rules: .......................................................................69


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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) ..........................25
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g..........27
Figure 3
Study flow chart....................................................................................29
Figure 4
Flow chart based on the S-K level: Correction Phase.............................48
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................81
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................83
Appendix C
SF-36 v2 ...............................................................................................84
Appendix D
Patient questionnaire English ver. (for Visit 23 or EOS visit) ................90


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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
APD
Automated Peritoneal Dialysis
AST
Aspartate aminotransferase
AZ
AstraZeneca
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAPD
Continuous Ambulatory Peritoneal Dialysis
CI
Confidence Interval 
CKD
Chronic Kidney Disease
CPS
Calcium Polystyrene Sulfonate
CRF
Case Report Form
CSA
Clinical Study Agreement
CSR
Clinical Study Report
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
eGFR
estimated Glomerular Filtration Rate
EOS
End of Study
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).
GFR
Glomerular Filtration Rate
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice


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Abbreviation or 
special term
Explanation
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
HD
Hemodialysis
HF
Heart Failure
IB
Investigator’s Brochure
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
PD
Peritoneal Dialysis
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-K
Serum potassium
SPS
Sodium Polystyrene Sulfonate
TEAE
Treatment Emergent Adverse Event
TID
three times daily
UACR
Urine Albumin-to-Creatinine Ratio
UPCR
Urine Protein-to-Creatinine Ratio
WBC
White Blood Cell
WBDC
Web Based Data Capture
ZS
Sodium Zirconium Cyclosilicate


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2
Rationale for study design, doses and control groups
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.3
Benefit/risk and ethical assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Redacted
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1.4
Study Design 
The study is an open label, single arm study with flexible dose regimen focused on assessing 
long-term safety and tolerability of ZS in Japanese subjects with hyperkalemia.
Correction Phase: If the subject is normokalemic (i-STAT potassium between 3.5 and 
5.0 mmol/L, inclusive) on the morning of Correction Phase Study Day 2 after 3 doses of ZS 
10 g, they will enter the Maintenance Phase. If the subject is not normokalemic, they will 
receive an additional 24 hours of ZS 10 g TID treatment (6 total doses). If the subject’s i-
STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, on the morning of 
Correction Phase Study Day 3, the subject will enter the Maintenance Phase. If the subject is 
not normokalemic, they will receive an additional 24 hours of ZS 10 g TID treatment (9 total 
Redacted
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doses). If the subject’s i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, on 
the morning of Correction Phase Study Day 4, the subject will enter the Maintenance Phase. If 
the i-STAT potassium value is still < 3.5 mmol/L or ≥ 5.1 mmol/L on the morning of 
Correction Phase Study Day 4, after 72 hours of TID treatment, the subject will be withdrawn 
from the study and referred to their normal health care provider for standard of care treatment. 
Subjects withdrawn from the Correction Phase of the study will return to the clinic 7 (± 1) 
days after their last dose of ZS for an End of Study (EOS) visit.
Maintenance Phase: Patients will initially be dosed with ZS at a starting dose of 5g QD. 
Potassium (i-STAT and central laboratory) will be measured as indicated in the study schedule 
(Table 2). During the Maintenance Phase, the ZS dose may be increased up to 15 g QD or 
decreased down to 5g QOD (or 2.5 g QD) based on i-STAT potassium measurements as 
outlined in Section 7.2.
Throughout all phases of the study, most potassium values will be measured at fasting before 
taking ZS. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, for a minimum of 8 hours prior to the blood 
collection. Potassium level should be determined by both i-STAT and the Central Laboratory 
on all occasions. Treatment decisions (eg, dose titration, stopping rules) will be made based on 
i-STAT potassium values, as these provide clinical sites with a real-time measurement, 
according to dose modification rules as described in Section 7.2. 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]), aldosterone, renin and 
hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms 
(ECGs) will be assessed during the study at the time points specified in Table 1 and Table 2. 
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, arrhythmias, or 
development of congestive heart failure or end stage renal failure.


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Figure 3
Study flow chart 
Long term maintenance phase
QD: once daily, QOD: every other day
10 g QD
5 g QD
5 g QOD or 2.5 g QD
Patients with K+
≥ 5.1 mmol/L
ZS 10 g three times a day until normokalemia
(max 72 hours)
15 g QD
Correction phase


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
Maintenance Phase
To assess open-label, long-term (12 months) 
safety and tolerability for ZS in Japanese 
subjects with hyperkalemia (serum potassium 
≥ 5.1 mmol/L).
Safety and tolerability as measured by adverse events
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
Maintenance Phase
!
To evaluate the proportion of ZS-treated 
subjects in whom normokalemia can be 
maintained over prolonged periods of 
time, using an individually titrated dose 
(5 g every other day [or 2.5 g once daily], 
5 g once daily, 10 g once daily or 15 g 
once daily)
!
Proportion of patients who can maintain 
normokalemia (defined as S-K level of ≥ 3.5 and 
≤ 5.0 mmol/L, inclusive) on ZS at each 
Maintenance Phase study visit
!
Proportion of patients with average S-K ≤ 5.1 
mmol/L
!
Proportion of patients with average S-K ≤ 5.5 
mmol/L
!
Proportions of patients who were normokalemic 
(S-K ≥ 3.5 and ≤ 5.0 mmol/L), hypokalemic (< 
3.5 mmol/L), or hyperkalemic (> 5.0 mmol/L) at 
each Maintenance Phase visit.
!
Subject-level average S-K over certain period of 
time
!
Observed values at visit and change from 
baseline in S-K over time
!
Number of normokalemic days during 
Maintenance Phase
!
Change in S-K level from the last on-treatment 
Maintenance Phase visit to the End of Study
!
To explore the time course of S-
Aldosterone and S-Bicarbonate
!
Change from baseline in S-Aldosterone over 
time 
!
Proportion of patients with normal S-
Aldosterone 
!
Change from baseline in S-Bicarbonate
!
Proportion of patients with normal S-
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Secondary Objectives:
Outcome Measures:
!
To evaluate the health state in the study 
population using SF-36 v2.
!
SF-36 v2 questionnaire
Correction Phase
To assess efficacy, safety and tolerability of 
10 g TID ZS in Japanese patients with 
hyperkalemia (serum potassium [S-K] ≥ 5.1 
mmol/L).
!
Observed values and change from Correction 
Phase baseline in S-K
!
Proportion of patients who achieved 
normokalemia at 24, 48 and 72 hours after start 
of dosing
!
Safety and tolerability as measured by adverse 
events reporting, vital signs, ECGs, physical 
examinations, and safety laboratory 
measurements during Correction Phase
2.3
Exploratory objectives
Exploratory Objectives:
Outcome Measures:
Maintenance Phase 
Patient reported outcomes:
To evaluate if patients prefer ZS QOD or OD 
using the patient questionnaire.
Patient questionnaire
Treatment period 
To explore change in doses and reasonings of 
the change of RAAS inhibitors during the 
treatment period.
!
Proportion of subjects increased RAASi doses
!
Proportion of subjects who decrease or 
discontinued RAASi doses
!
Proportion of subjects who increased at least 
once RAASi due to each reason
!
Proportion of subjects who 
decreased/discontinued at least once RAASi due 
to each reason
!
Time to first reduction/discontinuation of 
RAASi
3.
PATIENT SELECTION, ENROLMENT, 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.


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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-minutes (± 15 minutes) 
apart, both ≥ 5.1 mmol/L and measured within 1 day before the first dose of ZS on 
Correction Phase Study Day 1.
4.
Patients who are on peritoneal dialysis (PD) can be enrolled if their SK level is ≥5.5 
and ≤ 6.5 mmol/L in two consecutive i-STAT potassium evaluation at least 24 
hours apart before Day 1 (in each evaluation, two i-STAT potassium measurements 
at least 1 hour apart are required). i-STAT potassium measurement should be 
performed in the morning before breakfast and in the evening before dinner in PD 
patients on continuous ambulatory peritoneal dialysis (CAPD) and automated 
peritoneal dialysis (APD), respectively.
5.
Ability to have repeated blood draws or effective venous catheterization.
6.
Women of childbearing potential must be using 2 forms of medically acceptable 
contraception (at least 1 barrier method) and have a negative pregnancy test within 
1 day prior to the first dose of ZS on Correction Phase Study Day 1. Women who 
are surgically sterile or those who are postmenopausal for at least 1 year are not 
considered to be of childbearing potential.
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
3)
history of severe leukocytosis or thrombocytosis
3.
Patients treated with lactulose, rifaxan (rifaximin), or other non-absorbed antibiotics 
for hyperammonemia within 7 days prior to first dose of ZS.


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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. Washout of SPS and CPS for 7 days (or longer) prior to the first 
dose of ZS is allowed, if termination of CPS or SPS is judged to be clinically 
acceptable by the investigator. Documented informed consent has to be obtained 
prior to the washout.
5.
Patients with a life expectancy of less than 12 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.
Hemodialysis patients (including those who are on both PD and hemodialysis [HD])
14.
Patients who have been on PD less than 6 months or more than 6 months with a 
history of hypokalemia within 6 months before Correction Phase Day 1
15.
Documented Glomerular Filtration Rate (GFR) < 15 mL/min within 90 days prior 
to study entry (Non peritoneal dialysis (PD) patients only)
16.
If patients joined ZS study in the past, the patients cannot join this study within the 
last 30 days of the last study drug administration day.
For procedures for withdrawal of incorrectly enrolled patients, see Section 3.4.
3.3
Patient enrolment 
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.


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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).
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 code cannot be 
reused.
3.4
Procedures for handling incorrectly enrolled
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 start treatment, 
and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is 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 (Not Applicable)
3.6
Methods for ensuring blinding (Not Applicable)
3.7
Methods for unblinding (Not Applicable)
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:


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!
Patient 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
!
Risk to patient as judged by investigator
!
Pregnancy
!
Require treatment with medications prohibited or contraindicated for use due to 
safety concerns with ZS
!
Patient develops potassium values which meet the IP discontinuation criteria 
described in Table 6 (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 during the Correction Phase conduct Visit5 
procedure soon after the discontinuation and conduct EOS Visit one week after last IP.
Patients who discontinue from study medication during the Maintainance Phase conduct 
Visit23 procedure soon after the discontinuation and conduct EOS Visit one week after last IP.
At the time of IP discontinuation, procedures will be performed in accordance with the 
required order whenever possible, see Section 4.2.4 and 4.2.11.


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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 
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 entered into the study, i.e. patients that are withdrawn prior to receiving 
open label treatment. These patients should have the reason for study withdrawal recorded as 
‘Eligibility criteria not fulfilled’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures.
3.10.2 Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.


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A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
reused. Withdrawn patients will not be replaced.
3.11
Interruption  of investigational product
Investigational product (IP) may be interrupted in situations such as an adverse event, 
laboratory abnormality other than potassium abnormality  (only during Maintainance Phase) at 
the investigator's discretion.
During an interruption of IP, the patient will return to the site at least every 7 (± 2) days as an 
extra visit for a potassium measurement and recording of any adverse events and concomitant 
medications (Patient will arrive at the clinic in the morning after fasting for at least 8 hours 
prior to potassium sample collection.). In case it is unlikely to re-start IP, patient should be 
discontinued from the IP. On each extra visit, investigator and sponsor should discuss the 
study continuation. When the patient re-start IP, dose should the same as the last dose before 
interrutption. If the IP was interrupted due to an AE, the causality of the AE must be judged 
by investigator to be not related to IP upon resuming the IP.
3.12
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.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
38 (90)
4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan for the Correction Phase
Study Visit
Visit 1
Visit 27
Visit 35
Visit 45
Visit 55
EOS6
Correction Phase Day
Screening
Day 17
Day 25
Day 35
Day 45
Day 106
Written informed consent
X
Eligibility criteria
X
Demographics
X
Medical History
X
SF-36 v2 questionnaire
X
Physical exam including weight
X8
X8
Access IVRS/IWRS
X
X
X9
X9
X9
Study drug (IP) dispensation
X
X9
X9
Study drug (IP) administration
X
X9
X9
ECG
X
X9
X9
X9
X
Vital signs
X
X9
X9
X
Concomitant medications
X
X
X
X
X
Adverse events
X10
X
X
X
X
Potassium1
X2
X3,11
X11
X12
X12
Serum Chemistry1
X
X9
X
Hematology1
X
X9
X
Aldosterone and renin1
X
Urinalysis1
X
X9
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 ZS. For diabetic patients all blood potassium samples should be collected prior to insulin 
administration whenever possible.
2.
Blood potassium will be measured twice 60 (±15) minutes apart within 1 day of first dose administration on 
Correction Phase Day 1(Visit 2) and at 4 hours (±15 min) after administration of the first dose of ZS. 
Potassium will be measured again 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 4 hours after the first dose. The Central Laboratory serum 
chemistry, hematology, aldosterone and renin samples will be collected at the same time as the 60 minutes i-
STAT screening potassium sample, but will be analysed only in confirmed hyperkalemic subjects.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
39 (90)
3.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) after the first dose on Correction Phase 
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.
Visit 3, 4 and 5 (Day 2, 3 and 4 for the Correction Phase) are the same as visit 6 Day 1 in the Maintenance 
Phase for patients achieving normokalemia in the morning the day of the visit. Patients not achieving 
normokalemia at Visit 4 will be dosed with ZS 10g TID for an additional 24h and then return to the site for 
Visit 5.
6.
EOS in Correction Phase only for patients NOT entering the Maintenance Phase, and occurs 7±1 day after 
the last administration of IP.
7.
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.
8.
A complete physical examination should be performed within 1 day of administration of the first dose of 
study drug on Correction Phase Day 1, and targeted physical examination will be conducted on EOS.
9.
If subject does not qualify for the Maintenance Phase on/before Correction Phase Day 4.
10. 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.
11.
Blood potassium will be measured upon return to the clinic to determine if the subject is eligible to enter the 
Maintenance Phase or if the subject should receive an additional 24 hours of dosing.
12.
Central laboratory potassium sample collected as part of the serum chemistry panel.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
40 (90)
Table 2
Study Plan for the Maintenance Phase
Study Visit
(Visit)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
EOS
Maintenance 
Phase Day5
(Day)
1
2
5
12
19
26
54
82
110
138
166
194
222
250
278
306
334
362
One 
week 
after 
last 
IP6
Targeted physical 
exam including 
weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36 v2 
questionnaire
X
Access 
IVRS/IWRS7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug (IP) 
dispensation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug (IP) 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Potassium1,2
X2,3,8
X2
X2,8
X2,8
X2,8
X2,8
X2
X2,8
X2
X2
X2,8
X2
X2
X2,8
X2
X2
X2,8
X2,8
X2,8
Serum chemistry1
X
X
X
X
X
X
X
X
X
X
X
Hematology1
X
X
X
X
X
X
X
X
X
X


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
41 (90)
Table 2
Study Plan for the Maintenance Phase
Study Visit
(Visit)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
EOS
Maintenance 
Phase Day5
(Day)
1
2
5
12
19
26
54
82
110
138
166
194
222
250
278
306
334
362
One 
week 
after 
last 
IP6
Aldosterone and 
renin
X
X
Urinalysis1
X
X
X
X
X
X
X
Urine HCG
X4
IP Reconciliation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient 
questionnaire
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 ZS. For diabetic patients all blood potassium samples should be 
collected prior to insulin administration whenever possible.
2.
Please see Table 6 for details on how to adjust the dose based on the measured potassium values.
3.
Maintenance Phase Study Day 1 sample will be the same sample as obtained on the last day of the Correction Phase.
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. Pregnancies are instead reported on the dedicated Case Report Form (CRF) page.
5.
During the 12 months Maintenance Phase, the scheduled visit may take place either up to 2 days early or late by Visit 10 and up to 3 days early or late 
from Visit 11.
6.
EOS occurs 7±1 day after the last administration of IP
7.
Access IVRS/IWRS on visit indicated or if patient permanently discontinues dosing before the end of Maintenance phase.
8.
Central laboratory potassium sample collected as part of the serum chemistry panel.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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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. The following rule will be 
applied for the patient who will be ineligible due to the deviation of inclusion criteria No. 3. If 
the patient is expected to meet the eligibility criteria based on the patient‘s disease condition, 
the patient can be re-enrolled (including one re-screening) only once after 30 days or later 
from the screening failure. In this case, new enrolment number will be allocated to the 
patient.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 ICF at Visit 1, the site investigator will use the IVRS/IWRS to 
obtain a unique patient enrolment number after collecting the demographic parameters from 
the patient (including sex, date of birth, race, ethnic group).
4.2
Treatment period
Table 1 and Table 2 provide an overview of the procedures performed at each visit during the 
treatment period, and further details are provided below. Changing the order of the procedures 
at a visit, e.g. for logistical reasons, would not constitute a protocol violation if agreed in 
advance and in writing between the site and the sponsor study physician.
4.2.1
Correction Phase Day 1 (Visit 2)
Patients will arrive in the morning, fasting (except water, coffee or tea, with or without milk 
and/or sugar, and essential medications) for a minimum of 8 hours prior to potassium sample 
collection at the clinic. Between 1 and 7 hours may be needed for the visit, during which the 
following assessments will be performed:
!
Administer the SF-36 v2 questionnaire. (The SF-36 v2 needs to be completed 
before the visit. If not, the patient should complete the questionnaire prior to any 
other study procedures.)
!
Review and confirm the patient eligibility for the study by assessing inclusion and 
exclusion criteria listed in Sections 3.1 and 3.2.
!
Collect blood samples for assessment of potassium 60 minutes apart (± 15 min). 
Potassium will be analyzed using i-STAT, and samples will be prepared for 
potential shipment to the Central Laboratory for each time-point.  
!
If either i-STAT potassium value is < 5.1 mmol/L the patient will be declared a 
screen failure and discontinue from the study.
!
If both i-STAT values are ≥ 5.1 mmol/L the following assessments will be 
performed:


Clinical Study Protocol
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Study Code D9482C00001
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Date 13 Sep 2018
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∀
Collect blood samples for assessment of hematology and clinical chemistry. 
(This sample can be collected at the same time as iSTAT sample collection. 
The patient should be informed that samples can be disposed of  in case i-
STAT potassium level <5.1 mmol/L and this process should be recorded 
before the sample collection)
∀
Collect urine samples for assessment of urinalysis parameters, including a 
pregnancy test if the patient is a woman of childbearing potential.
∀
Aldosterone and renin collected prior to 10 am (1000) after the subject has 
been in an upright position for at least 2 hours and before recording the ECG 
and physical examination.
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
Patient medical and surgical history including co-morbidities will be obtained with 
the review of selection criteria.
!
Perform 12-lead Electrocardiogram (ECG).
!
Perform a complete physical examination including weight, see Section 5.2.2.
!
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.
Patients who meet all inclusion/exclusion criteria will be entered into the trial and the 
following procedures will take place: 
!
The site will access the IVRS/IWRS and the system will assign the patient a 
Correction Phase IP kit. 
!
The first doses of study IP will be administered as a suspension in water. The 
patient will be shown/instructed on how to mix and administer the IP, following 
which the patient is allowed to break the fast.
!
4 hours (± 15 min) after dose administration a potassium sample (i-STAT and 
Central Laboratory) will be collected. 
!
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 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 the 
Correction Phase Day 2 (Visit 3).
!
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 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
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sample for potassium determination (i-STAT and Central Laboratory) will be 
collected and an ECG will be recorded. 
∀
If the potassium level is > 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. Patient will return to the clinic 7 (±1) days later for an EOS visit. 
∀
If the potassium level is ≤6.5 mmol/L as determined by i-STAT, and the ECG 
does not exhibit 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 Correction phase Day 2 (Visit 3).
!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L.
4.2.2
Correction Phase Day 2 (Visit 3)
Subjects will arrive at the clinic in the morning after fasting for at least 8 hours prior to 
potassium sample collection. 
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the investigational product dosing boxes and sachets and make 
note of the time the doses were taken and any unused investigational products on 
the eCRF and source documents.
!
Potassium values will be evaluated by i-STAT and the Central Laboratory.
!
If the i-STAT potassium value is between 3.0 and 3.4 mmol/L inclusive, the subject 
should not take a study IP doses that day and return the next day to assess 
potassium.
-
1 hour (± 15 min) after first serum potassium measurement a potassium sample 
(i-STAT and Central Laboratory) will be collected.
!
If the i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, the 
subject will enter the Maintenance Phase and complete the procedures detailed in 
Section 4.2.5.
!
If the i-STAT potassium value is ≥ 5.1 mmol/L, the subject will receive an 
additional 24 hours of ZS 10 g TID and the following procedures will be 
performed:
∀
The site will access the IVRS/IWRS and provide the 7-digit subject 
identification number. The system will assign the subject an investigational 
product kit.
∀
An ECG will be performed (Section 5.2.3).
∀
The morning dose of ZS will be administered in the clinic as a suspension in 
water.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
45 (90)
∀
1 hour (± 15 min) after dose administration a potassium sample (i-STAT and 
Central Laboratory) will be collected.
∀
Patients with i-STAT potassium levels ≤ 6.5 and ≥3.5 mmol/L at the 1 hour (± 
15 minutes) post Dose 1 blood draw will be sent home with 2 doses of study 
drug and instructions on how to take ZS. 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 the Correction Phase Day 3 (Visit 4).
∀
If the potassium level is > 6.5 mmol/L as determined by the i-STAT at the 1 
hour (± 15 minutes) post Dose 1 blood draw, the patient will be discontinued 
from the study. Patient will return to the clinic 7 (±1) days later for an EOS 
visit. 
!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L.
4.2.3
Correction Phase Day 3 (Visit 4)
Subjects will arrive at the clinic in the morning after fasting for at least 8 hours prior to 
potassium sample collection. 
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the investigational product dosing boxes and sachets and make 
note of the time the doses were taken and any unused investigational products on 
the eCRF and source documents.
!
Potassium values will be evaluated by i-STAT and the Central Laboratory.
!
If the i-STAT potassium value is between 3.0 and 3.4 mmol/L inclusive, the subject 
should not take a study IP doses that day and return the next day to assess 
potassium. 
!
If the i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, the 
subject will enter the Maintenance Phase and complete the procedures detailed in 
Section 4.2.5. 
!
If the i-STAT potassium value is ≥ 5.1 mmol/L, the subject will receive an 
additional 24 hours of ZS 10 g TID and the following procedures will be 
performed:
∀
The site will access the IVRS/IWRS and provide the 7-digit subject 
identification number. The system will assign the subject an investigational 
product kit.
∀
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
∀
An ECG will be performed (Section 5.2.3).


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
46 (90)
∀
The morning dose of ZS will be administered in the clinic as a suspension in 
water.
∀
Subjects will then be sent home with 2 doses of study drug and instructions on 
how to take ZS. They will be requested to fill out a dosing schedule card 
indicating when they took ZS.
∀
Subjects will return to the clinic the following morning and bring the used 
investigational product boxes and sachets and dosing schedule card with 
them.
!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L.
4.2.4
Correction Phase Day 4 (Visit 5) (Visit 5 is only for patients who needed 72 hour 
correction phase.)
Subjects will arrive at the clinic in the morning after fasting for at least 8 hours prior to 
potassium sample collection. 
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the investigational product dosing boxes and sachets and make 
note of the time the doses were taken and any unused investigational products on 
the eCRF and source documents.
!
Potassium values will be evaluated by i-STAT and the Central Laboratory. 
!
If the i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, the 
subject will enter the Maintenance Phase and complete the procedures detailed in 
Section 4.2.5.
!
If the i-STAT potassium value is < 3.5 or ≥ 5.1 mmol/L following 72 hours of 
dosing with ZS 10 g TID, the following procedures will be performed:
∀
Collect blood samples for assessment of hematology and clinical chemistry.
∀
Collect urine samples for assessment of urinalysis parameters.
∀
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
∀
An ECG will be performed (Section 5.2.3).
∀
The site will access the IVRS/IWRS, provide the 7-digit subject identification 
number, and document that the subject did not qualify for the Maintenance 
Phase.
∀
Subjects will then DISCONTINUE from the study, and receive standard of 
care at the discretion and the direction of his/her own physician. However, the 
subject will need to return to the clinic in the morning, fasting for at least 8 


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
47 (90)
hours prior to potassium sample collection, 7 (± 1) days later after the last 
administration of IP for an End of Study visit.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
48 (90)
Figure 4
Flow chart based on the S-K level: Correction Phase
Start Correction phase
S-K: <3.0, >6.5
Discontinue
Pre dose: 2 times measurement (60 minutes 
apart)
S-K: ≥5.1 
In both value
S-K: <5.1
At least one value
Discontinue
Day 1
4 hours after 1st dose
S-K: <4.0, ≥6.1
S-K: ≥4.0, <6.1
Go home:
2nd and 3rd 
dose in home
Stay in hospital
Day 1
90 minutes after 2nd dose
S-K: ≥3.5, ≤6.5
S-K: ≥3.0, ≤3.4*
Go home:
3rd dose in home
Go home:
NO 3rd dose in home
Day 2
Pre dose
S-K: ≥3.5, ≤5.0
S-K: ≥3.0, ≤3.4*
Go to Day 3
S-K: Serum potassium, QD: Once daily, TID: Three times daily
*: Confirmation by an additional measurement after 10 minutes is required.
S-K: ≥5.1, ≤6.5
Day 2
S-K check at
1 hour after 1st 
S-K measure
NO ZS dose in 
Day 2
Start 
Maintenance 
phase
With 5g QD
Day 2
1 hour after 1st dose
S-K: ≥3.5, 
≤6.5
S-K: ≥3.0, 
≤3.4*
Go home:
2nd and 3rd 
dose
Go home:
NO 2nd and 
3rd dose
Stay in hospital
Stay in hospital


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
49 (90)
S-K: <3.0, >6.5
Discontinue
Day 3
Pre dose
S-K: ≥3.5, ≤5.0
S-K: ≥3.0, ≤3.4*
S-K: ≥5.1, ≤6.5
Go home:
NO ZS dose
In Day 3
Start 
Maintenance 
phase
With 5g QD
Go home:
ZS 10g TID
In Day 3
Day 4
Pre dose
S-K: ≥3.5, ≤5.0
S-K: ≥3.0, ≤3.4*
S-K: ≥5.1, ≤6.5
Study
discontinuation
Start 
Maintenance 
phase
With 5g QD
Study
discontinuation
S-K: Serum potassium, QD: Once daily, TID: Three times daily
*: Confirmation by an additional measurement after 10 minutes is required.
4.2.5
Maintenance Phase Day 1 (Visit 6)
The Maintenance Phase Day 1 will take place on the day the subject achieves an i-STAT 
potassium value between 3.5 and 5.0 mmol/L, inclusive, after 24 (Visit 3), 48 (Visit 4), or 72 
hours (Visit 5) of ZS 10 g TID treatment during the Correction Phase and procedures listed below 
should take place immediately after procedures of visit 3, 4 or 5, as applicable. 
The following assessments will be performed:


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
50 (90)
!
Clinical chemistry will be performed (Sample will be the same sample as obtained 
on the last day of the Correction Phase).
!
An ECG will be performed (Section 5.2.3).
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
A targeted physical examination including weight (Section 5.2.2).
!
The clinic staff access the IVRS/IWRS to record that the subject entered the 
Maintenance Phase. The system will assign the subject a new Maintenance Phase 
investigational product kit containing an additional supply of ZS. 
!
The first dose of ZS during the Maintenance Phase will be administered in the clinic 
as a suspension in water. The clinic staff will solicit any adverse events.
!
Subjects will be sent home. They will be requested to fill out a dosing schedule card 
indicating when they took ZS. Subjects will return to the clinic on Maintenance 
Phase Day 2 and bring the used investigational product boxes and sachets and 
dosing schedule card with them.
4.2.6
Maintenance Phase Day 2 (Visit 7)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. Subjects need to bring kit previously dispensed at 
Maintenance Phase Day 1.
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product sachets and make note of 
when the doses were taken and any unused investigational products on the eCRF 
and source documents.
!
An ECG will be performed (Section 5.2.3).
!
Prior to ZS administration, potassium samples (i-STAT and Central Laboratory) 
will be collected.  If the i-STAT value is > 5.0 mmol/L or between 3.0 and 3.4 
mmol/L while receiving 5 g QD, a second potassium measurement (i-STAT and 
Central Laboratory) will be obtained 10 (± 2) minutes later. If both i-STAT values 
are as stated above, the dose will be adjusted in accordance with Section 7.2, Table 
6.
!
The ZS dose will be administered in the clinic as a suspension in water.
!
Subjects will be sent home. They will be requested to fill out a dosing schedule card 
indicating when they took ZS. Subjects will return to the clinic for the next 
scheduled visit and bring the used investigational product boxes and sachets and 
dosing schedule card with them.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
51 (90)
4.2.7
Maintenance Phase Day 5 (Visit 8)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. Subjects need to bring kit previously dispensed at 
Maintenance Phase Day 1.
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product sachets and make note of 
when the doses were taken and any unused investigational products on the eCRF 
and source documents.
!
An ECG will be performed (Section 5.2.3).
!
Blood samples for the assessment of hematology will be collected.
!
Prior to ZS administration, blood samples for i-STAT potassium and assessment of 
clinical chemistry including S-K will be collected. If the i-STAT value is > 5.0 
mmol/L while receiving 5 g QD, 5 g QOD (or 2.5 g QD), 10 g QD or 15 g QD or 
between 3.0 and 3.4 mmol/L, inclusive, a second potassium measurement (i-STAT
and Central Laboratory) will be obtained 10 (± 2) minutes later. If both i-STAT 
values are as stated above, the dose will be adjusted in accordance with Section 7.2, 
Table 6.
!
The ZS dose will be administered in the clinic as a suspension in water.
!
Subjects will be sent home. They will be requested to fill out a dosing schedule card 
indicating when they took ZS. Subjects will return to the clinic for the next 
scheduled visit and bring the used investigational product boxes and sachets and 
dosing schedule card with them.
4.2.8
Maintenance Phase Day 12 (Visit 9)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. 
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product boxes and sachets and make 
note of when the doses were taken and any unused investigational products on the 
eCRF and source documents.
!
An ECG will be performed (Section 5.2.3). 
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
A targeted physical examination including weight (Section 5.2.2). 
!
Blood samples for the assessment of hematology will be collected.
!
Prior to ZS administration, blood samples for i-STAT potassium and assessment of 
clinical chemistry including S-K will be collected. If the i-STAT value is > 5.0 
mmol/L while receiving 5 g QD, 5 g QOD (or 2.5 g QD), 10 g QD or 15 g QD or


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between 3.0 and 3.4 mmol/L, inclusive, a second potassium measurement (i-STAT 
and Central Laboratory) will be obtained 10 (± 2) minutes later. If both i-STAT values 
are as stated above, the dose will be adjusted in accordance with Section 7.2, Table 
6.
!
The clinic staff will access the IVRS/IWRS and provide the 7-digit subject 
identification number and the i-STAT potassium value. The system will assign the 
subject a new Maintenance Phase investigational product kit containing an 
additional supply of ZS.
!
The ZS dose will be administered in the clinic as a suspension in water.
!
Subjects will be sent home with the investigational product kit and instructions on 
how to take ZS. They will be requested to fill out a dosing schedule card indicating 
when they took ZS. Subjects will return to the clinic for the next scheduled visit and 
bring the used investigational product boxes and sachets and dosing schedule card 
with them.
4.2.9
Maintenance Phase Day 19 (Visit 10)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. Subjects need to bring kit previously dispensed at 
Maintenance Phase Day 12.
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product sachets and make note of 
when the doses were taken and any unused investigational products on the eCRF 
and source documents.
!
An ECG will be performed (Section 5.2.3). 
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
Blood samples for the assessment of hematology will be collected.
!
Prior to ZS administration, blood samples for i-STAT potassium and assessment of 
clinical chemistry including S-K will be collected. If the i-STAT value is > 5.0 
mmol/L while receiving 5 g QD, 5 g QOD (or 2.5 g QD), 10 g QD or 15 g QD or 
between 3.0 and 3.4 mmol/L, inclusive, a second potassium measurement (i-STAT
and Central Laboratory) will be obtained 10 (± 2) minutes later. If both i-STAT values 
are as stated above, the dose will be adjusted in accordance with Section 7.2, Table 
6.
!
The ZS dose will be administered in the clinic as a suspension in water.
!
Subjects will be sent home. They will be requested to fill out a dosing schedule card 
indicating when they took ZS. Subjects will return to the clinic for the next 
scheduled visit and bring the used investigational product boxes and sachets and 
dosing schedule card with them.


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4.2.10 Maintenance Phase Day 26- Day 334 (Visit 11- Visit 22)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. 
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product boxes and sachets and make 
note of when the doses were taken and any unused investigational products on the 
eCRF and source documents.
!
Prior to ZS administration, potassium samples (i-STAT and Central Laboratory) will 
be collected. S-K will be evaluated as part of the clinical chemistry sample on Visits 
11, 13, 16, 19 and 22. If the i-STAT value is > 5.0 mmol/L while receiving 5 g QD, 
5 g QOD (or 2.5 g QD), 10 g QD or 15 g QD or between 3.0 and 3.4 mmol/L, 
inclusive, a second potassium measurement (i-STAT and Central Laboratory) will be 
obtained 10 (± 2) minutes later. If both i-STAT values are as stated above, the dose
will be adjusted in accordance with Section 7.2, Table 6.
!
Samples will be collected prior to any IP administration.
∀
Blood samples for assessment of hematology and clinical chemistry including 
S-K (Visits 11, 13, 16, 19 and 22).
∀
Aldosterone and renin collected prior to 10 am (1000) after the subject has 
been in an upright position for at least 2 hours and before recording the ECG 
and physical examination (Visits 16).
∀
Urine for urinalysis parameters (Visits 11, 13, 16, 19 and 22).
!
An ECG will be performed (Section 5.2.3) (Visits 11, 12, 13, 16, 19 and 22).
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
A targeted physical examination including weight (Section 5.2.2).
!
The site will access the IVRS/IWRS and provide the 7-digit subject identification 
number and the i-STAT potassium value. The system will assign the subject a new 
Maintenance Phase investigational product kit containing an additional supply of 
ZS. 
!
The ZS dose will be administered in the clinic as a suspension in water.
!
Subjects will be sent home with the investigational product kit and instructions on 
how to take ZS. They will be requested to fill out a dosing schedule card indicating 
when they took ZS. Subjects will return to the clinic for the next scheduled visit and 
bring the used investigational product boxes and sachets and dosing schedule card 
with them. 


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4.2.11 Maintenance Phase Day 362 (Visit 23)
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection. 
!
Administer the SF-36 v2 questionnaire. The patient should complete the 
questionnaire prior to any other study procedures.
!
Enter the patient questionnaire in patients who were prescribed ZS 5 g QOD.
!
The clinic staff will solicit any adverse events, note any changes in concomitant 
medications, note if the subject has visited a doctor or emergency room since the 
last visit, examine the returned investigational product boxes and sachets and make 
note of when the doses were taken and any unused investigational products on the 
eCRF and source documents.
!
Blood samples for i-STAT potassium and assessment of hematology and clinical 
chemistry including S-K will be collected.
!
Aldosterone and renin collected prior to 10 am (1000) after the subject has been in 
an upright position for at least 2 hours and before recording the ECG and physical 
examination.
!
Assessment of urinalysis parameters.
!
An ECG will be performed (Section 5.2.3).
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
A targeted physical examination including weight (Section 5.2.2).
!
Subjects will be instructed to return in 7 (± 1) days after the last administration of 
IP for the End of Study visit. 
4.3
Follow-up period (EOS)
Follow up visit will be performed at Day 10 for Correction Phase, and 7 ±1 days following the 
last study IP administration in Maintenance Phase, or 7 ±1 days following the last study IP 
administration for patients who are withdrawn from the study medication.
!
Subjects will arrive at the clinic in the morning, fasting for at least 8 hours prior to 
potassium sample collection.
!
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 ZS 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.


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!
An ECG will be performed (Section 5.2.3).
!
Obtain vital signs (pulse rate and blood pressure) (Section 5.2.4).
!
A targeted physical examination including weight (Section 5.2.2).
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 and Table 2). 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.
5.1.2
Aldosterone and Renin Samples
Aldosterone and renin samples will be collected as summarized in Table 1 and Table 2. 
Samples will be collected prior to 10 am (1000) after the subject has been upright (sitting or 
standing) for at least 2 hours and prior to any ECG/physical examination assessments.
Aldosterone samples should be collected into serum separator tubes and renin samples should 
be collected into EDTA tubes. All samples must be processed to serum (aldosterone) or 
plasma (renin) according to the central laboratory manual, and immediately frozen (~ –20°C). 
All serum and plasma samples should be examined and any hemolyzed samples MUST be 
redrawn.
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 and Table 2). Additional 


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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.
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site.
Table 3
Laboratory Safety Variables
Haematology
Clinical Chemistry (serum)
B-Hemoglobin (Hb)
S-Total Protein
B-Hematocrit
S-Albumin
B-Erythrocyte count (RBC)
S-Bicarbonate
B-Total leukocyte count (WBC)
S-Blood Urea Nitrogen
B-Platelet count
S-Creatinine
S-Bilirubin, total
Urinalysis
S-Alkaline phosphatise (ALP)
U-PH
S-Glucose
U-Specific gravity
S-Sodium
U-Glucose 
S-Potassium1
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-Protein
U-Human chorionic gonadotropin (HCG) (only 
for females of childbearing potential) 2
Additional Laboratory Tests
S-Aldosterone
P-Renin
1.
Blood potassium will be tested by i-STAT and Central Laboratory
2.
Urine-HCG will be measured at clinic, used 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 


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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, on Correction Phase Visit 2, 5 and EOS visit for patients NOT entering the 
Maintenance Phase, and on Maintenance Phase Visits 6 (blood chemistry), 8, 9, 10, 11, 13, 16, 
19, 22, 23 and EOS.
The Correction Phase Visit 2 urine pregnancy test for women of childbearing potential is 
performed as part of the screening procedure prior to any IP administration, Correction Phase 
EOS visit for patients NOT entering the Maintenance Phase and at Maintenance Phase EOS 
visit.
Urinalysis, will be performed by the Central Laboratory at Correction Phase Visit 2, 5 and 
EOS visit for patients NOT entering the Maintenance Phase, and on Maintenance Phase Visits 
11, 13, 16, 19, 22, 23 and EOS.
Note: Whenever possible, all blood draws collected prior to meals should be collected prior to 
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 Correction Phase Visit 2, and targeted 
physical examination will be conducted during the Correction Phase EOS visit for patients not 
entering the Maintenance Phase. During the Maintenance Phase targeted physical 
examinations will be performed at Visits 6, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 
and EOS.
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. 
The targeted physical examination includes the following: weight (weighed on the same scale 
in the same state of dress), skin, extremities, cardiovascular including assessment of signs of 
heart failure, lungs, and abdomen. 
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 and Table 2. 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 Correction Phase Visits 2, 3, 4, 5, EOS visit for patients NOT 
entering the Maintenance Phase, and on Maintenance Phase Visits 6, 7, 8, 9, 10, 11, 12, 13, 


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16, 19, 22, 23 and EOS. When applicable ECGs will be performed after the aldosterone and 
renin samples are drawn and before the first daily dose of IP. In addition, for patients who 
have i-STAT potassium levels ≥ 6.1 mmol/L or <4.0 mmol/L at the 4 hours post 1st dose time 
point on the Correction Phase 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.
5.3
Other assessments
The SF-36 v2 questionnaire will be administered in Japanese. The results will be recorded in 
the eCRF.
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.


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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 and Table 5 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: Correction 
Phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume 
Total (mL)
V 2
(D 1)
V 3
(D 2)
V 4
(D 3)
V 5
(D 4)
EOS
(D 10)
Hematology
2
12
0-14
1
6
Clinical 
Chemistry
2.5
12
0-14
1
7.5
Aldosterone and 
renin
6
12
6
Potassium 
(i-STAT and 
Central Lab S-K)
4.5
3-41,5
23
1
15
15
40.5
Maximum 
blood volume 
Total (mL)
28.5
9
4.5
9
9
60
V= Visit; D=Day
1.
Potassium will be measured twice 60 (±15) minutes apart within 1 day of first dose administration on 
Correction Phase Day 1(Visit 2) and 4 hours (±15 min) after administration of the first dose of ZS; An extra 
potassium will be measured at 90 minutes (±15 minutes) after taking the second dose for patients with i-
STAT potassium ≥ 6.1 or <4.0 mmol/L at the 4 hour post Dose 1
2.
On Correction Phase Day 1(Visit 2), the Central Laboratory clinical chemistry, hematology, aldosterone 
and renin samples will be collected at the same time as the 60 minutes i-STAT screening potassium sample, 
but will be analysed only in confirmed hyperkalemic subjects.
3.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) post 1st dose on Correction Phase Day 2 
(Visit 3)
4.
Clinical chemistry and hematology samples only for patients with i-STAT potassium values < 3.5 or ≥ 
5.1 mmol/L as measured fasting on Correction Phase Day 4 (Visit 5)


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Central laboratory S-K sample collected as part of the clinical chemistry


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Table 5
Volume of blood to be withdrawn from each patient: Maintenance Phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood 
volume 
Total (mL)
V6
D1
V7
D2
V8
D5
V9
D12
V10
D19
V11
D26
V12
D54
V13
D82
V14
D110
V15
D138
V16
D166
V17
D194
V18
D222
V19
D250
V20
D278
V21
D306
V22
D334
V23
D362
EOS
Hematology
2
1
1
1
1
1
1
1
1
1
1
20
Clinical 
Chemistry
2.5
1
1
1
1
1
1
1
1
1
1
1
27.5
Aldosterone 
and renin
6
1
1
12
Potassium 
(i-STAT and 
Central Lab 
S-K1)
4.5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
85.5
Maximum 
blood 
volume 
Total (mL)
7
4.5
9
9
9
9
4.5
9
4.5
4.5
15
4.5
4.5
9
4.5
4.5
9
15
9
145
V=Visit; D=Day
1. 
Potassium will be measured fasting prior to the daily dose. Central laboratory S-K sample collected as part of the serum clinical chemistry at Visit 6, 8, 9, 
10, 11, 13, 16, 19, 22, 23 and EOS.


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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase, that fulfils one or more of 
the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may 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 


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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
!
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 


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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.
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.


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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. 
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.


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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 subject 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.
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 


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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
!
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 


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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) 2.5 g
Powder for Oral Suspension in 
a sachet
AstraZeneca 
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
7.2
Dose and treatment regimens
Sodium Zirconium Cyclosilicate (ZS) should be administered orally as a suspension in water. 
Correction Phase: ZS 10g TID for 24, 48 or 72 hours (3, 6 or 9 doses). Patients will enter the 
Maintenance phase after 24, 48 or 72h if the morning i-STAT potassium is between 3.5 and 
5.0 mmol/L, inclusive.
Maintenance Phase: The starting dose is ZS 5 g QD. The ZS dose may be increased in 
increments of 5 g up to a maximum of 15 g QD or decreased to a minimum of 5 g QOD (or 
2.5 g QD) dependent upon i-STAT potassium measurements (see Dose modification rules in 
Table 6).


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Table 6
Dose modification rules:
Current dose
i-STAT Potassium Value (mmol/L)
Dose Adjustment
5g QOD or 2.5 g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
Discontinue dosing
No change
5g QD
Discontinue dosing
5g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
5g QOD or 2.5 g QD
No change
10g QD
Discontinue dosing
10g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
5g QD
No change
15g QD
Discontinue dosing
15g QD
≤ 2.9 
3.0-3.4
3.5-6.5
>6.5
Discontinue dosing
10g QD
No change
Discontinue dosing
For subjects who require a lower dose than 5 g QD, the first 75 subjects will have their dose 
reduced to 5 g QOD if this their potassium values indicate that they need this lower dose at 
any time during the first 6 months of the maintenance phase, and then be switched to 2.5 g QD 
for the final Month 6 (Visit 17) to Week 52 (end of treatment), if their potassium values are 
still such that this lower dose is required. The remaining 75 subjects will receive the reduced 
dose of 2.5 g QD for  the first 6 months (up to Visit 17) of the maintenance phase, and then be 
switched to 5 g QOD for the final Month 6 (Visit 17) to Week 52 (end of treatment), if a their 
potassium values confirm that a lower dose is still required.
5 g QOD
2.5 g QD
2.5 g QD
5 g QOD
Lowest dose during the Maintenance phase
1st to 75th
enrolled patients
76th to 150th
enrolled patients
Day1
Visit 17
Week 52


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Any time the ZS dose is adjusted, the subject will return to the site 7 (± 2) days later as an 
extra visit for a potassium measurement and recording of any adverse events and concomitant 
medications(Subjects will arrive at the clinic in the morning after fasting for at least 8 hours 
prior to potassium sample collection.). There is no limit to the number of dose titrations 
allowed. Subjects will receive up to 12 months of treatment with open-label ZS.
If a patient develops i-STAT potassium values between 3.0 mmol/L and 3.4 mmol/L, 
inclusive (confirmed by taking a second potassium measurement after a 10 ± 2 minute 
interval) during the Correction Phase the subject will be directed to not take any more study 
drug for the remainder of the day and return the next day to continue in the study. E.g. Patients 
with potassium values between 3.0 mmol/L and 3.4mmol/L on Day 2 will not take the drug 
the rest of the doses on Day 2, and will return fasting to have their potassium tested again on 
Day 3 and continue their therapy. If the potassium has normalized, the patients will start 
Maintenance Phase from the day. If patients with potassium values between 3.0 mmol/L and 
3.4 mmol/L on Day 3, the patients will not take the drug the rest of the doses on Day 3, and 
will return fasting to be assessed for entering into the Maintenance Phase on Day 4.
Patients with i-STAT potassium <3.0 mmol/L (confirmed by taking a second potassium 
measurement after a 10 ± 2 minute interval) 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 Correction 
Phase and subsequent the Maintenance Phase. 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 


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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 Investigational Product Storage Manager 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.
7.7
Concomitant and other treatments 
All concomitant medications taken by the patient from 7 days prior to the Correction Phase
Day 1 until Maintenance Phase EOS visit, or the end of the study (7 ± 1 days after the last 
dose of IP) for patients, will be recorded (including the reasons for 
increase/decrease/initiation/discontinuation of RAASi doses after Correction Phase Day 1). 
It is expected that patients with diabetes will be enrolled. Use of insulin/insulin analog is not 
restricted however 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 must not 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.
Any time a RAAS inhibitor or diuretic dose is adjusted or initiated during the Maintenance 
Phase, the subject will return to the site 7 (± 2) days later for a potassium measurement and 
recording of adverse events and concomitant medications (Subjects will arrive at the clinic in 
the morning after fasting for at least 8 hours prior to potassium sample collection.). If required
the dose of ZS will adjusted or stopped based on the rules in this protocol.
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 ZS to mitigate the risk of drug interactions. 


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Drugs that should be taken 2 hours before or after ZS 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
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 dosed 
and any subsequent amendments will be documented, with final amendments completed prior 
to database lock.
8.2
Sample size estimate
The sample size is estimated so that sufficient safety data of at least 100 Japanese subjects 
treated by ZS for at least one year can be generated, as required by ICH E1 guideline.  
Assuming approximately 35% drop out rate, approximately 150 subjects would be enrolled to 
this open-label study.
8.3
Definitions of analysis sets
Analysis sets will be defined for each of correction phase and maintenance treatment phase.
8.3.1
Full analysis sets
All efficacy analyses will be performed using an Intent-to-Treat (ITT) principle based on the 
full analysis sets.
For the correction phase, the full analysis set will include all patients that receive the 
correction phase ZS dose and have any post-baseline correction phase S-K values.


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For the subsequent long-term maintenance phase, the full analysis set will include all patients 
who receive ZS dose during maintenance phase and have any post-baseline maintenance 
phase S-K values.
8.3.2
Safety analysis sets 
For the correction phase, the safety analysis set will include all patients as treated with at least 
one dose of correction phase ZS and had any correction phase safety data. 
For the subsequent long-term maintenance phase, the safety analysis set will include all 
patients as treated with at least one dose of maintenance phase ZS and had any maintenance 
phase safety data.
8.4
Outcome measures for analyses
8.4.1
Efficacy variables (Secondary)
Maintenance phase
!
Proportion of patients who can maintain normokalemia (defined as S-K level of ≥ 
3.5 and ≤ 5.0 mmol/L, inclusive) on ZS at each Maintenance Phase study visit
!
Proportion of patients with average S-K ≤ 5.1 mmol/L
!
Proportion of patients with average S-K ≤ 5.5 mmol/L
!
Proportions of patients who were normokalemic (S-K ≥ 3.5 and ≤ 5.0 mmol/L), 
hypokalemic (< 3.5 mmol/L), or hyperkalemic (> 5.0 mmol/L) at each Maintenance 
Phase visit.
!
Subject-level average S-K over certain period of time
!
Observed values at visit and change from baseline in S-K over time
!
Number of normokalemic days during Maintenance Phase
!
Change in S-K level from the last on-treatment Maintenance Phase visit to the End 
of Study
!
Change from baseline in S-Aldosterone over time 
!
Proportion of patients with normal S-Aldosterone 
!
Change from baseline in S-Bicarbonate 
!
Proportion of patients with normal S-Bicarbonate
!
SF-36 v2 questionnaire
Correction phase 
!
Observed values and change from Correction Phase baseline in S-K


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!
Proportion of patients who achieved normokalemia at 24, 48 and 72 hours after start 
of dosing
!
Safety and tolerability as measured by adverse events reporting, vital signs, ECGs, 
physical examinations, and safety laboratory measurements during Correction 
Phase
8.4.2
Efficacy variables (Exploratory)
!
Patient questionnaire on preference for low intensity ZS dosing(QOD or QD)
!
Proportion of subjects increased RAASi doses
!
Proportion of subjects who decrease or discontinued RAASi doses
!
Proportion of subjects who increased at least once RAASi due to each reason
!
Proportion of subjects who decreased/discontinued at least once RAASi due to each 
reason 
!
Time to first reduction/discontinuation of RAASi
8.4.3
Safety Variables
In this study, the following safety data will be collected: adverse events reporting, vital signs, 
ECGs, physical examinations, and safety laboratory measurements.
8.5
Methods for statistical analyses
8.5.1
Analyses of efficacy variables
Efficacy analyses will be performed separately for the correction phase and maintenance 
phase.
For continuous variables, the values at visit and change from baseline (and percent change 
from baseline, if appropriate) will be summarized by descriptive statistics.  For categorical 
variables frequency and percentage will be summarized. Model-based point estimates and 
95% CIs will also be presented if appropriate. Time to event (such as RAASi reduction) will 
be displayed with Kaplan-Meier plot. No formal statistical testing will be performed in this 
study.
8.5.2
Analysis of Safety data
Safety analyses will be performed separately for the correction phase and maintenance phase. 
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. Kidney 
function will be evaluated by assessments of creatinine, eGFR, urine protein-to-creatinine 
ratio (UPCR) and urine albumin-to-creatinine ratio (UACR) over time. Liver function will be 
evaluated by assessing bilirubin, AST and ALT.


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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.
Vital signs, ECGs and laboratory measurements will also be summarized descriptively. 
8.5.3
Interim analysis
An interim analysis may be performed when all enrolled subjects completed at least 6-month 
visit, for the purpose of regulatory submission.
An interim analysis is planned in this study. The data of interim analysis will be cut off when 
the last subject goes through Visit 17. An interim analysis will include all patients' data 
available until data cut-off even if patients withdraw prior to Visit 17 including analysis at the 
correction phase endpoints as well as safety evaluation up to Visit 17.
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


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!
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 
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 Q3 2019.
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.


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9.4
Data management by AstraZeneca or delegate
Data management will be performed by AstraZeneca Data Management Center staff or other 
party, 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 
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.


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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Institutional Review Board (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.
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.


Clinical Study Protocol
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
79 (90)
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.
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 


Clinical Study Protocol
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Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
80 (90)
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.
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 D9482C00001
Version 5.0
Date 13 Sep 2018
81 (90)
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 D9482C00001
Version 5.0
Date 13 Sep 2018
82 (90)
!
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 D9482C00001
Version 5.0
Date 13 Sep 2018
83 (90)
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.


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
84 (90)
Appendix C
SF-36 v2


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
85 (90)


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
86 (90)


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
87 (90)


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
88 (90)


Clinical Study Protocol Appendix C
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
89 (90)


Clinical Study Protocol Appendix D
Drug Substance ZS
Study Code D9482C00001
Version 5.0
Date 13 Sep 2018
Version 1.0 25 Sep 2017
90 (90)
Appendix D
Patient questionnaire English ver. (for Visit 23 or EOS visit)
Study Number: D9482C00001
Site Number:
Subject Number: 
Visit Number:
Assessment Date:
Q1. In the study you are participating in, two dosages of once daily and once in every other 
day are tested.  Since you have experienced both dosages, please answer what you felt about 
these dosages when you compare both.
□ 1. I prefer once daily intake
□ 2. I somewhat prefer once daily intake
□ 3. Either is okay to me
□ 4. I somewhat prefer once in every other day intake
□ 5. I prefer once in every other day intake
Q2. If you felt anything else about the study drug intake, please comment.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9482c00001-csp-v5
Document Title:
D9482C00001 Clinical Study Protocol version 5
Document ID:
Doc ID-003303500
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Sep-2018 12:51 UTC
Content Approval
13-Sep-2018 10:12 UTC
Content Approval
13-Sep-2018 07:30 UTC
Content Approval
13-Sep-2018 07:49 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
Redacted
Redacted
Redacted
Redacted

SAP_000.pdf: 
Statistical Analysis Plan, ANGEL
Version number 4.0
Form Doc Number: LDMS_001_00026934
Parent Doc Number: 
Statistical Analysis Plan
Study Code
D9482C00001
Edition Number
4.0
Date
17-Jun-2019
A Phase 3 Multicenter Open-label Maintenance Study to Investigate the 
Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese 
Subjects With Hyperkalemia


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
2
A Phase 3 Multicenter Open-label Maintenance Study to Investigate the 
Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese 
Subjects With Hyperkalemia 
Study Statistician
Date


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
3
A Phase 3 Multicenter Open-label Maintenance Study to Investigate the 
Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese 
Subjects With Hyperkalemia 
Global Product Statistician
Date


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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..................................................................................9
1.
STUDY DETAILS.............................................................................................10
1.1
Study objectives................................................................................................. 10
1.2
Study design ...................................................................................................... 11
1.3
Number of subjects ............................................................................................13
2.
ANALYSIS SETS .............................................................................................13
2.1
Definition of analysis sets .................................................................................. 13
2.1.1
Enrolled subjects................................................................................................13
2.1.2
Full analysis sets ................................................................................................ 13
2.1.3
Safety analysis sets ............................................................................................ 14
2.2
Protocol deviations............................................................................................. 14
3.
PRIMARY AND SECONDARY VARIABLES.................................................14
3.1
Primary variables (Safety)..................................................................................14
3.2
Secondary variables ........................................................................................... 15
3.2.1
Efficacy in Maintenance phase...........................................................................15
3.2.2
Efficacy in Correction Phase ..............................................................................16
3.2.3
Safety in Correction Phase .................................................................................16
3.3
Exploratory variables ......................................................................................... 16
4.
ANALYSIS METHODS....................................................................................16
4.1
General principles.............................................................................................. 16
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/Time windows...........................................................................................17
4.1.4
Last on-treatment ............................................................................................... 19
4.1.5
Handling of drop outs and missing data..............................................................19
4.1.5.1
Missing central lab individual measurements of S-K..........................................19


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
5
4.1.5.2
Handling of early study discontinuation .............................................................19
4.1.6
Descriptive summary of continuous variables.....................................................20
4.1.7
Descriptive summary of categorical variables.....................................................20
4.1.8
Descriptive summary and analysis of binomial proportions................................20
4.1.9
Repeated measures mixed model for log-transformed S-K .................................20
4.2
Analysis methods...............................................................................................20
4.2.1
Study patients ....................................................................................................20
4.2.1.1
Disposition of patients........................................................................................ 20
4.2.2
Demographics and baseline characteristics.........................................................21
4.2.3
Extent of Exposure.............................................................................................22
4.2.3.1
Study Medication...............................................................................................22
4.2.3.2
Prior and concomitant medication ......................................................................23
4.2.3.3
Measurements of Treatment Compliance ...........................................................24
4.2.4
Efficacy .............................................................................................................24
4.2.4.1
Efficacy in the Maintenance Phase.....................................................................24
4.2.5
Efficacy in the Correction Phase ........................................................................27
4.2.6
Exploratory........................................................................................................28
4.2.7
Safety.................................................................................................................29
4.2.7.1
Adverse events...................................................................................................29
4.2.7.2
Clinical Laboratory evaluation ...........................................................................30
4.2.7.3
Vital signs.......................................................................................................... 32
4.2.7.4
ECGs .................................................................................................................32
5.
INTERIM ANALYSES .....................................................................................33
6.
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE)..........33
7.
REFERENCES (NOT APPLICABLE)...............................................................33
8.
APPENDIX ....................................................................................................... 33
8.1
Focus of Interim Analysis .................................................................................. 33
LIST OF TABLES
Table 1
Dose Adjustment during MP .................................................................12
Table 2
Visit window for correction phase.........................................................18
Table 3
Visit window for maintenance phase .....................................................18
Table 4
Demographics.......................................................................................21
Table 5
Disease-related characteristics...............................................................21
Table 6
RAASi dose changes.............................................................................28
Table 7
Potentially Clinically Significant Abnormalities for Laboratory 
Values...................................................................................................31


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
6
Table 8
Potentially Clinically Significant Abnormalities for Vital Signs ............32
Table 9
Categorical evaluation of QTc prolongation ..........................................33


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AZ
AstraZeneca
BUN
Blood Urea Nitrogen
CI
Confidence Interval 
CKD
Chronic Kidney Disease
CP 
Correction Phase 
CPS
Calcium Polystyrene Sulfonate
DAE
Adeverse Event leading to discontinuation of study drug
DBP
dialystolic blood pressure
DM
Diabetes Mellitus
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
eGFR
estimated Glomerular Filtration Rate
EOS
End of Study
FAS
Full analysis set
GGT
Gamma-glutamyl transferase
HF
Heart Failure
IC
Informed Consent
IP
investigational product
i-STAT
A portable blood analyser
ITT
Intent-to-Treat 
IxRS
Interactive Voice/Web Response System
LSMean
Least sqaure mean
MedDRA
Medical Dictionary for Regulatory Activities
MP
Maintenance Phase 
QD
once daily
QOD
every other day 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
8
Abbreviation or 
special term
Explanation
RAASi
Renin angiotensin aldosterone system inhibitors
SAE
Serious Adverse Event 
SAF
Safety analysis set 
SBP
Systolic blood pressure
SD
Standard Deviation
SE
Standard Error
S-K
Serum potassium
SPS
Sodium Polystyrene Sulfonate
TEAE
Treatment Emergent Adverse Event
TID
three times daily
UACR
Urine Albumin-to-Creatinine Ratio
UPCR
Urine Protein-to-Creatinine Ratio
ZS
Sodium Zirconium Cyclosilicate


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
9
AMENDMENT HISTORY
Date
Brief description of change
N/A
18-Dec-2018
Update the following points : 
-
Added search criteria for comorbidities and RAASi 
-
Updated sensitivity analyses for Central lab assay change for S-K 
-
Updated sensitivity analyses for iSTAT potassium 
-
Added subgroup analyse of S-K and AEs
-
Updated the summary of exposure
-
Added analysis of RAASi dose change as per protocol amendment 
-
Added analysis of Questionnaire for QOD or QD regimen
-
Added Adverse events of special interest
-
Clarified “on-treatment” definition, especially for under QOD regimen
-
Added detail of an approach to IA 
5-Feb-2019
Update the following points : 
-
Clarified visit aping rule for unscheduled visit
-
Age/weight cut-offs were updated
-
Deleted summary for days per dose period for which interpretation is 
difficult
-
Added subgroup evaluation for S-K and AEs 
-
Added < 2.5 mmol/L category for hypokalemia summary
-
Updated compliance calculation to provide more precise value
17-Jun-2019
-Added clarification for the visit mapping and for number of normokalemic days 
derivation. 
-Removed descriptive summary of 3-component summary scores for SF36v2, 
and clarified that scoring will be done based on the standard algorithm.  


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
10
1.
STUDY DETAILS
1.1
Study objectives
Primary Objective:
Outcome Measure:
Maintenance Phase
To assess open-label, long-term (12 months) 
safety and tolerability for ZS in Japanese 
subjects with hyperkalemia (serum potassium 
≥ 5.1 mmol/L).
Safety and tolerability as measured by adverse events
reporting, vital signs, ECGs, physical examinations, 
and safety laboratory measurements.
Secondary Objectives:
Outcome Measures:
Maintenance Phase
!
To evaluate the proportion of ZS-treated 
subjects in whom normokalemia can be 
maintained over prolonged periods of 
time, using an individually titrated dose 
(5 g every other day [or 2.5 g once daily], 
5 g once daily, 10 g once daily or 15 g 
once daily)
!
Proportion of patients who can maintain 
normokalemia (defined as S-K level of ≥ 3.5 and 
≤ 5.0 mmol/L, inclusive) on ZS at each 
Maintenance Phase study visit
!
Proportion of patients with average S-K ≤ 5.1
mmol/L
!
Proportion of patients with average S-K ≤ 5.5 
mmol/L
!
Proportions of patients who were normokalemic 
(S-K ≥ 3.5 and ≤ 5.0 mmol/L), hypokalemic (< 
3.5 mmol/L), or hyperkalemic (> 5.0 mmol/L) at 
each Maintenance Phase visit.
!
Subject-level average S-K over certain period of 
time
!
Observed values at visit and change from 
baseline in S-K over time
!
Number of normokalemic days during 
Maintenance Phase
!
Change in S-K level from the last on-treatment 
Maintenance Phase visit to the End of Study 
(EOS)
!
To explore the time course of S-
Aldosterone and S-Bicarbonate
!
Change from baseline in S-Aldosterone over 
time 
!
Proportion of patients with normal S-
Aldosterone 
!
Change from baseline in S-Bicarbonate 
!
Proportion of patients with normal S-
Bicarbonate


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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Secondary Objectives:
Outcome Measures:
!
To evaluate the health state in the study 
population using SF-36 v2.
!
SF-36 v2 questionnaire
Correction Phase
To assess efficacy, safety and tolerability of 
10 g TID ZS in Japanese patients with 
hyperkalemia (serum potassium [S-K] ≥ 5.1 
mmol/L).
!
Observed values and change from Correction 
Phase baseline in S-K
!
Proportion of patients who achieved 
normokalemia at 24, 48 and 72 hours after start of 
dosing
!
Safety and tolerability as measured by adverse 
events reporting, vital signs, ECGs, physical 
examinations, and safety laboratory 
measurements during Correction Phase
Exploratory Objective:
Outcome Measure:
Maintenance Phase
Patient reported outcomes:
To evaluate if patients prefer ZS QOD or OD
using the patient questionnaire.
Patient questionnaire
Treatment period
To explore change in doses and reasonings of
the change of RAAS inhibitors during the
treatment period.
!
Proportion of subjects increased RAASi doses
!
Proportion of subjects who decrease or 
discontinued RAASi doses
!
Proportion of subjects who increased at least 
once RAASi due to each reason
!
Proportion of subjects who 
decreased/discontinued at least once RAASi due 
to each reason
!
Time to first reduction/discontinuation of RAASi
1.2
Study design
The study is an open label, single arm study with flexible dose regimen focused on assessing 
long-term safety and tolerability of ZS in Japanese subjects with hyperkalemia.
Correction Phase: If the subject is normokalemic (i-STAT [A portable blood analyser] 
potassium between 3.5 and 5.0 mmol/L, inclusive) on the morning of Correction Phase Study 
Day 2 after 3 doses of ZS 10 g, they will enter the Maintenance Phase. If the subject is not 
normokalemic, they will receive an additional 24 hours of ZS 10 g TID treatment (6 total 
doses). If the subject’s i-STAT potassium value is between 3.5 and 5.0 mmol/L, inclusive, on 
the morning of Correction Phase Study Day 3, the subject will enter the Maintenance Phase. If 
the subject is not normokalemic, they will receive an additional 24 hours of ZS 10 g TID 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
12
treatment (9 total doses). If the subject’s i-STAT potassium value is between 3.5 and 5.0 
mmol/L, inclusive, on the morning of Correction Phase Study Day 4, the subject will enter the 
Maintenance Phase. If the i-STAT potassium value is still < 3.5 mmol/L or ≥ 5.1 mmol/L on 
the morning of Correction Phase Study Day 4, after 72 hours of TID treatment, the subject 
will be withdrawn from the study and referred to their normal health care provider for 
standard of care treatment. Subjects withdrawn from the Correction Phase of the study will 
return to the clinic 7 (± 1) days after their last dose of ZS for an End of Study (EOS) visit.
Maintenance Phase: Patients will initially be dosed with ZS at a starting dose of 5g QD. 
During the Maintenance Phase, the ZS dose may be increased up to 15 g QD or decreased 
down to 5g QOD (or 2.5 g QD) based on i-STAT potassium measurements as outlined in 
Table 1.
Table 1
Dose Adjustment during MP
Current dose
i-STAT Potassium Value (mmol/L)
Dose Adjustment
5g QOD or 2.5 g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
Discontinue dosing
No change
5g QD
Discontinue dosing
5g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
5g QOD or 2.5 g QD
No change
10g QD
Discontinue dosing
10g QD
≤ 2.9 
3.0-3.4
3.5-5.0
5.1-6.5
>6.5
Discontinue dosing
5g QD
No change
15g QD
Discontinue dosing
15g QD
≤ 2.9 
3.0-3.4
3.5-6.5
>6.5
Discontinue dosing
10g QD
No change
Discontinue dosing
Throughout all phases of the study, most potassium values will be measured at fasting before 
taking ZS. Nothing should be taken by mouth except water, coffee or tea, with or without milk 
and/or sugar, and essential medications, for a minimum of 8 hours prior to the blood 
collection. Potassium level should be determined by both i-STAT and the Central Laboratory 
on all occasions. Treatment decisions (eg, dose titration, stopping rules) will be made based on 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
13
i-STAT potassium values, as these provide clinical sites with a real-time measurement, 
according to dose modification rules. 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]), aldosterone, renin and 
hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms 
(ECGs) will be assessed. 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, arrhythmias, or 
development of congestive heart failure or end stage renal failure.
1.3
Number of subjects
Sample size of in total 150 subjects to be enrolled to this study was determined so that at least 
safety data of 100 subjects treated by ZS as long as one year will be collected, assuming 35% 
drop out rate.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Efficacy and safety analysis sets will be defined for each of correction phase and maintenance 
treatment phase.
2.1.1
Enrolled subjects 
All subjects who signed informed consent. 
2.1.2
Full analysis sets
All efficacy analyses will be performed using an Intent-to-Treat (ITT) principle based on the 
full analysis sets.
FAS-CP : For the correction phase (CP), the full analysis set will include all patients that 
receive at least one dose of  ZS during the correction phase and have any post-baseline 
correction phase S-K values.
FAS-MP : For the subsequent long-term maintenance phase (MP), the full analysis set will 
include all patients who receive at least one dose of ZS during maintenance phase and have 
any post-baseline maintenance phase S-K values.


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Edition Number 4.0
Date 17-Jun-2019
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2.1.3
Safety analysis sets 
SAF-CP: For the correction phase, the safety analysis set will include all patients treated with 
at least one dose of correction phase ZS and had any correction phase safety data. 
SAF-MP: For the subsequent long-term maintenance phase, the safety analysis set will include 
all patients treated with at least one dose of maintenance phase ZS and had any maintenance 
phase safety data.
2.2
Protocol deviations
Protocol deviations will be identified programmatically or manually prior to database lock. 
Subjects who deviate from important protocol conditions (e.g. selected inclusion/exclusion 
criteria) will be reported as having important protocol deviations. 
Important protocol deviations would include but not limited to:
∀
Patients who received ZS but did not meet Inclusion/Exclusion criteria
∀
Patients who received prohibited concomitant medication or non-drug therapy 
∀
Patients who received wrong ZS dose regimen (including incorrect up-/down-
titration) 
∀
Study drug compliance < 80% or > 120%.
No protocol deviations will lead to exclude subjects from analysis. All the efficacy analyses 
will be based on the FAS and all the safety analyses will be based on SAF for each phase. 
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary variables (Safety) 
Safety and tolerability of long-term ZS treatment (starting with 5g QD, flexible titration 
between 2.5g QD (5g QOD) and 15g QD) in patients with hyperkalemia will be evaluated by 
the following safety measures : 
!
Adverse Events (AEs)  
!
Safety clinical laboratory assessments
!
Vital signs 
!
ECGs   


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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3.2
Secondary variables 
3.2.1
Efficacy in Maintenance phase
Efficacy of long-term ZS treatment in patients with hyperkalemia will be evaluated by the 
following efficacy measures: 
!
Proportion of patients who can maintain normokalemia (defined as S-K level of ≥ 
3.5 and ≤ 5.0 mmol/L, inclusive) on ZS at each Maintenance Phase study visit
!
Proportion of patients with average S-K ≤ 5.1 mmol/L
!
Proportion of patients with average S-K ≤ 5.5 mmol/L
!
Proportions of patients who were normokalemic (S-K ≥ 3.5 and ≤ 5.0 mmol/L), 
hypokalemic (< 3.5 mmol/L), or hyperkalemic (> 5.0 mmol/L) at each Maintenance 
Phase visit.
!
Subject-level average S-K over the certain period of time (as specified below)
∀
entire MP [Day 2 to Day 362]
∀
Month 3 to Month 12 [Day 82 to Day 362]
∀
Day 2 to Month 3[Day 2 to Day 82]
∀
Month 4 to Month 6 [Day 110 to Day 166]
∀
Month 7 to Month 9 [Day 194 to Day 278]
∀
Month 10 to Month 12 [Day 306 to Day 362]
!
Observed values at visit and change from baseline in S-K over time up to Week 
52[Day 362]
!
Number of normokalemic days during Maintenance Phase
!
Change in S-K level from the last on-treatment Maintenance Phase visit to the End 
of Study
!
Change from baseline in S-Aldosterone over time
!
Proportion of patients with normal S-Aldosterone 
!
Change from baseline in S-Bicarbonate over time 
!
Proportion of patients with normal S-Bicarbonate
!
SF-36 v2 questionnaire


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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3.2.2
Efficacy in Correction Phase 
Efficacy in the Correction Phase ZS treatment in patients with hyperkalemia will be evaluated 
by the following efficacy measures: 
!
Observed values and change from Correction Phase baseline in S-K through to 72 
hours
!
Proportion (and cumulative proportion) of patients who achieved normokalemia at 
24, 48 and 72 hours after start of dosing
3.2.3
Safety in Correction Phase 
Safety in the Correction Phase ZS treatment will be evaluated by the same variables as 
described in section 3.1.
3.3
Exploratory variables 
!
Patient questionnaire
!
Proportion of subjects increased RAASi doses
!
Proportion of subjects who decrease or discontinued RAASi doses
!
Proportion of subjects who increased at least once RAASi due to each reason
!
Proportion of subjects who decreased/discontinued at least once RAASi due to each 
reason
!
Time to first reduction/discontinuation of RAASi
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.
Unless otherwise specified, all efficacy analyses will be carried out on the FAS and all safety 
analyses will be based on the SAF, for each study phase (CP or MP).
4.1.1
Objectives and hypotheses 
The objectives of this study is to assessing the safety, tolerability and efficacy of long-term 
treatment up to 52 weeks with ZS flexible dose regimen (starting with 5g QD, up-/down-
titration between 2.5g QD (5g QOD) and 15g QD). There are no confirmatory statistical 
testing in this study and all analyses will be interpreted in a descriptive manner.


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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4.1.2
Definitions
4.1.2.1
Baseline Value
For S-K, Correction Phase (CP) baseline value will be established by the mean of 2 different 
S-K values, recorded 60 minutes apart (to confirm qualification for study entry) on the 
Correction Phase (CP) Day 1. Maintenance Phase (MP) baseline value will be defined as the 
measurement taken in the morning of the day of entering maintenance phase (Visit 6, MP Day 
1). Note that two types of baseline (CP baseline and MP baseline) are defined only for S-K.
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 immediately 
prior to the start of the first dose of ZS during the Correction Phase. Typically, the baseline 
refers to the measurements obtained within 1 day (24 hours) of start of correction phase ZS 
treatment. 
4.1.2.2
Change and Percent Change from Baseline
Change from baseline to any Time (Day or Hour) t in 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 (Day or Hour) t 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/Time windows
In principle, analyses will based on nominal visit basis, only if scheduled visit is available. In 
absence of scheduled visit, the unscheduled visits and discontinuation visit will be mapped 
according the below windows and utilized for by-visit analysis (Table 2 and Table 3). 
If scheduled visit is missing, 
!
If an unscheduled visit exists for that visit window, it will be used. 
!
If two or more unscheduled visits are available for the same window, the one closes 
to nominal target day will be used. 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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!
If two unscheduled observations are equally close to target day, the last observation 
will be used. 
As outlined in the table, S-K measurement taken within 1 day (2 days on QOD regimen) after 
last dose will be regarded as on-treatment and used in analysis. Unscheduled S-K 
measurement taken more than 1 day (2 days on QOD regimen) after last dose of ZS could be 
mapped to EOS (Follow up) visit.  
Table 2
Visit window for correction phase
Study Visit
Nominal Day 
Target Day
FromTo
1
Screening (CP Baseline) 
-
-1
2
CP Day 1 (CP Baseline) 
1
1
1
3
CP Day 2
2
2
2
4
CP Day 3
3
3
3
5
CP Day 4
4
4
4
EOS
CP Follow Up
10
5
17
Table 3
Visit window for maintenance phase
Study Visit Nominal Day 
Target Day
From
To*
6
MP Day 1 (MP Baseline) 1
1
1
7
MP Day 2
2
2
3
8
MP Day 5
5
4
8
9
MP Day 12
12
9
15
10
MP Day 19
19
16
22
11
MP Day 26 
26
23
39
12
MP Day 54
54
40
67
13
MP Day 82  
82
68
95
14
MP Day 110
110
96
123
15
MP Day 138
138
124
151
16
MP Day 166 
166
152
179
17
MP Day 194
194
180
207
18
MP Day 222 
222
208
235
19
MP Day 250  
250
236
263
20
MP Day 278 
278
264
291


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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Study Visit Nominal Day 
Target Day
From
To*
21
MP Day 306
306
292
319
22
MP Day 334
334
320
347
23
MP Day 362 
362
348
Last dose + 1 day
(2 days, on QOD 
regimen)
EOS
MP Follow Up
last dose + 7 days
last dose +2 days
(+3 days, on 
QOD regimen)
last dose + 14 days
*S-K measurements more than 1 day (2 days, on QOD regimen) after last dose will be regarded off-treatment 
and will be mapped to the EOS visit. 
Note : Any available measurements regardless of scheduled or unscheduled will be taken into 
account when summarizing the incidence of certain event based on most extreme (lowest or 
highest) values in safety evaluation (e.g. analysis of incidence of hypokalemia, etc).  
4.1.4
Last on-treatment 
The last on-treatment value is defined as the last measurements taken within 1 day (2 days, on 
QOD regimen) after last ZS dose (scheduled or unscheduled). For by-visit summary, the last 
on-treatment measurement during the respective phase will be additionally displayed. 
4.1.5
Handling of drop outs and missing data
4.1.5.1
Missing central lab individual 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 visit. 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. 
4.1.5.2
Handling of early study discontinuation
For subjects who discontinue the study medication before completion, the last assessment will 
be mapped according to the algorithm outlined in section 4.1.3.


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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4.1.6
Descriptive summary of continuous variables
Descriptive summary of continuous variables includes n, mean, standard deviation (SD), 
median, minimum and maximum). In the summary of change or percent change from baseline 
values, 95% confidence interval (95%CI) for the mean (percent) change from baseline will be 
calculated based on t-distribution. 
4.1.7
Descriptive summary of categorical variables
Descriptive summary of categorical variables will consist of frequencies and percentages. 
4.1.8
Descriptive summary and analysis of binomial proportions
For proportions of responders (e.g. patients with normokalemia), percentage and its exact 
(Clopper-Pearson) 95%CI will be provided.
4.1.9
Repeated measures mixed model for log-transformed S-K 
A longitudinal repeated measures analysis using direct likelihood will be performed. The SAS 
procedure PROC MIXED will be used. The dependent variable will be the log-transformed S-
K values measured post-baseline during the MP. The least square means (LSMeans) and its 
95%CIs for each visit (time point) as well as the average over certain period of time will be 
derived from the model by specifying appropriate contrasts. The model estimates (LSMeans 
and 95%CIs) will be back transformed to original scale. 
The model will include the fixed categorical effect of Visit and fixed continuous covariate of 
CP baseline S-K, MP baseline S-K and baseline eGFR. Age category (<55, 55-65, >= 65 
years) and binary indicators for presence of Heart Failure, CKD, Diabetes and RAASi use will 
also be included. An unstructured matrix of within-subject error variance covariance will be 
used. The denominator degrees of freedom will be calculated according to Kenward-Roger 
method. 
4.2
Analysis methods
4.2.1
Study patients
4.2.1.1
Disposition of patients 
The disposition of subjects for the enrollment period, correction phase treatment period, the 
maintenance phase 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 correction phase will include SAF-CP. This summary will 
include subjects completing and discontinuing the correction phase treatment period. 
The summary of disposition in the maintenance phase treatment will include SAF-MP. This 
summary will include subjects completing and discontinuing the maintenance treatment 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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period up-to Visit 17 (MP Day 194) and up-to Visit 23 (MP Day 362), broken down by 
reasons for discontinuation. 
The summary of disposition in CP follow up period will include all subjects who discontinued 
correction phase or completed correction phase but did not enter MP. The summary of 
disposition in MP follow up period will include all subjects who discontinued or completed 
MP. For each, summary will include subjects completing and discontinuing the follow up 
period, broken down by reason for discontinuation. 
4.2.2
Demographics and baseline characteristics
Demographic and other baseline characteristics, including disease-related characteristics will 
be summarized, using the SAF-CP as well as SAF-MP. 
Demographic and baseline characteristics are listed in Table 4. Disease-related common 
baseline characteristics are listed in Table 5. 
Table 4
Demographics
Characteristics
Summarized as 
Categories
Sex
Categorical 
Male, Female
Age
Categorical and Continuous
<65,  >= 65 years
<75, >= 75 years
Body Weight
Categorical and Continuous 
< 65, >= 65 kg
BMI
Continuous
Height
Continuous
Race
Categorical
Asian, Other
Table 5
Disease-related characteristics
Characteristics
Summarized as 
Categories
CP Baseline S-K 
Categorical and Continuous
< 5.5 mEq/L, 
5.5-< 6.0 mEq/L, 
>= 6.0 mEq/L  
Baseline eGFR*
Categorical and Continuous: 
<15 mL/min/1.73m2, 
15-<30 mL/min/1.73m2
30-<60 mL/min/1.73m2
>= 60 mL/min/1.73m2
Comorbidity – Heart Failure
Categorical
Yes, No
Comorbidity -  Diabetes 
Categorical
Yes, No
Comorbidity -  CKD 
Categorical
Yes, No


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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Characteristics
Summarized as 
Categories
RAAS Inhibitor Use 
Categorical 
Yes, No
Diuretic Use
Categorical
Yes, No
On peritoneal dialysis
Categorical
Yes, No
*eGFR derived by Japan guideline formula; 
#
∃
2
1.094
0.287
eGFR[mL/min/1.73m ]
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 
the analysis set (ie, each denominator includes the number of subjects with missing/unknown 
values for the characteristic).
Comorbidities will be based on medical history (ongoing), using the following search criteria:
!
HF will be searched by standardised MedDRA query (SMQ) (narrow) “Cardiac 
failure”.
!
DM will be searched by SMQ (narrow) “Hyperglycaemia/new onset diabetes 
mellitus”.
!
CKD will be searched by SMQ (narrow) “Chronic kidney disease”.
Current medications were based on concomitant medication used at the time of 1st dose of ZS, 
using the following search criteria : 
!
Current RAASi use will be searched by anatomical therapeutic chemical (ATC) 
class ‘C09’ or ‘C03DA’
!
Current Diuretic use will be ATC class ‘C03’, 'C02LG', 'C07CB', 'C09BA', or 
'C09DA'
Medical 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-
CP as well SAF-MP. 
4.2.3
Extent of Exposure
4.2.3.1
Study Medication
Correction phase
Duration of exposure (defined as the last CP dose date – first CP dose date + 1), and number 
of doses taken (at most 9) will be summarized by categorical/continuous descriptive statistics, 
using SAF-CP.  


Statistical Analysis Plan 
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Edition Number 4.0
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Maintenance phase
The following summary will be provided using SAF-MP.  
The extent of exposure to study medication during the MP (defined as the last MP dose date –
first MP dose date + 1) will be summarized with number (%) of subjects with certain duration, 
where the categorization would be 1-7, 8-30, 31-90, 91-180, 181-270, 271-360, and > 360. 
The mean (SD), median, and range of the number of days of exposure will also be presented. 
In addition, total subject-years/days will be calculated using the sum of the exposure to study 
medication for all subjects. 
The extent of exposure to each ZS dose level during the MP will be defined as sum of the dose 
intervals (end date - start date + 1) during which that dose level is given. The extent of 
exposure to each ZS dose level will also be summarized using continuous summary statistics 
and total subject-years/days to each dose level. The summary will be presented also by 
subjects’ maximum dose level. 
Following summaries of exposure during MP will be provided to describe the distribution of 
dose level actually administered in the study:
!
number (%) of subjects with at least one dose taken by dose level
!
number (%) of subjects by mode dose level (dose level used for longest duration per 
subject), by maximum dose level, and by last dose level
!
Summary statistics of mean daily dose (sum of all administered dose (g) divided by 
duration of exposure (day)) during entire maintenance phase
Note: the drug interruption period will also be considered as part of duration of 
exposure (denominator) but will add “0” dose to the numerator.
Further, dose regimen on the target day of scheduled visit will be summarized with 
proportions of patients treated by each dose regimen on that day to show the general 
distribution of dose regimen over time. In addition, proportion of subjects with each sequence 
of dose change will be summarized, if considered meaningful. 
4.2.3.2
Prior and concomitant medication 
Prior medications are defined as medications taken with a start date that falls before the first 
dose of study medication (ZS) of Correction Phase.
Concomitant medications include medications that started prior to, but continued after, the 
first day of a study phase, or medication changes (including newly initiated medications) 
during a study phase. 
All prior medication and concomitant medications will be coded with the WHO Drug 
Dictionary, and summarised by phase for their respective safety analysis sets. 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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4.2.3.3
Measurements of Treatment Compliance
Percent treatment compliance is calculated for the maintenance phase. For each type of 
medication, percent compliance is defined as the sum of ZS doses actually taken divided by 
the sum of dispensed ZS doses that should have been taken.  A subject is considered 
compliant if percent compliance is ≥ 80% and ≤ 120%. In this calculation, period of 
temporary interruption will also be counted in the period when ZS should have been taken as 
assigned by IxRS.
4.2.4
Efficacy 
4.2.4.1
Efficacy in the Maintenance Phase 
Analysis of S-K related variables
!
Proportion of patients who can maintain normokalemia (defined as S-K level of ≥ 
3.5 and ≤ 5.0 mmol/L, inclusive) on ZS at each Maintenance Phase study visit
Number (%) of subjects who can maintain normokalemia at each Mainteance Phase study visit 
and last on treatment visit will be tabulated with binomial proportion and its 95%CI. 
!
Proportions of patients who were hypokalemic (< 3.5 mmol/L) or hyperkalemic (> 
5.0 mmol/L) at each Maintenance Phase visit.
For each visit and last on treatment, patients will be classified to either normokalemic, 
hypokaelmic or hyperkalemic by their S-K value. Number and proportion for each category 
will be tabulated. 
!
Observed values at visit and change from baseline in S-K over time
Observed S-K values at each visit/last on treatment and changes from CP baseline and from 
MP baseline will be summarized by descriptive summary statistics. For changes from baseline, 
95%CI will be also presented.
!
Subject-level average S-K over certain period of time
!
Proportion of patients with average S-K ≤ 5.1 mmol/L 
!
Proportion of patients with average S-K ≤ 5.5 mmol/L
Average S-K level per subject will be calculated over the certain period of time (as specified 
in section 3.2.1).  Continuous summary statistics will be provided for each. In addition, 
number (%) of subjects meeting <= 5.1 or <=5.5 mmol/L will also be summarized with 
binomial proportion and its 95%CI.
!
Model-based estimates for S-K over time as well as average S-K levels over certain 
period of time 


Statistical Analysis Plan 
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Edition Number 4.0
Date 17-Jun-2019
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The log-transformed S-K data will be analysed with mixed model as described in section 
4.1.9. All post-baseline data will be included into the model. The LSMean and 95%CI at each 
timepoint as well as over certain period of time (as specified in section 3.2.1) will be produced 
using appropriate contrasts. The estimates and 95%CIs will back-transformed to original scale 
and tabulated.
!
Number of normokalemic days during Maintenance Phase
The number of normokalemic days during the MP will be calculated assuming that the time 
interval between assessments is normokalemic only if both the beginning and end assessments 
for that time interval display normal S-K values. If an intermediate scheduled assessment time 
point is missing, then the scheduled assessment is regarded as not normokalemic. In order to 
determine this variable all scheduled or unscheduled fasting S-K will be take into calculation. 
Descriptive statistics and 95%CI for mean for the number of normokalemic days will be 
provided.
!
Change in S-K level from the last on-treatment Maintenance Phase visit to the End 
of Study
To investigate if S-K increases after stopping treatment, change in S-K from last on-treatment 
visit to MP EOS (MP follow up) visit will be summarized with continuous summary statistics 
and 95%CI for mean.
Sensitivity analysis for missing S-K values 
For the mean S-K over time, longitudinal repeated measures model specified above will serve 
as a sensitivity check to missing S-K values. It provides estimates of S-K over time had
subjects remained on ZS for planned 52 weeks under the Missing At Random assumption.
Further sensitivity analyses may be conducted depending on the volume of missing data as 
well as on the reason of study discontinuation.
Sensitivity analysis with iSTAT potassium measurements
Since the ZS dose adjustment during study is based on iSTAT measurement, analyses with 
categorized values (e.g. proportion of subjects with normokalemia) are expected to be 
sensitive to which of S-K or iSTAT K are analysed.
Summary of Potassium value over time, proportion of subjects with normokalemia and 
number of normokalemic days will be repeated using iSTAT potassium measurements instead 
of S-K values provided by Central lab. Only observed iSTAT values measured within last ZS 
dose + 1 day (+ 2days on QOD regimen) will be used.
Sensitivity analyssi with iSTAT potassium measurements for Correction Phase will be also 
carried out as outlined in section 4.2.5
Analysis with S-K adjusted for assay change bias


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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Assay for S-K in Covance 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.
Summary of S-K over time as well as proportion of subjects (normokalemia, hyperkalemia, 
hypokalemia) will be repeated using S-K adjusted for assay change instead of S-K values 
provided by Central lab. 
Subgroup analysis of S-K related variables
The summary of proportions (normokalemia, hyperkalemia, hypokalemia) by visit and mean 
change from baseline will be provided by the following subgroups : 
!
By Heart Failure (Yes, No) 
!
By CKD (Yes, No)
!
By DM (Yes, No) 
!
By Baseline RAASi use (Yes, No) 
!
By Baseline Diuretics use (Yes, No) 
!
By Baseline eGFR  (<30, 30-<60, >= 60) 
!
By Baseline S-K (< 5.5, 5.5 -< 6.0,  >=6.0 mmol/L) 
!
By Baseline Weight (<65. >= 65 kg) 
!
By Age (<65, >= 65 years,  < 75, >= 75 years) 
!
By Gender 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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Analysis of S-Aldosterone and S-Bicarbonate
!
Change from baseline in S-Aldosterone over time 
!
Change from baseline in S-Bicarbonate over time
Observed values at each visit (including last on treatment) and changes from baseline will be 
summarized by descriptive summary statistics.  For change from baseline, 95%CI will be also 
presented.
!
Proportion of patients with normal S-Aldosterone 
!
Proportion of patients with normal S-Bicarbonate
Number (%) of subjects who can maintain normal S-Aldosterone levels and S-Bicarbonate, 
respectively, at each Maintenance Phase study visit and last on treatment visit will be 
tabulated with binomial proportion and its 95%CI. Normal reference ranges provided by 
Central laboratory vendor will be used for these analyses.
!
SF-36 v2 questionnaire
In the CSR, only descriptive summary will be provided. Any further analyses of SF-36 v2 
questionnaire will be reported outside the CSR. Note that the scoring for SF-36v2 will be 
based on standard algorithm using the validated software by OPTUM. 
Descriptive summary at baseline and Week 52 will be provided for the following variables 
∀
eight subscale composite scores (Physical Functioning (PF), Role-Physical 
(RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social 
Functioning (SF), Role-Emotional (RE), Mental Health (MH))
∀
physical component summary (PCS) score and mental component summary 
(MCS) scores from standard 2-component model
Number (%) of patients with each category will be provided for the following variable :
∀
Reported Health Transition score (HT) (compared to 1 year ago)
4.2.5
Efficacy in the Correction Phase 
!
Observed values and change from Correction Phase baseline in S-K
Descriptive summary for observed values and changes from baseline through to 24, 48 and 72 
hours post dose as well as last on treatment value will be descriptively summarized. 
!
Proportion of patients who achieved normokalemia at 24, 48 and 72 hours after start 
of dosing


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Number (%) of patients achieved normokalemia at 24, 48 and 72 hours post dose as well as 
last on treatment value with its 95%CIs will be provided. 
Both analyses will be repeated with iSTAT potassium measurements. 
4.2.6
Exploratory 
!
Patient questionnaire
Number (%) of patients falling in each questionnaire category will be presented.  
RAASi dose change related variables
Baseline RAASi user will be determined based on the information collected on CRF (CM 
module).  A patient is considered to be on RAASi, if (s)he used RAASi on the day of first CP 
dose (Day1) of ZS.
RAASi use at end of treatment will be determined based on the information collected on 
CRF(CM module). Patients are regarded as discontinued RAASi, if (s)he is no longer on 
RAASi at the end of treatment (last ZS dose date). 
During the study, any dose change of RAASi will be recorded on the separate CRF module
(RAASIT), with the corresponding reason for changes. While it is anticipated there will be 
various pattern of RAASi changes, investigators are guided to choose either of “increase”, 
“decrease” or “no change”, relative to previous RAASi intensity, based on whether their 
intention of treatment change was to intensify, to diminish, or neither. 
Table 6
RAASi dose changes
For 
Variable
Condition 
Baseline 
RAASi user
Subjects who discontinued RAASi 
-
No RAASi medication at the end of 
ZS treatment 
Baseline 
RAASi user
Subjects who increased RAASi doses
-
at least one dose increase events 
-
no dose decrease events 
Baseline 
RAASi user
Subjects who decreased/discontinued 
RAASi doses
-
at least one dose decrease events 
-
no dose increase events 
Baseline 
RAASi user
Subjects who did not change RAASi 
intensity 
-
no records of “increase” or “decrease” 
events during study.
Baseline 
RAASi user
Subjects who increased at least once 
RAASi due to each reason
at least one cause-specific increase events 
(e.g. “titration”) 
regardless of trajectory of RAASi changes 
before or after that increase.


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
29
Table 6
RAASi dose changes
For 
Variable
Condition 
Baseline 
RAASi user
Subjects who at least once 
decreased/discontinued due to each reason
-
at least one cause-specific decrease 
events (e.g. “high potassium”) 
-
regardless of trajectory of RAASi 
changes before or after that decrease
Baseline 
RAASi non-
user
Subject who initiated RAASi
-
at least one dose increase events 
-
regardless of the trajectory of after 
that dose increase
For each of above category, proportion of subjects will be calculated. 
Further, time to first reduction/discontinuation of RAASi will be presented with Kaplan Meier 
plot for baseline RAASi user. Subjects will be censored at the last day of ZS dose. 
4.2.7
Safety 
4.2.7.1
Adverse events
Adverse events will be classified by the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be considered Treatment-Emergent if onset is on or after first 
dose of ZS and on or before last dose of ZS + 1 day (+ 2days, on QOD regimen). AEs starting 
before 1st AEs with onset during correction phase and those with onset during maintenance 
phase will be separately summarized, unless otherwise specified. Adverse events starting 
before first dose of ZS or more than 1 day (+2days, on QOD regimen) after last dose of ZS 
will only be listed. 
All Adverse events (including SAEs)
Summary of following TEAEs will be separately presented for Correction Phase as well as for 
Maintenance Phase by SOC and PT. Number and proportion of subjects with these events as 
well as the events rates will be provided.   
!
Most common AEs (i.e. reported by >= 2% of patients based on Preferred Term) 
!
Any AEs
!
Deaths
!
Serious AEs (SAEs) 
!
AEs leading to drug discontinuation (DAEs) 
!
AEs by maximal intensity 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
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!
AEs related to study drug
In addition, incidence of AEs by MP study period (Day 1-7, Day 8-30, Day 31-90, Day 91-
180, Day 181-270, Day 271-360, After Day 360) will be presented.
Adverse events of special interest (AEOSI)
Oedema-related events
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 as well as exposure corrected 
event rates. 
Subgroup analysis of Adverse Events
Any treatment-emergent AEs stratified by age (<65, >= 65 years,  <75, >= 75 years), gender, 
comorbidities (HF, CKD and DM), use of medications (RAASi and Diuretics), baseline S-K 
(<5.5, 5.5-<6.0, >= 6.0 mmol/L), baseline eGFR (<30, 30-< 60, >= 60 mL/min/1.73m2) and 
baseline weight (<65, >= 65kg) will be provided by SOC and PT.  
4.2.7.2
Clinical Laboratory evaluation 
Change from baseline over time
For continuous variables, observed values and changes from baseline to each post-baseline 
visit (including last on-treatment value) will be summarized by descriptive statistics.
For categorical variables, shift table from baseline to post-baseline visit (including last on 
treatment value) 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 in 
each study phase with a lowest S-K assessment (regardless of scheduled or unscheduled) <3.5 
mmol/L (mild hypokalemia) and will be repeated for a more severe definition of < 3.0 
mmol/L (moderate hypokaelmia) and of < 2.5 mmol/L (severe hypokalemia). 


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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Other potentially clinically significant laboratory abnormalities will also be identified based 
on the most extreme (lowest and/or highest) post-baseline values and tabulated with number 
and proportion of subjects meeting each criterion. 
Table 7
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
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
Additional laboratory data summaries
Shift table for UACR categories
Shift table form subjects with UACR in categories of 0-< 30 mg/g (normoalbuminuria), 30-< 
300 mg/g (microalbuminuria) and >= 300 mg/g (macroalbuminuria) will be summarized using 
baseline and last on-treatment values. 
Shift table for eGFR categories 


Statistical Analysis Plan 
Study Code D9482C00001
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Shift tables for subjects with eGFR in categories of 0-< 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 will be summarized using 
baseline and last on-treatment values. 
4.2.7.3
Vital signs
Summary statistics for changes from baseline over time (including last on treatment) for each 
parameters (SBP, DBP and body weight) will be provided.
In addition, potentially clinically significant abnormal changes at any time post-baseline will 
be summarized with number of subjects and proportions. 
Table 8
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
4.2.7.4
ECGs 
Number of subjects with clinically significant abnormality (as assessed by investigator) will 
be summarized for baseline and post-baseline visits. Summary for most extreme value and last 
on treatment evaluation will also be presented.
Summary statistics for changes from baseline over time (including last on treatment value) for 
each parameter (heart rate (HR), P, PR, QRS, QT and QTcF) will be provided. Here QTcF 
will be derived by below formula. 
1/3
(60 / HR)
QT
QTcF %
where, QT is in msec and HR is in bpm. 
Abnormal prolongation of QTc (QTcF) will be summarized based on criteria specified in the 
table below. The most extreme (highest) value for a subject during treatment will be used this 
summary.


Statistical Analysis Plan 
Study Code D9482C00001
Edition Number 4.0
Date 17-Jun-2019
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Table 9
Categorical evaluation of QTc prolongation
Parameter
Criterion
QTcF
>450 msec
>480 msec
>500 msec
Change from baseline in QTcF
>30 msec 
>60 msec
5.
INTERIM ANALYSES
An interim analysis is planned in this study for the purpose of regulatory submission. The data 
cut-off for interim analysis will be when the last subject passed the Visit 17. The interim 
analysis will include safety/efficacy evaluation for the correction phase as well as 
safety/efficacy evaluation for maintenance phase up to Visit 17.
6.
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE) 
7.
REFERENCES (NOT APPLICABLE) 
8.
APPENDIX 
8.1
Focus of Interim Analysis  
As in section 5, one interim analysis (IA) including data up to Visit 17 is planned. 
In principle, all planned analysis for safety and efficacy analyses will be carried out with the 
subset of data up to Visit 17, hence the target time period should be replaced as such. 
In addition, the following variables will be scoped out since the data is expected to be
immature at the time of IA. 
-
S-K analysis - change from last maintenance visit to follow up visit 
-
Questionnaire related to low dose regimen (5g QOD or 2.5g QD) 
-
SF36v2


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