Clinical trial NCT03528681
Conditions: Hyperkalemia
Sponsor: AstraZeneca
Start date: 2021-05-06; Completion date: 2022-09-15
Enrollment: 270 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of two different doses (5 and 10 g) of ZS orally administered once daily (qd) vs placebo in maintaining normokalemia in initially hyperkalemic patients having achieved normokalemia following 24 or 48 hours of initial ZS therapy (10g TID).

Detailed description:
This study will be conducted in approximately 35 centers in China. Before patients are randomized to the double-blind phase, they will receive open-label ZS for 24 or 48 hours during the initial phase. It is expected that approximately 490 patients will need to be enrolled, to have approximately 280 patients entered into the open-label initial phase resulting in 250 patients being randomized in the 28-day treatment study phase. Enrolment will be stopped when 250 patients have been initiated with the 28-day randomized treatment study phase.

Arms: arm 1: Suspension administered 10g orally once daily for 28 days after the open label initial phase. arm 2: Suspension administered 5g orally once daily for 28 days after the open label initial phase. arm 3: Suspension administered orally placebo once daily for 28 days after the open label initial phase.
Interventions: intervention 1: Sodium Zirconium Cyclosilicate 5g intervention 2: Sodium Zirconium Cyclosilicate 10g intervention 3: Placebo
Intervention descriptions: intervention 1: Suspension administered Sodium Zirconium Cyclosilicate 5g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days. intervention 2: Suspension administered Sodium Zirconium Cyclosilicate 10g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days. intervention 3: Suspension administered orally placebo once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.

Protocol documents:
Prot_000.pdf: 
1 (101)
Sponsor:   AstraZeneca AB, 151 85 Södertälje, Sweden
Clinical Study Protocol 
Drug Substance
ZS
Study Code
D9480C00001
Version
6.0
Date
19 August 2020
A phase 3 multicenter, prospective, randomized, double-blind, placebo-
controlled study to investigate the safety and efficacy of ZS (sodium 
zirconium cyclosilicate), in patients with hyperkalemia-HARMONIZE Asia






4 (101)
Section 
4.3.5
to
Section 4.3.13
28-day randomized 
treatment study phase 
Day 2–Day 29 
(Visit 6 – Visit 14)
Updated the following information across the 
section that the patient will bring the used 
and/or unused IP
and completed
dosing 
schedule card with them. 
Updated 
the 
applicable 
sentences in the 
section to clarify 
that the patients 
need to bring both 
the used and/or 
unused  IP and 
completed dosing 
schedule card  for 
IP accountability.
Section 8.2 
Sample Size Estimate
Updated the following information:
The sample size is determined to detect a 
clinically meaningful difference in the primary 
endpoint of the mean S-K during the 28-day 
randomized treatment study phase Study Days 
8-29 between each active dose (high to low) vs. 
placebo control. Assuming an inter-subject 
standard deviation of 0.50, approximately 
320250 patients, (128100 patients per active 
dose treatment arm and 6450 patients for 
placebo control arm), will provide >95>90%
power to detect a mean difference of 0.30 in 
mean S-K during Study Days 8-29, comparing 
each active dose (high to low) vs. placebo 
control using a two-sided t-test at a significance 
level of 5%. Assuming 9590% of patients will 
be normokalemic after treatment in the open 
label initial phase with at least 1 dose of ZS 10g
(see Section 7.2), approximately 337280 
patients will be needed to enter the open-label 
initial phase.  
The power and sample size is determine based 
on the number of patients required to evaluate 
the primary hypothesis of the study. However, 
in the testing sequence presented in Table 6, the 
open-label initial phase mean change from 
baseline of S-K 48 hours after first dose of ZS 
10g will be evaluated first. A sample size of 
320280 patients will provide >99% power to 
detect a more than 18% relative reduction (i.e., 
1.05 absolute reduction) in mean change from 
Updated to reflect 
the 
statistical 
considerations for  
the 
revised 
number 
of 
planned 
patients 
for the study.




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Section 1.3.3
Clinical benefit-risk balance
Updated information about the known and expected 
benefits and risks and reasonably expected adverse events 
of ZS based on the latest Investigators Brochure version 
9.0.
Section 1.4 
Study Design
Updated the study design figure and the number of study 
visits to 14-15 visits which reflects the updated Open-Label 
Initiation Phase. Depending on the potassium value, 
patients can be randomized after achieving normokalemia 
after 24 or 48 hours of receiving open label ZS.
Section 1.4 – Figure 3
Study flow chart
Updated the study design figure and the number of study 
visits to 14-15 visits which reflects the updated Open-Label 
Initiation Phase.
Section 2.2
Secondary objectives
Updated information to reflect the Open-Label Initial 
Phase across the study objectives and clarify further the 
definition of secondary outcome measures.
Section 3.2 
Exclusion Criteria
Exclusion criteria # 13-16 was added to exclude patients 
with history of QT prolongation, Congenital long QT 
syndrome, etc. as there is a risk that ZS can further prolong 
QT 
and 
could 
put 
patients 
at 
 
risk 
of 
proarrhythmic/arrhythmic condition.
Section 3.7
Methods for unblinding
Updated to clarify that only Investigators will have access 
to the unblinding procedure in IWRS/IVRS in case of 
unblinding situation.
Section 3.9
Discontinuation of 
Investigational Product
Clarified that the QTc(f) algorithm (QT interval corrected 
by the Fridericia method) is recommended for QTc 
calculation.
Clarified the End of Study (EOS) scheduling between the 
28-day randomized treatment phase and  open-label 
initiation phase.
Section 3.10
Criteria for Withdrawal
Deleted paragraph about IP treatment withdrawal and 
clarified further in section 3.9.
Section 4 (Table 1): 
Study Plan detailing the 
procedures: optional Pre-
screening, screening and open-
label initial phase
Updated the table and footnote to reflect the changes for 
the Open-Label Initial Phase and Eligibility Criteria 
assessment at Randomization Visit for consistency with 
Table 2.


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Section 4 (Table 2): 
Study Plan detailing the 
procedures: 28-day randomized 
treatment study phase
Updated the table to accurately reflect the visit name of 
Randomization Visit for the 28-day randomized treatment 
study phase.
Section 4.3.2
Open-label initial phase Day 2 
(Visit 4)
Updated the section to reflect the changes for the Open-
Label Initial Phase and further guidance on site actions 
relating to the patient’s i-STAT potassium values during 
the Open-Label Initial phase.
Section 4.3.3
Randomization Visit - For 
patients not entering the 28-day 
randomized treatment study 
phase
Updated the section name to provide guidance on site 
actions for patients who will not enter the 28-day 
randomized treatment study phase at the end of the Open-
Label Initial phase.
Section 4.3.4
Randomization Visit - For 
patients entering the 28-day 
randomized treatment study 
phase
Additional clarifications on the randomization procedure 
for patients who achieve i-STAT potassium values 
between 3.5 – 5.0 mmol/L, inclusive after 24 hours  or 48 
hours  during the open-label initial phase.
Section  4 - Figure 4
Flow chart based on the S-K 
level, which will be measured 
by i-STAT
Updated the Flow chart to clarify the site actions based on 
the i-STAT potassium levels of the patient.
Section 5.2.1
Laboratory Safety Assessments
Updated to clarify that sample tubes and sample sizes will 
not vary since all materials will be provided by a central 
laboratory.
Section 5.2.1 – Table 3
Laboratory Safety Variables
Included S-Aldosterone in the sample collection guidelines 
requiring patients to be either standing or seated upright for 
at least 2 hours before sample collection.
Clarified that all patients must be on fasting when 
collecting blood chemistry & hematology at Day 1 of 
Open-Label Initial Phase.
Section 5.2.3 
ECG
Deleted the previous typographical error on subsection 
5.2.3.1 28-day randomized treatment study phase Day 29 
(Visit 14).
Description for ECG recording was updated to be 
consistent with the content in Section 4.3.1.
Additional guidance for ECG data collection for patients 
with pacemakers.


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Section 5.2.4 
Vital Signs
Updated that blood pressure should be checked in both 
arms at visit 3 to be consistent with Table 1.
Section 5.10
Volume of Blood
Updated the information to clarify subjects who achieve 
normokalemia after 24-hour treatment can be randomized 
earlier.
Updated Table 5 to accurately reflect the visit name of 
Randomization Visit.
Section 5.11
Guidance related to 
assessments, and procedures 
during COVID-19 pandemic
Added new section to provide guidance on study 
assessments and procedures during the COVID-19 
pandemic.
Section 6.2
Definitions of Serious Adverse 
Event
Added additional SAE reporting requirement includes 
reporting of malignant tumors during study conduct.
Section 6.5
Overdose
Added additional clarification on the definition of the ZS 
overdose during the study. 
Section 7.2
Dose and Treatment Regimen
Updated the section to reflect the changes for the Open-
Label Initial Phase and further guidance on site actions 
relating to the patient’s i-STAT potassium values during 
the Open-Label Initial phase.
Section 8.1
Statistical Considerations
Clarified that Statistical Analysis Plan will be finalized 
prior to Database Lock.
Section 8.3.1
Full analysis sets (FAS)
Corrected the typographical error in the acronym FAS-
RPT to “FAS-RTP”.
Section 8.4.2
Secondary efficacy variables
Updated information to reflect the Open-Label Initial 
Phase in the secondary efficacy variables and clarify 
further the definition of secondary outcome measures.
Updated the typographical error of the efficacy endpoint: 
Exponential (instead of Expected) rate of Change in S-K 
levels.
Section 8.5
Methods for statistical analyses
Removed paragraph of ”Definitions of Baseline” as the 
information will be detailed in the Statistical Analysis Plan 
(SAP).
Section 8.5.3
Safety Analysis
Updated information on the definition of safety variables 
for analysis of Adverse Event and added clarifications on 
the analysis of hypokalemia.








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Section 1.1 (Background and rationale for conducting this study): This section was updated 
to better reflect how hyperkalemia is treated. Minor typographical errors and formatting was 
updated.
Section 1.2 (Rationale for study design, doses and control groups): This section was updated 
to better reflect the rationale for the study design and the doses selected. Minor typographical 
errors and formatting was updated in this section.
Section 1.3 (Benefit/risk and ethical assessment): This section was updated to better reflect 
the benefits, risks, and benefit-risk balance of the study.
Section 2 (Study objective): Minor typographical errors and formatting was updated in this 
section. In particular, physical examination was added to “Outcome Measures” under the 
“Safety Objective” to ensure all collected data relevant to patient safety are thoroughly 
analyzed. 
Section 3.2 (Exclusion criteria): The wording in exclusion criterion 3 was improved. 
Exclusion 15 was added to clarify that the study is in outpatients.
Section 3.6 (Methods for ensuring blinding): This section was updated to provide additional 
details on blinding during the 28-day randomized treatment study phase. 
Section 3.9 (Discontinuation of investigational product): This section was updated to 
emphasize that patients will discontinue when i-STAT potassium values are < 3.0 mmol/L at 
any time during the study or > 6.2 mmol/L during the 28-day randomized treatment study 
phase, and that discontinued patients must immediately receive appropriate medical treatment 
to manage their hypo- or hyperkalemia. In addition the discontinuation criteria for QTc 
prolongation were re-worded to align better with when QTc prolongation begins to represent 
a medical risk.
Section 4 (Table 1): The study plan and timing of procedures for the 48-hour open-label initial 
phase (Table 1) was updated as demographics will be collected and the IVRS/IWRS accessed 
on visit 1, and to reflect that AE collection will begin after the patient has signed informed 
consent. Throughout section 4, minor typographical errors and formatting was updated to 
improve the wording.
Section 4.2 (Treatment period): This section was updated in line with the updates in Table1 
and Table 2, and to clarify that sites may change the order of the procedures at a visit if agreed 
in advance with the sponsor study physician.
Section 4.2.1 (48-hour open-label initial phase Day 1): This section was updated to clarify 
how to handle patients with i-STAT potassium <4.0 mmol/L at the 4 hour post Dose 1 blood 
draw.
Section 4.2.3 (48-hour open-label initial phase Day 3): Vital signs were added to the study 
procedures in this section to align with Tables 1 and 2.
Section 4.2.9 (28-day randomized treatment study phase Day 15): Vital signs were added to 
the study procedures in this section to align with Table 2.
Section 4.2.13 (28-day randomized treatment study phase Day 29): Vital signs were added to 
the study procedures in this section to align with Table 2.


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Section 4.3 (Follow-up period): Vital signs were added to the study procedures in this section 
to align with Table 2.
Section 4: Figure 4 was added to provide the study flow chart based on the S-K level, which 
will be measured by i-STAT.
Section5.1 .1(Efficacy assessments-Potassium): This section was updated to better reflect the 
assessment for potassium throughout the study.
Section 5.2.1 (Laboratory safety assessments): This section was updated to clarify that urine 
samples will be collected at the EOS visit.
Section 5.2.2 (Physical examination): This section was updated to add targeted physical 
examination to the 48-hour open-label initial phase Day 3 procedures.
Section 5.2.4.1 (Pulse Rate and blood pressure): More details were added to the description 
of how pulse rate and blood pressure will be assessed.
Section 5.10 (Table 4): The footnote was updated to add an extra potassium assessment 90 
minutes after taking the second dose of ZS for patients with i-STAT potassium ≥ 6.1 or < 4.0 
mmol/L 4 hours after the first ZS Dose.
Section 6.3.1 (Time period for collection of adverse events): This section was updated to 
specify that Adverse Events (including SAEs) will be collected from the signing of the 
informed consent until the EOS visit.
Section 7.1 (Identity of investigational product): This section was updated to align with a 
change in drug packaging.
Section 7.2 (Dose and treatment regimens): This section was updated to provide guidance on 
how to handle patients developing hypokalemia while receiving ZS.
Section 7.7 (Concomitant and other treatments): This section was updated with more details 
on prohibited medications.
Section 8.2 (Sample size estimate): The sample size estimate text was revised to clarify that 
the study is powered for all test specified in the confirmatory testing sequence. Also, a typo 
was corrected to clarity that the standard deviation used in the sample size calculation was 
the “inter-subject standard deviation” and not the “intra-subject standard deviation.
Section 8.3 (Definitions of analysis sets): The definition of the Full Analysis Set (FAS) and 
the Safety Analysis Set (SAF) were revised to align with the ICH E9- and CRGI Statistical 
Guidance.
Section 8.4.3 (Safety Variables): This section was updated to include the physical 
examinations and ECGs as safety variables.
Section 8.5 (Methods of statistical analyses): This section was revised to remove repetitive 
statements and to explicitly define the fixed hierarchical testing sequence of the study. Also, 
to include that sensitivity analyses will be performed to test the robustness of the primary and 
key secondary objectives.




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CLINICAL STUDY PROTOCOL SYNOPSIS
A phase 3 multicenter, prospective, randomized, double-blind, placebo-
controlled study to investigate the safety and efficacy of ZS (sodium 
zirconium cyclosilicate), in patients with hyperkalemia-HARMONIZE 
Asia
International Co-ordinating Investigator
Prof. Xueqing Yu, Professor of Medicine, Director, Institute of Nephrology, The First Affiliated 
Hospital, Sun Yat-Sen University. 58th Zhongshan Road II, GuangZhou, China 510080
Study site(s) and number of patients planned
This study will be conducted in approximately 35 centers in China.  Before patients are 
randomized to the double-blind phase, they will receive open-label ZS for 24 or 48 hours during 
the initial phase. It is expected that approximately 490 patients will need to be enrolled, to have 
approximately 280 patients entered into the open-label initial phase resulting in 250 patients 
being randomized in the 28-day randomized treatment study phase. Enrolment will be stopped 
when 250 patients have been initiated with the 28-day randomized treatment study phase. 
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2021
Phase 3
Estimated date of last patient completed
Q1 2022
Study design
This is a prospective, randomized, double-blind, placebo-controlled, phase 3 study to 
investigate the safety and efficacy of ZS in patients with hyperkalemia. This study consists of 
Pre-screening period which is optional, screening period (1 day), the open-label initial phase 
(24 or 48 hours), the 28-day randomized treatment study phase, and follow-up period (7±1 days 
after the last administration of study medication). 
Optional Prescreening procedures will be performed, using i-STAT (A portable blood analyser) 
potassium values, to determine the consenting patients eligibility to enter the screening phase 
at Visit 1. If i-STAT potassium value is <5.1 mmol/L the patient will be declared a pre-screen 
failure. Screening procedures will be performed to determine patient eligibility during 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 the  open-label initial phase. In the open-label initial 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
16 (101)
phase, patients will receive open-label ZS at a dose of 10g per os (PO) three times a day (tid) 
for 24 or 48 hours, depending on potassium value. Once normokalemia (i-STAT potassium 
between 3.5 and 5.0 mmol/L, inclusive) is restored (whether after 24 or 48 hours, i.e., by the
morning of Study Day 2 or Day 3),  patients will then be randomized in the ratio of 2:2:1 into 
the double-blind 28-day randomized treatment study phase to receive ZS 5g once daily (qd), 
10g qd or placebo qd for the following 28 days. Treatment will end on Day 29 visit, which will 
be followed by the end of study (EOS) visit taking place 7±1 days after the last administration 
of study medication.
For patients who do not enter the 28-day randomized treatment study phase, the last visit will 
be 7±1 days after the last treatment dose in the open-label initial phase.
Objectives
Primary Objective:
Outcome Measure:
To evaluate the efficacy of  two different 
doses (5 and 10 g) of ZS orally 
administered once daily (qd) for 28 days 
in maintaining normokalemia (serum 
potassium [S-K] between 3.5-5.0 mmol/L, 
inclusive) 
in 
normokalemic 
patients 
following treatment in the open-label 
phase for hyperkalemic patients (two 
consecutive i-STAT potassium values ≥ 
5.1 mmol/L, taken 60 minutes apart) at 
baseline.
Comparison between placebo and each ZS 
treatment group (high to low) with regard to the 
mean S-K level during the 28-day randomized 
treatment study phase Days 8-29.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
17 (101)
Secondary Objectives:
Outcome Measures:
Open-label initial phase:
To evaluate the proportion of patients 
who achieve normokalemia after the 
completion of open-label initial phase 
treatment.
28-day randomized treatment study phase:

To evaluate the efficacy of ZS in 
patients with hyperkalemia for the 
following subgroups*:
- chronic kidney disease (CKD)
- diabetes mellitus (DM)
- heart failure (HF)
- those 
on 
renin-angiotensin-
aldosterone 
system 
(RAAS) 
inhibitors.

To evaluate the effect of  ZS on serum-
Aldosterone (S-Aldo) and plasma-
Renin (P-Renin) levels.
Open-label initial phase efficacy endpoints:

Proportion 
of 
patients 
who 
achieve 
normokalemia during the open-label initial 
phase at 24 hours and at the end of the open-
label phase.

Exponential rate of change in S-K levels 
(blood) during the open-label initial phase.

Mean change (absolute and percent change) 
from baseline in S-K levels (blood) at all 
measured time intervals (See Table 1) post-
dose during the open-label phase.

Time to normalization in S-K levels 
(normalization defined as S-K levels 
between 3.5-5.0 mmol/L, inclusive) during 
the open-label phase.
28-day randomized treatment study phase 
efficacy endpoints:

The proportion of patients who remain 
normokalemic (as defined by S-K between 
3.5 5.0 mmol/L, inclusive) at the end of the 
28-day randomized treatment study phase 
and 
during 
the 
28-day 
randomized 
treatment study phase.

The number of days patients remain 
normokalemic 
during 
the 
28-day 
randomized treatment study phase.

The mean change and mean percent change 
in S-K levels evaluated relative to both 
baselines.

The time to hyperkalemia (defined as S-K 
≥ 5.1mmol/L).

The mean changes in S-Aldo and P-Renin 
levels.
*    Primary efficacy endpoint and the secondary efficacy endpoint of the proportion of patients who remain 
normokalemic (as defined by S-K between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized 
treatment study phase will be evaluated in patients with hyperkalemia for these subgroups. More details will 
be provided in the SAP.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
18 (101)
Safety Objectives:
Outcome Measures:

To evaluate the effect of ZS on other 
serum electrolytes in both the open-
label initial phase and the 28-day 
randomized treatment study phase.

To evaluate the safety and tolerability 
profiles of ZS in both the open-label 
initial 
phase 
and 
the 
28-day 
randomized treatment study phase.

Serum calcium [S-Ca], serum magnesium 
[S-Mg], serum
sodium [S-Na], serum 
phosphate [S-PO4], serum bicarbonate [S-
HCO3], and blood urea nitrogen [BUN].

Adverse events (AEs), serious AEs (SAEs), 
vital signs (VS), physical examinations.

ECG

Clinical laboratory evaluations, including 
assessment of hypokalemia.
Target patient population
The target patient population includes male or female patients aged ≥ 18 to ≤ 90 years with 
hyperkalemia, defined as two consecutive i-STAT potassium values, measure 60-minutes apart, 
both ≥ 5.1mmol/L within 1 day of the first ZS dose. 
Duration of treatment
The study may start with an optional Pre-screening visit. Patients with i-STAT potassium value 
is equal or more than 5.1 mmol/L will enter the screening. The study will follow with a screening 
period, and all baseline parameters should be measured/collected up to 1 day prior to 
administration of first dose of study drug on the open-label initial phase Day 1. 
During the open-label initial phase, patients will receive ZS per os (PO) at a dose of 10g three 
times a day (tid) for 24 or 48 hours, depending on potassium value. Once normokalemia (i-
STAT potassium between 3.5 and 5.0 mmol/L, inclusive) is restored (whether after 24 or 48 
hours, i.e., by the morning of Study Day 2 or Day 3), patients will then be randomized in a ratio 
of 2:2:1 to the double-blind 28-day randomized treatment study phase to receive ZS 5g, 10g or 
placebo, PO qd for the following 28 days. Patients in the double-blind treatment phase will be 
required to complete the Day 29 visit and the EOS visit which is 7±1 days after the last 
administration of study medication. For patients who do not enter the 28-day randomized 
treatment study phase the last visit will be 7±1 day after the last treatment dose in the open-label 
initial phase. The total expected study duration for each individual patient is approximately 5-6 
weeks.
Investigational product, dosage and mode of administration
Open-label initial phase:

ZS 10g will be administered orally three times a day (tid) for 24 or 48 hours 
as an oral suspension.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
19 (101)
28-day randomized treatment study phase:

ZS 5g will be administered orally once daily (qd) for 28 days as an oral 
suspension.

ZS 10g will be administered orally once daily (qd) for 28 days as an oral 
suspension.

Matching Placebo for ZS will be administered orally once daily (qd) for 28 
days as an oral suspension.
Please note: If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 
3.4 mmol/L, inclusive, during the open-label initial treatment phase, the patient will be directed 
to not take any more ZS for the remainder of that day and return the next day to assess potassium, 
if the potassium is then between 3.5 and 5.0 mmol/L, the patient will be randomized.
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 28-day randomized treatment study phase, dosing will be reduced from qd to once every 
other day (qod) for the remainder of the study. 
Patients with confirmed i-STAT potassium <3.0 mmol/L in both phases should discontinue 
from therapy.
Patients with confirmed i-STAT potassium >6.2 mmol/L during the 28-day randomized 
treatment study phase should discontinue from therapy.
Statistical methods
Separate efficacy and safety analyses will be performed for the open-label initial phase and the 
28-day randomized treatment study phase. All patient analysis sets will be confirmed and 
documented in a Statistical Analysis Plan (SAP) prior to database lock. The study will have 
prospectively defined patient analysis sets for the open-label initial phase and 28-day 
randomized treatment study phase.
For the open-label initial phase, the full analysis set will include all patients registered in the 
open-label initial phase. The safety analysis set, for the open-label initial phase, will include all 
patients with at least one dose of IP during this treatment phase, and will be analyzed on an as-
treated basis. 
For the subsequent 28-day randomized treatment study phase, the full analysis set will include 
all randomized patients. The safety analysis set, for the 28-day randomized treatment study 
phase, will include all patients with at least one dose of the 28-day randomized treatment study 
phase IP among those randomized, and will be analyzed on an as-treated basis. 
Unless otherwise specified, all efficacy analyses will be carried out on the full analysis sets, 
which is based on the Intension-to-Treat (ITT) principle; and all safety analyses will be based 
on the safety analysis sets. 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
20 (101)
The null hypothesis for the study is that there is no treatment difference (in mean S-K levels 
Days 8-29) between each ZS dose (high to low) versus placebo control. The alternative 
hypothesis is that ZS is more effective than the placebo control in maintaining mean 28-day 
randomized treatment study phase Day 8-29 serum potassium levels (3.5-5.0 mmol/L, inclusive) 
among hyperkalemic patients in whom normokalemia is established during the open-label initial 
phase.
All efficacy analyses will be based on the S-K values obtained from the Central Laboratory. If 
Central Laboratory data are missing, they will be replaced by i-STAT values adjusted with the 
mean paired difference between i-STAT and S-K values collected at the same visit. More details
on how to handle dropouts and missing data will be provided in the SAP. 
The primary endpoint in the study will be the model-based least squares means (LSMEANS) of 
all available S-K values during the 28-day randomized treatment study phase Days 8-29. A log 
transformation will be applied to the S-K levels, since historical data shows that S-K 
measurements follows a log-normal distribution, and also to stabilize the variance. A 
longitudinal model (SAS PROC MIXED) will then be used to simultaneously compare each 
active dose (high to low) versus placebo control for the 28-day randomized treatment study 
phase to estimate the least squares means Day 8-29 values. The model will include all S-K data 
collected at the scheduled visits between Day 8-29 as response variables, with baseline 
covariates for the open-label initial phase eGFR, the open-label initial phase S-K values, the 28-
day randomized treatment study phase S-K values as well as age (<55, 55-64, >64 years), 
country and baseline binary indicators for RAAS inhibitors, chronic kidney disease, heart 
failure, and diabetes mellitus as fixed effects terms and patients are random effect term. In 
addition, the primary efficacy endpoint and the secondary efficacy endpoint of the proportion 
of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/L, inclusive) 
at the end of the 28-day randomized treatment study phase will be evaluated for the subgroups 
(i.e., CKD DM, HF and those on RAAS inhibitors). More details will be described in the SAP.
Secondary efficacy endpoints will include:

The proportion of patients who remain normokalemic (as defined by S-K 
between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized 
treatment study phase and during the 28-day randomized treatment study 
phase.

The number of days patients remain normokalemic during the 28-day 
randomized treatment study phase.

The mean change and mean percent change in S-K levels evaluated relative 
to both baselines.

The time to hyperkalemia (defined as S-K ≥ 5.1 mmol/L).

The mean change in S-Aldo and P-Renin levels.


Clinical Study Protocol Synopsis
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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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Safety endpoints will include adverse events (AEs), serious AEs (SAEs), vital signs, clinical 
laboratory evaluations, physical examinations, ECGs, and other serum electrolytes (specifically, 
serum calcium [S-Ca], serum magnesium [S-Mg], serum sodium [S-Na], serum phosphate [S-
PO4], serum bicarbonate [S-HCO3], and blood urea nitrogen [BUN]).
The confirmed i-STAT potassium value on Study Day 2 or Day 3 of the open-label initial phase 
will be used to established the patient’s eligibility into the 28-day randomized treatment study 
phase, however central laboratory S-K values will be used for all analyses. 
Sensitivity analyses will be conducted to assess the robustness of the results of the primary 
analysis and the secondary analysis of the proportion of normokalemic patients at the end of the 
28-day randomized treatment study phase and during the 28-day randomized treatment study 
phase.
There is no planned interim analysis in this study.
Assuming an inter-subject standard deviation of 0.50, approximately 250 patients, (100 patients 
per active dose treatment arm and 50 patients for placebo control arm), will provide >90% 
power to detect a mean difference of 0.30 in mean 28-day randomized treatment phase Day 8-
29, comparing each active dose (high to low) vs. placebo control  using a two-sided t-test at a 
significance level of 5%. Assuming 90% of patients will be normokalemic after treatment in the 
open label initial phase (see Section 7.2), approximately 280 patients will be needed to enter the 
open-label initial phase.  


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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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TABLE OF CONTENTS
VERSION HISTORY..........................................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................................. 15
TABLE OF CONTENTS................................................................................................... 22
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................... 27
1.
INTRODUCTION ............................................................................................. 29
1.1
Background and rationale for conducting this study ........................................... 29
1.2
Rationale for study design, doses and control groups.......................................... 32
1.3
Benefit/risk and ethical assessment .................................................................... 33
1.3.1
Clinical benefits.................................................................................................34
1.3.2
Clinical risks...................................................................................................... 34
1.3.3
Clinical benefit-risk balance............................................................................... 35
1.3.4
Conclusions ....................................................................................................... 35
1.4
Study Design...................................................................................................... 36
2.
STUDY OBJECTIVES...................................................................................... 38
2.1
Primary objective............................................................................................... 38
2.2
Secondary objectives.......................................................................................... 39
2.3
Safety objectives................................................................................................ 40
2.4
Exploratory objectives (Not applicable) ............................................................. 40
3.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 40
3.1
Inclusion criteria ................................................................................................ 40
3.2
Exclusion criteria ............................................................................................... 41
3.3
Patient enrolment and randomization .................................................................42
3.4
Procedures for handling incorrectly enrolled or randomized patients.................. 43
3.5
Methods for assigning treatment groups............................................................. 43
3.6
Methods for ensuring blinding ........................................................................... 44
3.7
Methods for unblinding...................................................................................... 44
3.8
Restrictions........................................................................................................ 44
3.9
Discontinuation of investigational product ......................................................... 44
3.9.1
Procedures for discontinuation of a subject from investigational product............ 46
3.10
Criteria for withdrawal....................................................................................... 46
3.10.1
Screen failures ................................................................................................... 46


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3.10.2
Withdrawal of the informed consent................................................................... 47
3.11
Discontinuation of the study............................................................................... 47
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 48
4.1
Optional Pre-screening period (Visit 1) .............................................................. 52
4.2
Enrolment/screening period (Visit 2).................................................................. 52
4.3
Treatment Period................................................................................................ 52
4.3.1
Open-label initial phase Day 1 (Visit 3).............................................................. 53
4.3.2
Open-label initial phase Day 2 (Visit 4).............................................................. 54
4.3.3
Randomization Visit - For patients not entering the 28-day randomized 
treatment study phase......................................................................................... 55
4.3.4
Randomization Visit - For patients entering the 28-day randomized 
treatment study phase......................................................................................... 56
4.3.5
28-day randomized treatment study phase Day 2 (Visit 6).................................. 56
4.3.6
28-day randomized treatment study phase Day 5 (Visit 7).................................. 57
4.3.7
28-day randomized treatment study phase Day 8 (Visit 8).................................. 57
4.3.8
28-day randomized treatment study phase Day 12 (Visit 9)................................ 58
4.3.9
28-day randomized treatment study phase Day 15 (Visit 10) .............................. 58
4.3.10
28-day randomized treatment study phase Day 19 (Visit 11) .............................. 59
4.3.11
28-day randomized treatment study phase Day 22 (Visit 12) .............................. 59
4.3.12
28-day randomized treatment study phase Day 26 (Visit 13) .............................. 60
4.3.13
28-day randomized treatment study phase Day 29 (Visit 14) .............................. 60
4.4
Follow-up period (EOS)..................................................................................... 61
5.
STUDY ASSESSMENTS.................................................................................. 65
5.1
Efficacy assessments.......................................................................................... 65
5.1.1
Blood potassium ................................................................................................ 65
5.2
Safety assessments............................................................................................. 65
5.2.1
Laboratory safety assessments............................................................................ 65
5.2.2
Physical assessments.......................................................................................... 67
5.2.3
ECG................................................................................................................... 67
5.2.4
Vital signs.......................................................................................................... 68
5.3
Other assessments (Not applicable).................................................................... 69
5.4
Pharmacokinetics (Not applicable)..................................................................... 69
5.5
Pharmacodynamics (Not applicable) .................................................................. 69
5.6
Genetics (Not applicable)................................................................................... 69
5.7
Biomarker analysis (Not applicable)................................................................... 69
5.8
Storage, re-use and destruction of biological samples......................................... 69
5.9
Labeling and shipment of biological samples ..................................................... 69
5.10
Volume of blood................................................................................................ 69


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5.11 
Guidance related to assessments, and procedures during COVID-19 
pandemic ........................................................................................................... 71
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 71
6.1
Definition of adverse events............................................................................... 72
6.2
Definitions of serious adverse event ................................................................... 72
6.3
Recording of adverse events............................................................................... 73
6.3.1
Time period for collection of adverse events ...................................................... 73
6.3.2
Follow-up of unresolved adverse events............................................................. 73
6.3.3
Variables............................................................................................................ 73
6.3.4
Causality collection............................................................................................ 74
6.3.5
Adverse events based on signs and symptoms.................................................... 74
6.3.6
Adverse events based on examinations and tests ................................................ 74
6.4
Reporting of serious adverse events ................................................................... 75
6.5
Overdose............................................................................................................ 75
6.6
Pregnancy .......................................................................................................... 76
6.6.1
Maternal exposure.............................................................................................. 76
6.6.2
Paternal exposure............................................................................................... 77
6.7
Medication Error................................................................................................ 77
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 78
7.1
Identity of investigational product(s).................................................................. 78
7.2
Dose and treatment regimens ............................................................................. 79
7.3
Labelling............................................................................................................ 80
7.4
Storage............................................................................................................... 80
7.5
Compliance........................................................................................................ 80
7.6
Accountability.................................................................................................... 80
7.7
Concomitant and other treatments ...................................................................... 80
7.7.1
Other concomitant treatment .............................................................................. 81
7.8
Post Study Access to Study Treatment (Not Applicable) .................................... 81
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 81
8.1
Statistical considerations .................................................................................... 81
8.2
Sample size estimate .......................................................................................... 82
8.3
Definitions of analysis sets................................................................................. 82
8.3.1
Full analysis sets (FAS)...................................................................................... 82
8.3.2
Safety analysis sets (SAF).................................................................................. 82
8.4
Outcome measures for analyses.......................................................................... 83
8.4.1
Primary efficacy variable ................................................................................... 83


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Study Code D9480C00001
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8.4.2
Secondary efficacy variables.............................................................................. 83
8.4.3
Safety Variables.................................................................................................84
8.5
Methods for statistical analyses.......................................................................... 84
8.5.1
Analysis of the primary variable......................................................................... 85
8.5.2
Analysis of the secondary and additional variables............................................. 86
8.5.3
Safety analysis ................................................................................................... 87
8.5.4
Analysis in subsets of patients............................................................................ 87
8.5.5
Interim analysis.................................................................................................. 87
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 88
9.1
Training of study site personnel ......................................................................... 88
9.2
Monitoring of the study...................................................................................... 88
9.2.1
Source data ........................................................................................................ 88
9.2.2
Study agreements............................................................................................... 89
9.2.3
Archiving of study documents............................................................................ 89
9.2.4
Deviation from the clinical study protocol.......................................................... 89
9.3
Study timetable and end of study........................................................................ 89
9.4
Data management by AstraZeneca or delegate ................................................... 89
10.
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
REQUIREMENTS............................................................................................. 91
10.1
Ethical conduct of the study ............................................................................... 91
10.2
Patient data protection........................................................................................ 91
10.3
Ethics and regulatory review .............................................................................. 91
10.4
Informed consent ............................................................................................... 92
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 93
10.6
Data Quality Assurance...................................................................................... 93
10.7
Dissemination of Clinical Study Data.................................................................94
10.8
Source Data ....................................................................................................... 94
10.9
Study and Site Start and Closure ........................................................................ 94
11.
LIST OF REFERENCES ................................................................................... 96


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Study Code D9480C00001
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Date 19 August 2020
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LIST OF TABLES
Table 1
Study Plan detailing the procedures: optional Pre-screening, 
screening and open-label initial phase ...................................................48
Table 2
Study Plan detailing the procedures: 28-day randomized treatment 
study phase ...........................................................................................50
Table 3
Laboratory Safety Variables..................................................................66
Table 4
Volume of blood to be withdrawn from each patient: optional pre-
screening and open-label initial phase ...................................................69
Table 5
Volume of blood to be withdrawn from each patient: 28-day 
randomized treatment study phase.........................................................70
Table 6
Confirmatory Testing Sequence ............................................................85
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 (Lou J et al 2016) ..........................33
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g..........35
Figure 3
Study flow chart....................................................................................37
Figure 4
Flow chart based on the Potassium level, which will be measured 
by i-STAT.............................................................................................62
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................97
Appendix B
Handling of Human Biological Samples................................................99
Appendix C
Guidance related to assessments and procedures during COVID-19 
pandemic............................................................................................. 101


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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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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
ACE
Angiotensin-converting-enzyme 
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ARBs
Angiotensin-receptor blockers
AST
Aspartate aminotransferase
AZ
AstraZeneca
AZRand
AZ global Randomization System
BP
Blood pressure
BUN
Blood Urea Nitrogen
CI
Confidence Interval 
CKD
Chronic Kidney Disease
CRO
Clinical Research Organization
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
DM
Diabetes mellitus 
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
EOS
End of Study
FAS
Full Analysis Set
FAS-OLP
Full Analysis Set for the Open-Label Initial Phase
FAS-RTP
Full Analysis Set for the 28-day Randomized Treatment Study Phase
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate


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Study Code D9480C00001
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Abbreviation or 
special term
Explanation
GGT
Gamma-glutamyl transferase
ICF
Informed Consent Form
ICH
International Conference on Harmonization
International 
Co-ordinating 
investigator
The Investigator co-ordinating the investigators and/or activities 
internationally
ITT
Intent-to-Treat 
Hb
Haemoglobin
HCG
Human chorionic gonadotropin
HF
Heart Failure
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
PGx
Pharmacogenetic research
PI
Principal Investigator 
PO
Per Os
PP
Per Protocol
P-Renin
Plasma-Renin
qd
once daily
qod
every other day 
RAAS
Renin-angiotensin-aldosterone system 
RBC
Red Blood Cell
S-Aldo
Serum-Aldosterone 
SAE
Serious adverse event 
SAF
Safety Analysis Set
SAF-OLP
Safety Analysis Set for the Open-Label Initial Phase
SAF-RTP
Safety Analysis Set for the 28-day Randomized Treatment Study Phase
SAP
Statistical Analysis Plan
SARs
Suspected Adverse Reactions
S-Ca
Serum calcium
S-HCO3
Serum bicarbonate 


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Study Code D9480C00001
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Abbreviation or 
special term
Explanation
S-K
Serum potassium
S-Mg
Serum magnesium 
S-Na
Serum sodium 
S-PO4
Serum phosphate 
SPS
Sodium Polystyrene Sulfonate
SST
Serum Separator Tube
tid
three times a day
VS
Vital Sign
WBC
White Blood Cell
WBDC
Web Based Data Capture
WHODrug
World health Organization Drug Dictionary
ZS
Sodium Zirconium Cyclosilicate (SZC)
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Potassium is a ubiquitous ion, involved in numerous processes in the human body. It is the most 
abundant intracellular cation and is critically important for numerous physiological processes, 
including maintenance of cellular membrane potential, homeostasis of cell volume, and 
transmission of action potentials. The main dietary sources are vegetables (tomatoes and 
potatoes), fruit (oranges, bananas) and meat. The normal potassium values in serum (S-K) are 
between 3.5 and 5.0 mmol/L, with the kidney being the main regulator of potassium values. The 
renal elimination of potassium is passive (through the glomeruli) with active reabsorption in the 
proximal tubule and the ascending limb of the loop of Henle. There is active excretion of 
potassium in the distal tubules and the collecting duct, both of which processes are controlled 
by aldosterone.
Hyperkalemia develops when there is excessive production (oral intake, tissue breakdown) or
insufficient elimination of potassium. Insufficient elimination, which is the most common cause 
of hyperkalemia, can be hormonal (as in aldosterone deficiency), pharmacologic (treatment with 
angiotensin-converting-enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs]) or, 
most commonly, due to reduced kidney function. Increased extracellular potassium values result 
in depolarization of the membrane potential of cells. This depolarization opens some voltage-
gated sodium channels, but not enough to generate an action potential. After a short period of 
time, the open sodium channels inactivate and become refractory, increasing the threshold to 
generate an action potential. This leads to impairment of the neuromuscular, cardiac, and 
gastrointestinal organ systems, and is responsible for the symptoms seen with hyperkalemia. Of 


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Study Code D9480C00001
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greatest concern is the effect on the cardiac system, where impairment of cardiac conduction 
can lead to fatal cardiac arrhythmias such as asystole or ventricular fibrillation. Because of the 
potential for fatal cardiac arrhythmias, hyperkalemia represents an acute metabolic emergency 
that must be immediately corrected.
The most common cause of hyperkalemia is renal insufficiency, and there is a close correlation 
between the degree of kidney failure and S-K values. In addition, a number of different 
commonly used drugs can cause hyperkalemia, such as ACE inhibitors, ARBs, potassium-
sparing diuretics (e.g., amiloride, spironolactone), nonsteroidal anti-inflammatory drugs (e.g., 
ibuprofen, naproxen, celecoxib), heparin, and certain cytotoxic and antibiotic drugs (e.g., 
cyclosporin and trimethoprim). Finally, beta-receptor blocking agents, digoxin or
succinylcholine are other well-known causes of hyperkalemia. In addition, advanced degrees of 
heart failure (HF), massive injuries, burns, or intravascular hemolysis cause hyperkalemia as 
can metabolic acidosis, most often as part of diabetic ketoacidosis.
Symptoms of hyperkalemia are non-specific and include malaise and muscle weakness or signs 
of cardiac arrhythmias, such as palpitations, bradycardia, or tachycardia. Often, however, the 
hyperkalemia is detected during routine screening blood tests for a medical disorder, or after 
complications have developed, such as cardiac arrhythmias or sudden death.
Diagnosis is established by S-K or plasma potassium measurements. Serum potassium values
are most commonly used for diagnosis and to evaluate treatment response. 
Treatment of hyperkalemia depends on the S-K values. In mild to moderate hyperkalemia acute 
treatment with a potassium-binding resin, combined with dietary advice (low potassium diet) 
and possibly modification of drug treatment (if treated with drugs causing hyperkalemia) will 
be standard of care. In severe hyperkalemia, or if arrhythmias are present, emergency lowering 
of potassium and close monitoring in a hospital setting are mandated. 
Sodium polystyrene sulfonate (sodium polystyrene sulfonate [SPS]; e.g., Kayexalate) 
is a resin that binds potassium in the intestine and increases fecal excretion, thereby 
reducing S-K values. However, as SPS has been shown to cause intestinal obstruction 
and potential rupture, diarrhea needs to be simultaneously induced, significantly 
reducing the palatability of the treatment. Even without the induction of diarrhea, a 
substantial proportion of patients complain of gastrointestinal symptoms, such as 
constipation, abdominal pain, cramping, distension, nausea, and vomiting. In addition, 
SPS is non-specific and also binds calcium and magnesium, thereby increasing the risk 
of inducing hypocalcemia and/or hypomagnesemia.
Intravenous insulin (administered with or without glucose to prevent hypoglycemia) to 
shift potassium into the cells and away from the blood.
Intravenous calcium gluconate or chloride decreases myocardial excitability and 
stabilizes the myocardium, reducing the risk for cardiac arrhythmias, but does not affect 
S-K.


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Study Code D9480C00001
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Severe cases not responding to other medical therapy may require dialysis.
Thus, the only pharmacologic therapy that increases elimination of potassium from the body is 
SPS. However, due to the need to induce diarrhea, SPS cannot be administered on a chronic 
basis. Even in the acute setting, the need to induce diarrhea, combined with inconsistent efficacy 
and a foul smell and taste, reduces the usefulness of SPS. Hence, there is a significant medical 
need for new and better treatment modalities for the acute as well as chronic treatment of 
hyperkalemia.
ZS-9 is a microporous zirconium silicate with a specific crystal geometry that confers a high, 
selective exchange capacity for potassium and ammonium ions. Sodium zirconium cyclosilicate 
(ZS) is a partially protonated form of ZS-9 that is being developed for the treatment of 
hyperkalemia.
ZS has been shown to bind potassium in the intestine of animals in exchange for hydrogen and 
sodium. The potassium-binding capacity of ZS has been shown in vitro to be approximately 10 
times that of SPS in the presence of calcium and magnesium cations, which would represent a 
significant therapeutic advantage over SPS. In vivo studies in dogs and rats demonstrated 
significant dose-related reductions in the fractional excretion of urinary potassium up to 95% 
without any change in serum magnesium or calcium levels. Toxicology studies have shown ZS 
to be well tolerated at doses up to ~2.3-fold higher than the maximum three times a day ZS dose 
planned for registration or ~14-fold higher than the recommended starting once daily dose of 5 
g per day. In addition, animal studies have demonstrated that ZS is not systemically absorbed, 
but exerts its effects locally in the gastrointestinal tract, significantly reducing the risk of any 
systemic toxicity. 
As of September 2019, the clinical efficacy and safety of ZS in the treatment of hyperkalaemia 
has been assessed in 9 Phase 2/Phase 3 studies: 6 randomised, double blind, placebo controlled 
studies and 3 open label dose titration studies. In these studies, 2343 subjects with 
hyperkalaemia received at least 1 dose of ZS.
Clinical studies in subjects with hyperkalaemia consistently demonstrated that initial treatment 
with ZS 10 g tid for 24 h up to 72 h resulted in clinically meaningful S-K reduction with a 
majority of subjects achieving normokalaemia within 24 to 48 hours. Moreover, subjects with 
higher baseline S K levels had greater reductions in S K levels.  Onset of efficacy was rapid 
with S-K reduction observed as early as 1 hour after dose intake.
After correction of hyperkalaemia, continued maintenance treatment for 28 days with ZS 5 g, 
10 g, or 15 g qd resulted in continued effective control of S K within the normokalemic range.  
The proportion of subjects who remained normokalemic at the end of treatment with ZS 5 g, 10 
g, and 15 g qd increased dose dependently (range: 71% to 85%) and was superior to placebo.  
In addition, long-term maintenance treatment of up to 12 months with ZS utilising a dose 
titration scheme with the starting dose of 5 g qd or 10 g qd, titrated to a maximum of 15 g qd or 
a minimum of 5 g qod was effective in maintaining normokalaemia in the majority of subjects.


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A detailed description of the chemistry, pharmacology, efficacy and safety of ZS is provided in 
the Investigator’s Brochure.
1.2
Rationale for study design, doses and control groups
This phase 3 study was intended to be included in applications for marketing authorization in 
the countries where the study is performed. ZS was approved in China for hyperkalemia based 
on overseas data at the end of 2019, now this is a post-approval commitment study for China.
A double-blind, placebo-controlled, randomized study represents the optimal design for 
obtaining unbiased estimates of treatment group differences for a new drug under development. 
Recognizing that all patients will receive active treatment during the open-label initial phase, 
combined with the fact that all patients will be monitored in the clinic for at least 4 hours after 
the initial dose of ZS, the level of hyperkalemia that could be included is not limited.
The randomized portion of the study (the 28-day randomized treatment study phase) is designed 
to assess whether extended administration of ZS maintains control of S-K values and to 
demonstrate that hyperkalemia recurs once ZS is withdrawn. Such design represents state-of-
the-art in demonstrating the need for ongoing longer-term treatment of a new drug under 
development. A 28-day randomized treatment study phase is selected as a compromise between 
ensuring a sufficiently long treatment period to demonstrate that ZS can maintain normokalemia 
over extended time, while not exposing patients with a potentially life-threatening condition to 
extended treatment with placebo. Eligibility for the open-label initial phase, eligibility for the 
28-day randomized treatment study phase, and potassium-related stopping criteria are based on 
i-STAT measurements as these decisions need to be made in ‘real-time’ due to the risk of 
potentially life-threatening cardiac arrhythmias associated with severe hyperkalemia or 
hypokalemia. However, all endpoint analyses will be based on standardized S-K measurements 
analyzed at a central laboratory. For treatment decisions (i.e., S-K values on i-STAT < 3.5 
mmol/L), a second i-STAT sample will be taken 10 minutes after the initial abnormal sample 
to ensure that treatment is only changed once hypokalemia is confirmed. For a treatment 
decision to be made, both samples, taken 10 minutes apart, need to be below 3.5 mmol/L.
The design of this study is similar to the global ZS-004 study. In study ZS-004 (Kosiborod M 
et al 2014), ZS was highly effective in reducing S-K in patients with hyperkalemia, 
demonstrating statistically significant improvement from baseline in S-K with ZS 10 g TID over 
the first 48 hours of dosing. Patients who achieved normokalemia after receiving ZS 10 g TID 
in the Acute Phase were randomized to 28 days of placebo, ZS 5 g qd, ZS 10 g qd, or ZS 15 g 
qd dosing during the Maintenance Phase. ZS was effective in maintaining normokalemia (S-K 
between 3.5 mmol/L and 5.0 mmol/L, inclusive), meeting the predefined primary efficacy 
endpoint of mean S-K value during Maintenance Phase Study Days 8 to 29 at all 3 doses of ZS. 
Treatment with ZS was well tolerated in the patients recruited in ZS-004. The doses studied in 
this study were selected considering both efficacy and tolerability of the doses studies in ZS-
004. Specific exclusion criteria ensure that appropriate patients, who are not at excess risk from 
treatment, will be enrolled. The multicenter design enhance the external validity, reproducibility, 
and generalizability of the results observed.




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Study Code D9480C00001
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a white, insoluble, powder provided in 5g and 10g sachets to be suspended in water for oral 
administration.
1.3.1
Clinical benefits
In randomized, double-blind, placebo-controlled trials, ZS rapidly corrected potassium levels 
and maintained normokalemia in patients with hyperkalemia including those with chronic 
kidney disease, heart failure, diabetes mellitus and RAASi use. ZS was effective regardless of 
the underlying cause of hyperkalemia, age, sex, race or baseline potassium level. 
ZS acts rapidly, statistically significantly reducing potassium within one hour (study ZS-003). 
With ZS10g TID, 77% of patients achieved normokalemia within 24 hours and 86% within 48 
hours. Median time to normokalemia was 2.2 hours (ZS-004). 
ZS is self-equilibrating. Potassium fell 0.8, 1.2 and 1.5 mmol/L at 48 hours among patients with 
baseline potassium <5.5, 5.5-5.9 and ≥6.0 mmol/L, respectively (ZS-004). Self-equilibration 
reduces the risk of hypokalemia and reflects the mechanism of action; as potassium levels 
normalize, less potassium is excreted into the GI tract and fewer cations are exchanged. 
ZS maintains normokalemia. Patients who achieved normokalemia with TID dosing were 
randomized to maintenance therapy with once daily ZS or placebo for 12 days (ZS-003) or 28 
days (ZS-004). ZS-003 met predefined efficacy endpoints at the 5 and 10g doses when 
compared with placebo. In ZS-004, ZS 5, 10 or 15g increased the number of normokalemic 
days (p ≤0.0001 for each dose vs placebo) and maintained potassium at lower levels than 
placebo (p≤0.0001 for all doses). ZS  maintained normokalemia for up to 12 months in the open 
label extension; when ZS was stopped, potassium rose to near baseline levels (ZS-004E).
Co-administration of ZS with clopidogrel, dabigatran, glipizide, losartan, furosemide, 
atorvastatin, amlodipine, warfarin, and levothyroxine identified no clinically meaningful drug-
drug interaction (ZS-009).
1.3.2
Clinical risks
The safety of ZS was evaluated in clinical trials for the reduction of hyperkalemia involving 
over 1,500 patients.
The most commonly reported adverse reaction was edema related events which were reported 
by 5.7% ZS patients; 1.7, 2.7, 5.2, and 14.3% of patients randomized to placebo, ZS 5 g, 10 g, 
or 15 g once daily up to one month, respectively. Fifty-three percent were managed with 
initiating a diuretic or adjusting a diuretic dose; the remainder did not require treatment.
In clinical trials, 4.1% of ZS patients developed hypokalemia with a serum potassium value less 
than 3.5 mmol/L, which was resolved with dose adjustment or discontinuation of ZS.


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1.3.3
Clinical benefit-risk balance
For correction of hyperkalemia, ZS 10g TID is recommended for up to 3 days until 
normokalemia is achieved. Thereafter, maintenance therapy is initiated with 5g qd and dose 
adjusted from 10g daily to 5g every other day to maintain normokalemia. 
Benefits and risks for ZS are summarized below:
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g
Hyperkalemia increases the risk of arrhythmic death; potassium lowering reduces this risk even 
if normokalemia is not achieved. Benefits of ZS over placebo in patients with hyperkalemia 
include rapidly reducing serum potassium to achieve normokalemia and maintenance of 
normokalemia. Advantages over currently available therapies include rapidity of potassium 
lowering, no clinically meaningful drug-drug interactions, no increase in gastrointestinal 
adverse events or hypomagnesemia. 
The risks identified with ZS treatment include hypokalemia and edema-related events. In this 
study, the risk for hypokalaemia is mitigated by periodic monitoring of potassium and 
adjustment of the dose of IP as necessary. Edema can be managed in line with standard clinical 
practice. No additional safety risks have so far been identified.
A detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ZS may be found in the Investigator’s Brochure.
1.3.4
Conclusions
Based on available data, the benefit-risk assessment for sodium zirconium cyclosilicate is 
favourable for correction of hyperkalemia (10g TID for up to 3 days) and for maintenance 
treatment of patients with hyperkalemia across the dose range 15g daily to 5g every other day. 


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1.4
Study Design 
This is a prospective, randomized, double-blind, placebo-controlled, phase 3 study to 
investigate the safety and efficacy of ZS in patients with hyperkalemia.
This study consists of the optional Pre-screening period, the screening period (1 day), the open-
label initial phase (24 or 48 hours),  the 28-day randomized treatment study phase and EOS visit 
which is 7±1 days after the last administration of study medication. For patients who failed in 
pre-screening and screening, the standard of care at the discretion and the direction will be given 
by his/her own physician. For patients who do not enter the 28-day randomized treatment study 
phase the last visit will be 7±1 day after the last treatment dose in the open-label initial phase.
The study comprises 14-15 visits: optional Pre-screening visit (Visit 1), enrolment visit (Visit 
2), entering visit to the open-label initial phase (Visit 3), treatment visit in the open-label initial 
phase (Visit 4, only for those not achieving normokalemia after 24 hours treatment), 
randomization visit to the 28-day randomized treatment study phase, treatment visit in the 28-
day randomized treatment study phase (Visit 6-13), safety visit in the 28-day randomized 
treatment study phase (Visit 14), and end of study (EOS) visit. For details on timing of visits, 
see Figure 3 below:


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Figure 3
Study flow chart
R=Randomization; DB=Double-blind; EOS=End of study; V=Visit, D=Day, tid=three times a day; qd=once daily 
a Pre-screening visit is optional. Patients who participate in the Pre-screening visit and meet all Pre-screening inclusion/exclusion criteria will be entered into 
the screening part of the study within 7 days.  
b Study Day for open-label initial phase, patients achieving normokalemia in the morning of Day 2 of the open-label initial phase will enter Study Day 1 of the 
28-day randomized treatment phase directly.
c Study Day for 28-day randomized treatment study phase. Day 3 of the open-label initial phase is the same day as Day 1 for 28-day randomized treatment study 
phase. For patients achieving normokalemia by the morning of Day 2 of the initial phase, that day would be the same day as Day 1 for 28-day randomized 
treatment study phase.
d EOS occurs 7±1 day after the last administration of study medication (same applies if patients leave the study during open-label initial phase)


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the efficacy of  two different 
doses (5 and 10 g) of ZS orally 
administered once daily (qd) for 28 days 
in maintaining normokalemia (serum 
potassium [S-K] between 3.5-5.0 mmol/L, 
inclusive) in normokalemic patients, 
following treatment in the open-label 
initial phase, for hyperkalemic patients 
(two consecutive 
i-STAT potassium 
values ≥ 5.1 mmol/L, taken 60 minutes 
apart) at baseline.
Comparison between placebo and each ZS 
treatment group (high to low) with regard to the 
mean S-K level during the 28-day randomized 
treatment study phase Days 8-29.


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2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
Open-label initial phase:

To evaluate the proportion of patients 
who achieve normokalemia after the 
completion of open-label initial phase 
treatment.
28-day randomized treatment study phase:

To evaluate the efficacy of ZS in 
patients with hyperkalemia for the 
following subgroups as applicable*:
-
chronic kidney disease (CKD)
-
diabetes mellitus (DM)
-
heart failure (HF)
-
those 
on 
renin-angiotensin-
aldosterone 
system 
(RAAS) 
inhibitors

To evaluate the effect of  ZS on serum-
Aldosterone (S-Aldo) and Plasma-
Renin (P-Renin) levels.
Open-label initial phase efficacy endpoints:

Proportion 
of 
patients 
who 
achieve 
normokalemia during the open-label initial 
phase at 24 hours and at the end of the open-
label phase

Exponential rate of change in S-K levels 
(blood) during the open-label initial phase

Mean change (absolute and percent change) 
from baseline in S-K levels (blood) at all 
measured time intervals (See Table 1) post-
dose during the open-label phase

Time 
to 
normalization 
in 
S-K 
levels 
(normalization defined as S-K levels between 
3.5-5.0 mmol/L, inclusive) during the open-
label phase
28-day randomized treatment study phase efficacy 
endpoints:

The proportion of patients who remain 
normokalemic (as defined by S-K between 
3.5-5.0 mmol/L, inclusive) at the end of the 
28-day randomized treatment study phase and 
during the 28-day randomized treatment study 
phase

The 
number 
of 
days 
patients 
remain 
normokalemic during the 28-day randomized 
treatment study phase

The mean change and mean percent change in 
S-K levels evaluated relative to both baselines  

The time to hyperkalemia (defined as S-K ≥ 
5.1mmol/L)

The mean changes in S-Aldo and P-Renin 
levels
*    Primary efficacy endpoint and the secondary efficacy endpoint of the proportion of patients who remain 
normokalemic (as defined by S-K between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized 
treatment study phase will be evaluated in patients with hyperkalemia for the subgroups. More details will be 
described in the SAP.


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2.3
Safety objectives
Safety Objectives:
Outcome Measures:

To evaluate the effect of ZS on other 
serum electrolytes in both the open-
label initial phase and the 28-day 
randomized treatment study phase.

To evaluate the safety and tolerability 
profiles of ZS in both the open-label 
initial 
phase 
and 
the 
28-day 
randomized treatment study phase.

Serum calcium [S-Ca], serum magnesium [S-
Mg], serum sodium [S-Na], serum phosphate 
[S-PO4], serum bicarbonate [S-HCO3], and 
blood urea nitrogen [BUN]

Adverse events (AEs), serious AEs (SAEs), 
vital signs (VS), physical examinations

ECG

Clinical laboratory evaluations, including 
assessment of hypokalemia
2.4
Exploratory objectives (Not applicable)
3.
PATIENT
SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
Optional Pre-screening part of the study
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent (pre-screening consent) prior to any study specific 
procedures 
2.
Female and male patients aged ≥18 and ≤ 90 years
Main part of the study
Above inclusion criteria 2 is also applied to the Main part of the study. In addition, for inclusion 
in the study patients should fulfil the following criteria:
3.
Provision of informed consent prior to any study specific procedures   
4.
Two consecutive i-STAT potassium values, measured 60-minutes (± 10 minutes) 
apart, both ≥ 5.1 mmol/L and measured within 1 day of the first ZS dose on open-
label initial phase Day 1
5.
Ability to have repeated blood draws or effective venous catheterization


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6.
Female patients must be 1 year post-menopausal, surgically sterile, or using an
acceptable method of contraception (an acceptable method of contraception is 
defined as a barrier method in conjunction with a spermicide) for the duration of the 
study (from the time they sign consent) and for 3 months after the last dose of 
ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, 
approved contraceptive implant, long-term injectable contraception, intrauterine 
device, or tubal ligation are allowed. Oral contraception alone is not acceptable; 
additional barrier methods in conjunction with spermicide must be used.
Note: Whenever possible, all blood draws collected prior to meals should be collected prior to 
insulin/insulin analog treatment.
3.2
Exclusion criteria
Optional Pre-screening part of the study
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.
Participation in another clinical study with an investigational product during the last 
3 months
3.
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
Main part of the study 
Above exclusion criteria are also applied to the Main part of the study. In addition, patients 
should not enter the study if any of the following exclusion criteria are fulfilled:
4.
Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due 
to excessive fist clenching to make veins prominent, difficult or traumatic 
venepuncture, or history of severe leukocytosis or thrombocytosis
5.
Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics 
for hyperammonemia within 7 days prior to the first dose of study drug
6.
Patients treated with resins (such as sevelamer acetate or sodium polystyrene 
sulfonate [SPS; e.g., Kayexalate®]), calcium acetate, calcium carbonate, or 
lanthanum carbonate, within 7 days prior to the first dose of study drug
7.
Patients with a life expectancy of less than 3 months


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8.
Patients who are severely physically or mentally incapacitated and who in the 
opinion of investigator are unable to perform the subjects’ tasks associated with the 
protocol
9.
Female patients who are pregnant, lactating, or planning to become pregnant
10. Patients with diabetic ketoacidosis
11. Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
12. Patients with cardiac arrhythmias that require immediate treatment
13. History of QT prolongation associated with other medications that required 
discontinuation of that medication
14. Congenital long QT syndrome 
15. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia.  Subjects with atrial fibrillation controlled by 
medication are permitted
16. QTc(f) > 550 msec
17. Patients on dialysis
18. Patients who are blood donors should not donate blood during the study and for 3
months following their last dose of ZS
19. Patients who need hospitalization after taking blood samples on day 1 of the open-
label initial phase 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomization
Patients enrolling in the study will provide consent in a two-stage process. Investigator(s) should 
keep a record provided by the sponsor, the patient screening log, of any patients who are 
considered for entering the  pre-screening.
Optional Pre-screening part of the study
The Investigator(s) will: 
1. Obtain signed Pre-screening informed consent from the potential patient or their 
guardian/legal representative before any study specific procedures are performed.
2. Consent to Pre-screening will be closed once sufficient patients have been enrolled to reach 
the required number of randomised patients. 


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Main part of the study
Patients who are eligible for participation in the study, will subsequently be offered the option 
of consenting to the main study and will need to sign the main study consent, in addition to the 
first consent. They will then undergo all other screening assessments for the screening part of 
study.
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 patients a unique enrolment number via IVRS/IWRS, beginning with ‘E#’.
3. Patients will remain associated with the same patient 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 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/randomization 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study medication.  There can be no exceptions to this rule.  Patients who are enrolled, 
but subsequently found not to meet all the eligibility criteria must not be randomized or initiated 
on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 
immediately, and a discussion should occur between the AstraZeneca study physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment.  The 
AstraZeneca study physician must ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
The randomization codes will be computer generated using the AZ global randomization system 
(AZRand) and loaded into the IVRS/IWRS database. Randomization codes will be generated 
in blocks to ensure approximate balance (2:2:1) between the three treatment arms (ZS 5g or ZS 
10g or placebo once daily).  Randomization will be stratified by country.


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3.6
Methods for ensuring blinding
The 28-day randomized treatment study phase will have a double blind design. Patients will 
take by mouth the entire contents of a single sachet qd, containing either ZS 5g, ZS 10g or 
placebo. The exterior of the sachets are identical. Individual sachets are enclosed in a carton 
with a tamper evident seal intended to be broken exclusively by patients just before taking the 
study drug. 
No member of the study team at AZ, or representative, personnel at study centers or any clinical 
research organization (CRO) handling data will have access to the randomization scheme during 
the conduct of the study, with the exception of the AZ personnel generating the randomization 
scheme as well as AZ Supply Chain, the Patient Safety data entry site and the CRO companies 
providing the IVRS/IWRS and carrying out the packaging and labeling of study medication. 
This documentation will be kept in a secure location until the end of the study.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized patient 
in the 28-day randomized treatment study phase, will be available to the Investigator(s) from 
the IVRS/IWRS in case of unblinding situation. Routines for this will be described in the 
IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization. The Investigator 
documents and reports the action to AstraZeneca, without revealing the treatment given to 
patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for Serious Adverse Event (SAE) that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. Treatment codes will not be 
broken for the planned analyses of data until all decisions on the evaluability of the data from 
each individual patient have been made and documented.
3.8
Restrictions
Patients on RAAS inhibitors and/or diuretics are not allowed to titrate or discontinue or  switch 
RAAS inhibitors and/or diuretic therapy during the study. For concomitant medications which 
are restricted during the study, please see Section 7.7.
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:

Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

Adverse Event


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
Severe non-compliance with the 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

Start dialysis while in the study

Patient unblinded due to emergency

Patients who change or switch RAAS inhibitor and/or diuretic dose during the study  

Patient develops severe hypokalemia (i-STAT potassium values <3.0 mmol/L) at any 
time during the study or has i-STAT level > 6.2 mmol/L during the 28-day randomized 
treatment study phase (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 has a clinically significant cardiac arrhythmia (see below) at any time in the 28-
day randomized treatment study phase, the patient should immediately receive 
appropriate medical treatment and be discontinued from study drug. Any of the 
following cardiac events will result in immediate discontinuation from the study drug 
(independent of whether it is in the open-label initial phase or the 28-day randomized 
treatment study phase):

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), widening of the QRS complex (>140 msec in the 
absence of pre-existing bundle branch block) or new onset peaked T-wave 

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. The QTc(f) algorithm 
(QT interval corrected by the Fridericia method) is recommended.


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Patients who discontinue from study medication during the 28-day randomized treatment study 
phase but agree to remain in the study should continue to follow protocol-specified procedures 
and assessments except for dispensing of study medication for the study. 
Any patient who is discontinued from the study treatment during open-label initiation phase 
will return to the clinic 7 (± 1) days after the last IP administration for an EOS visit. Note: 
Discontinuation of investigational product does not necessarily imply discontinuation of follow-
up or termination of all study participation.
3.9.1
Procedures for discontinuation of a subject from investigational product 
At any time, patients are free to discontinue investigational product or withdraw from the study 
(i.e., investigational product and assessments – see Section 3.10), without prejudice to further 
treatment.  A patient that decides to discontinue investigational product will always be 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

Patient lost to follow-up

Death
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.


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3.10.2 Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn patients will not be replaced.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at undue 
risk because of clinically significant findings that are assessed as causally related to study drug 
and are not considered to be consistent with continuation of the study.
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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4. STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan detailing the procedures: optional Pre-screening, screening and 
open-label initial phase
Study Visit
Visit 1
Visit 2
Visit 3
Visit 48
Rand. 
Visit
EOS10
Initial Phase Day
Pre-
screen 3
Screen
Day 114
Day 214
Day
2 or 314
Day 9 
(+1d)
Accepted visit window during 
prolonged public holidays18
Day 4-16
Written informed consent
X
X
Eligibility criteria
X
X11
X
Demographics
X
X
Medical History
X11
Physical exam including weight
X11, 15
X15
X15
Access IVRS/IWRS
X
X
X12
Study drug (IP) dispensation
X
Study drug (IP) administration
X
X
ECG
X11
X
X
X
Vital signs
X11
X
X
Concomitant medications
X11
X
X
X
Adverse events
X16
X
X
X
Serious adverse events
X17
X
X
X
X
Potassium6, 13
X2
X4
X5
X9
X9
Clinical chemistry1,6
X11
X
X
Hematology1,6
X11
X
X
Urinalysis 1,6
X11
X
X
Urine HCG
X7,11
X7
IP Reconciliation
X
1.
Parameters to be measured are detailed in Table 3. 
2.
Blood potassium will be measured only by i-STAT at the Pre-screening visit (Visit 1). 
3.
Pre-screening visit is optional. Patients who meet all Pre-screening inclusion/exclusion criteria will be entered 
into the screening part of the study within 7 days.
4.
Potassium will be measured twice 60 (±10) minutes apart within 1 day of first dose administration on the 
open-label initial phase Day 1(Visit 3) and at 1,2 and 4 hours (±15 min) after administration of the first dose 
of ZS. Potassium will be measured again at 90 minutes (±15 min) after taking the second dose for patients 
with i-STAT potassium ≥ 6.1 mmol/L or < 4.0 mmol/L4 hour after the first dose.


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5.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) after the first dose on the open-label initial 
phase Day 2 (Visit 4). Patients achieving normokalemia (3.5 to 5.0 mmol/L, inclusive) based on the predose 
potassium value will skip the Visit 4 and will continue on the same day to the Randomization Visit procedures.
6.
Serum clinical chemistry, including S-K, hematology and urinalysis will be measured fasting (nothing by 
mouth except water only for a minimum of 8 hours prior to collection). On the open-label initial phase Day 
1(Visit 3), the Central Laboratory clinical chemistry and hematology samples will be collected at the same 
time as the 60 minutes i-STAT screening potassium sample.
7.
For women of childbearing potential, urine-HCG will be measured at clinic, using the tube provided by 
Central Laboratory.  
8.
For patients who achieve normokalemia (3.5 to 5.0 mmol/L, inclusive) based on the predose i-STAT 
potassium value for open-label initial phase Day 2, will proceed to the Randomization Visit. For patients with 
i-STAT potassium values >5.0 mmol/L, they will continue on with the remaining procedures. 
9.
Central laboratory S-K sample collected as part of the serum clinical chemistry.
10. EOS in the open-label initial phase only for patients NOT entering the 28-day randomized treatment study 
phase, and occurs 7±1 day after the last administration of IP.
11. Baseline parameters should be measured/collected up to 1 day prior to administration of the 1st dose of study 
drug on the open-label initial phase Day 1(Visit 3).
12. If patient achieves normokalemia (3.5 to 5.0 mmol/L, inclusive) based on the predose potassium value of 
open-label initial phase Day 2 or Day 3, access IVRS/IWRS to proceed with the Randomization Visit. If the 
patient permanently discontinues dosing before the end of the open-label initial phase dosing period, access 
IVRS/IWRS to register subject as not randomized.
13. For diabetic patients all blood potassium samples should be collected prior to insulin administration whenever 
possible.
14. Study Day in Table 1 is for the open-label initial phase.
15. A complete physical examination should be performed within 1 day prior to administration the first dose of 
study drug on the open-label initial phase Day 1, and targeted physical examination will be conducted on the 
open-label initial phase Day 3 and 9 for patients not entering the 28-day randomized treatment study phase. 
Please refer to Section 5.2.2.
16. AEs will be collected after the patient has signed the main study informed consent, so during the Day 1 (Visit 
3), investigator need to check if any AE happened since from main study inform consent. 
17. Only SAEs will be collected after the patient has singed the optional Pre-screening informed consent. 
18. The defined wider visit window can be applied, if patients are not able to strictly follow the pre-specified visit 
schedules, due to a prolonged public holiday. 


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Table 2
Study Plan detailing the procedures: 28-day randomized treatment study phase
Study Visit
Rand. 
Visit
Visit  
6
Visit  
7
Visit  
8
Visit  
9
Visit  
10
Visit 
11
Visit 
12
Visit 
13
Visit 
14
EOS
9
28-day randomized 
treatment study 
phase Day7
Day 
112
Day 
212
Day 
512
Day  
812
Day 
1212
Day 
1512
Day 
1912
Day 
2212
Day 
2612
Day 
2912
Day 
3512
Accepted visit 
window during 
prolonged public 
holidays8
Day 
3-6
Day 
7-9
Day 
10-13
Day 
14-17
Day 
18-20
Day 
21-24
Day 
25-27
Day  
28-31
Day 
32-43
Eligibility criteria
X
Physical exam
including weight3, 13
X
X
X
X
Access 
IVRS/IWRS10
X
X
X
X
Study 
drug 
(IP) 
dispensation11
X
X
X
X
Study 
drug 
(IP) 
administration4
X
X
X
X
X
X
X
X
X
ECG3
X
X
X
X
X
X
Vital signs3
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
Adverse 
events 
(including SAEs)
X
X
X
X
X
X
X
X
X
X
X
Potassium6
X2
X
X
X
X
X2
X
X
X
X2
X2
Clinical chemistry1,3
X
X
X
X
Hematology1,3
X
X
X
X
Urinalysis 1,3
X
X
X
X
Urine HCG
X5
IP Reconciliation
X
1.
Parameters to be measured are detailed in Table 3. 
2.
Potassium will be measured fasting prior to the 1st daily dose as part of the clinical chemistry panel on Day 
1, 15, 29, 35 in the 28-day randomized treatment study phase. 
3.
Physical Exam, ECG, Vital signs, weight, urinalysis, clinical chemistry including S-Aldo and P-Renin, and 
hematology parameters will be measured fasting (nothing by mouth except water for a minimum of 8 hours
prior to potassium sample collection at the clinic); On the 28-day randomized treatment study phase Days 
1,15, 29, and 35(EOS), blood sample which including S-Aldo and P-Renin test need to be collected prior to 
10am after  the patient has been upright for at least 2 hours and before the ECG. 
4.    Study drug will be administrated in the clinic on Day 1,2,5,8,12,15,19,22 and 26. 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 


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measurement after a 10 ± 2-minute interval, and both i-STAT values meet the study drug adjustment rule), 
dosing will be reduced from qd to every other day for the remainder of the study.
5.
For women of Childbearing potential, using-HCG will be measured at clinic, using the tube provided by 
Central Laboratory.
6.
All potassium samples are analyzed by i-STAT and by the Central Laboratory on all occasion. And 
haemolysed samples should not be sent to the Central Lab for potassium, the sample should be re-drawn to 
obtain a sample showing no haemolysis. For diabetic patients all blood potassium samples should be collected 
prior to insulin administration whenever possible.
7.
If a scheduled clinic visit falls on a weekend or short public holiday during the 28-day randomized treatment 
study phase, the scheduled visit may take place either 1 day early or 1 day late (i.e., within±24 hours of the 
scheduled day) for the 28-day randomized treatment study phase Days 5, 8, 12, 15, 19, 22, 26 and 35, up to 
2 days late for the 28-day randomized treatment study phase Day 2 or 2 days early for Day 29. If the Day 29 
visit is conducted early, the patient must take IP through Day 28 per protocol.
8.
The defined wider visit window can be applied, if patients, are not able to strictly follow the pre-specified 
visit schedules, due to a prolonged public holiday. If the wider visit windows are applied for a particular visit, 
it is important that visits before and after such a visit also follows the wider visit windows. This will only 
apply during prolonged public holidays. Patients are expected to follow the pre-specified visit schedule once 
the prolonged holiday period is over.
9.
EOS occurs 7±1 day after the last administration of IP.
10.
Access IVRS/IWRS on visit indicated or if patient permanently discontinues dosing before the end of the 28-
day randomized treatment study phase.
11.
Due to a public holiday, patients may visit the clinic up to two days after the pre-specified visit schedules, the 
site investigator can access the IVRS/IWRS in an earlier visit; and the system will assign the patient a new 
28-day randomized treatment study phase IP kit containing an additional 7-day supply of IP.
12.   Study Day in Table 2 is for the 28-day randomized treatment study phase.
13.  Targeted physical examination will be conducted on Days 1, 15, 29, and Day 35 (EOS) during the 28-day 
randomized treatment study phase, please refer to Section 5.2.2.


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4.1
Optional Pre-screening period (Visit 1)
The Pre-screening visit is optional. Study procedures will be performed according to the Study 
Plan in Table 1.
At Pre-screening, the consenting patients are assessed to ensure that they meet eligibility criteria 
for the optional Pre-screening part of the study. Patients who do not meet these criteria must not 
be entered in the optional Pre-screening part of the study. 
Review and confirm the patient’s eligibility for the optional Pre-screening part of the 
study by assessing inclusion and exclusion criteria listed in Sections 3.1 and 3.2.
One potassium sample will be assessed using i-STAT. 
If i-STAT potassium value is <5.1 mmol/L the patient will be declared a pre-screen 
failure and discontinue from the study. There is no limit to the number of pre-
screenings a patient can take part in.
Record SAEs
Note: Patients who meet all optional Pre-screening inclusion/exclusion criteria and i-STAT 
potassium value is ≥5.1 mmol/L will be entered into the screening part of the study within 7 
days. 
4.2
Enrolment/screening period (Visit 2)
Study procedures will be performed according to the Study Plan in Table 1.
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be entered in the study. 
Patients can be re-screened once during the clinical trial period. A new ICF does not need to be 
signed before re-screening if the original ICF was signed within 30 days and has not been 
revised.
After a patient has signed the ICF for the screening part of the study at Visit 2 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).
4.3
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.


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4.3.1
Open-label initial phase Day 1 (Visit 3)
Patients will arrive in the morning, fasting (nothing by mouth except water for a minimum of 8 
hours prior to potassium sample collection at the clinic). 
The following assessment will be performed: 
Review and confirm the patient’s eligibility for the study by assessing inclusion and 
exclusion criteria listed in Sections 3.1 and 3.2.
Two  potassium samples for assessment, using both i-STAT and the Central 
Laboratory, will be collected 60 minutes (± 10 min) apart. 
If either i-STAT potassium value is <5.1 mmol/L the patient will be declared a screen 
failure and withdrawn from the study.
If both i-STAT values are ≥5.1 mmol/L the following samples will be collected:
A blood sample for standard assessment of hematology and clinical chemistry
Urine for standard assessment of urinalysis parameters including a pregnancy 
test if the patient is a woman of childbearing potential 
Obtain vital signs (pulse rate and blood pressure)
Patient medical and surgical history including co-morbidities (over previous 6 
months) 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 an open-
label initial phase IP kit 
The first doses of study IP will be administered as a slurry/suspension in water. The 
patient will be shown/instructed on how to mix and administer the IP 
1 hour (± 15 min) after dose administration a blood potassium sample (i-STAT and 
Central Laboratory) will be collected, following which the patient is allowed to break 
the fast
Two additional blood potassium samples (i-STAT and Central Laboratory) will then 
be taken at 2 and 4 hours (±15 min) after dose administration. 


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Patients with i-STAT potassium levels < 6.1 and ≥ 4.0mmol/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 for the open-
label initial Phase Day 2 (Visit 4)
Patients with i-STAT potassium ≥ 6.1 or < 4.0 mmol/L at the 4 hour post Dose 1 
blood draw will stay in the clinic and take the second dose of study drug 
approximately 4-hours after the first dose. They will then remain in the clinic an extra 
90 minutes (± 15 minutes)  after taking the second dose when another blood sample 
for potassium determination (i-STAT and Central Laboratory will be collected and 
an ECG will be recorded).
If i-STAT potassium levels are > 6.2 mmol/L as determined by the i-STAT at the 90-
minute post Dose 2 blood draw, the patient will be discontinued from the study. 
Patients will return to the clinic 7 (±1) days later for an EOS visit. 
If i-STAT potassium levels are ≤6.2 mmol/L and the ECG does not show any of the 
ECG withdrawal criteria, the patient will be sent home with the third dose of study 
drug and the dosing card and return to the clinic in the morning of the open-label 
initial phase Day 2 (Visit 4). 
See Section 7.2 regarding how to handle patients with potassium < 3.5mmol/L.
4.3.2
Open-label initial phase Day 2 (Visit 4)
Patients will arrive fasting at the clinic in the morning (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the IP and make note of the time the doses were taken and any unused IP on 
the eCRF and source documents.
Potassium levels will be evaluated by i-STAT and the Central Laboratory. i-STAT 
potassium measurement will be done during the visit to determine the next steps of 
procedures.
-
If the i-STAT potassium value is < 3.5mmol/L, see Section 7.2 regarding how 
to handle patients. 
-
If the i-STAT potassium value is between 3.5 and 5.0 mmol/L inclusive the 
patient will skip the remaining procedures for initial phase Day 2 and will be 
randomized (on the same day) into the 28-day randomized treatment study phase, 
and complete the remaining procedures detailed in Section 4.3.4. In this case 
Visit 4 will be skipped completely and the patient will conduct the 
Randomization visit instead. No data entry is done in the Visit 4 eCRF.


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-
If the i-STAT potassium value is ≥ 5.1 mmol/L, the patient will receive an 
additional 24 hours of ZS 10g TID and the following procedures will be 
performed.
An ECG will be performed (Section 5.2.3)
Following completion of the above procedures, the first daily dose of IP will be 
administered in the clinic as a slurry/suspension in water, followed by the 1 hour post 
Dose 1 blood draw (see Figure 4 for the flow chart based on the potassium value), 
after which the patient is allowed to break the fast. 
Patients will then be sent home with study drug and instructions on how to take the 
IP. They will be requested to fill out a dosing schedule card indicating when they 
took the IP. 
Patients will return to the clinic the following morning and bring the used and/or 
unused IP and completed dosing schedule card with them.
4.3.3
Randomization Visit - For patients not entering the 28-day randomized treatment 
study phase
On Day 3 of the Open-Label initial phase, patients will arrive at the clinic in the morning, fasting 
(nothing by mouth except water for a minimum of 8 hours prior to potassium sample collection 
at the clinic). They will bring the used and/or unused IP and completed dosing schedule card 
with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the IP and make note of the time the doses were taken and any unused IP on 
the eCRF and source documents. 
Vital signs (pulse rate and blood pressure) will be obtained. 
Potassium levels will be evaluated by i-STAT and the Central Laboratory. 
If the i-STAT potassium value is within the normal range (3.5 to 5.0 mmol/L, 
inclusive) the patient will be randomized into the 28-day randomized treatment 
study phase and complete the procedures detailed in (Section 4.3.4). 
However if the i-STAT potassium value is > 5.0 mmol/L or < 3.5 mmol/L the 
below assessments will be performed:
-
Samples will be collected: Blood samples for the standard assessment of 
clinical chemistry; blood sample for standard assessment of hematology; 
Urine for standard assessment of urinalysis parameters
-
An ECG will be performed (Section 5.2.3)
-
Perform physical examination including weight (Section 5.2.2)


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-
Withdraw the patient from the open-label initial phase and access 
IVRS/IWRS to register subject as not randomized.
-
Patients will then DISCONTINUE from the study medication, and 
receive standard of care at the discretion and the direction of his/her own 
physician. However, the patient will need to return to the clinic 7 (± 1) 
days later for an EOS visit in the morning, fasting, nothing by mouth 
except water (Section 4.4).
4.3.4
Randomization Visit - For patients entering the 28-day randomized treatment 
study phase
The Day 1 of the 28-day randomized treatment study phase will take place on the day when the 
patient achieves an i-STAT potassium value between 3.5 and 5.0 mmol/L, inclusive, after 24 or 
48 hours  of ZS 10 g TID treatment during the open-label initial phase.
The following assessments will be performed:
Samples will be collected prior to any IP administration:
Blood samples for standard assessment of hematology and clinical chemistry 
including S-K 
Urine for standard assessment of urinalysis parameters
An ECG will be performed (Section 5.2.3). 
A targeted physical examination including weight (Section 5.2.2). 
Site investigator access the IVRS/IWRS and randomize the patient. The system will 
assign the patient a study IP kit (Week 1) containing a 7-day supply of IP. 
If the 28-day randomized treatment study phase Day 2 visit falls on a public holiday 
or weekend, the patient should be informed when next to return to the clinic. They 
will be requested to fill out a dosing schedule card indicating when they took the IP and 
when they ate breakfast each day and to bring the used and/or unused IP and completed 
dosing schedule card with them when they return to the clinic. 
4.3.5
28-day randomized treatment study phase Day 2 (Visit 6)
If the scheduled 28-day randomized treatment study phase Day 2 clinic visit falls on a weekend 
or a short public holiday the Day 2 visit (Visit 6) may occur up to 2 days late. 
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 


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The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents. 
Potassium samples (i-STAT and Central Laboratory) will be collected prior to IP 
administration.
Patients will return to the clinic, in the morning, three (3) days later (the 28-day 
randomized treatment study phase Day 5) and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.6
28-day randomized treatment study phase Day 5 (Visit 7)
Investigator are required to plan each patient’s visit schedule in an optimal way and in 
accordance with the CSP. If patients are not able to accomplish a pre-specified visit during the 
28-day randomized treatment study phase, due to a prolonged public holiday, a “wider” visit 
window can be applied (see Table 2). Patients are expected to follow the pre-specified (tighter 
visits) visit schedule once the prolonged holiday period is over.
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents. 
Potassium samples (i-STAT and Central Laboratory) will be collected prior to any IP 
administration.
Patients will return to the clinic, in the morning, three (3) days later (the 28-day 
randomized treatment study phase Day 8) and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.7
28-day randomized treatment study phase Day 8 (Visit 8)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents. 
Prior to IP administration, potassium samples (i-STAT and Central Laboratory) will 
be collected 


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An ECG will be performed (Section 5.2.3). 
The site will access the IVRS/IWRS. The system will assign the patient a new 28-
day randomized treatment study phase IP kit (Week 2) containing an additional 7-
day supply of IP. 
Patients will return to the clinic, in the morning, four (4) days later (the 28-day 
randomized treatment study phase Day 12) and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.8
28-day randomized treatment study phase Day 12 (Visit 9)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents. 
Potassium samples (i-STAT and Central Laboratory) will be collected prior to any IP 
administration. 
Patients will return to the clinic, in the morning, three (3) days later (the 28-day 
randomized treatment study phase Day 15) and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.9
28-day randomized treatment study phase Day 15 (Visit 10)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP,  and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP sachets and make note of the time the doses were taken and 
any unused IP on the eCRF and source documents. 
Vital signs (pulse rate and blood pressure) will be obtained.
The following tests will be performed before any IP administration
i-STAT blood potassium assessment 
Blood samples for a standard assessment of clinical chemistry including, S-K 
Blood for a standard assessment of hematology parameters 
Urinalysis parameters 


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An ECG will be performed (Section 5.2.3)
A targeted physical examination will be performed (Section 5.2.2)
The site will access the IVRS/IWRS. The system will assign the patient a new 28-
day randomized treatment study phase IP kit for use in Week 3 containing an 
additional 7-day supply of IP.
Patients will return to the clinic, in the morning, four (4) days later (the 28-day 
randomized treatment study phase Day 19 and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.10 28-day randomized treatment study phase Day 19 (Visit 11)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents.
Potassium samples (i-STAT and Central Laboratory) will be collected prior to any IP 
administration. 
Patients will return to the clinic, in the morning, three (3) days later (the 28-day 
randomized treatment study phase Day 22) and bring the used and/or unused IP and 
completed dosing schedule card with them. 
4.3.11 28-day randomized treatment study phase Day 22 (Visit 12)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP,  and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents.
Blood samples for measurement of potassium (i-STAT and Central Laboratory) will 
be collected.
An ECG will be performed (Section 5.2.3)
The site will access the IVRS/IWRS. The system will assign the patient a new 28-
day randomized treatment study phase IP kit (Week 4) containing an additional 7-
day supply of IP.


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Patients will return to the clinic, in the morning, four (4) days later (the 28-day 
randomized treatment study phase Day 26) and bring the used and/or unused IP and 
completed dosing schedule card with them.
4.3.12 28-day randomized treatment study phase Day 26 (Visit 13)
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents.
Blood samples for measurement of potassium (i-STAT and Central Laboratory) will 
be collected.
Patients will return to the clinic, in the morning, three (3) days later (Day 29), fasting, 
nothing by mouth except water and bring the used and/or unused IP and completed 
dosing schedule card with them.
4.3.13 28-day randomized treatment study phase Day 29 (Visit 14)
Please note: If the Day 29 visit is conducted early, the patient must take IP through the 28-day 
randomized treatment study phase Day 28 per protocol. In this instance IP will be administered 
after all of the Day 29 procedures have been conducted.
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). They will bring the used 
and/or unused IP, and completed dosing schedule card with them. 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications, 
examine the returned IP and make note of the time the doses were taken and any 
unused IP on the eCRF and source documents. 
Vital signs (pulse rate and blood pressure) will be obtained.
The following tests will be performed:
i-STAT blood potassium assessment 
Blood samples for a standard assessment of clinical chemistry including, S-K 
Blood for a standard assessment of hematology parameters 
Urinalysis parameters


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An ECG will be performed (Section 5.2.3)
A targeted physical examination will be performed (Section 5.2.2)
Patients will be instructed to return to the clinic, in the morning, 7 ±1 days following 
the last study IP administration (the 28-day randomized treatment study phase Day 
35) for an EOS visit.
4.4
Follow-up period (EOS)
Follow up visit will be performed at Day 9 for the open-label initial phase, and Day 35 for the 
28-day randomized treatment study phase, or 7 ±1 days following the last study IP 
administration for patients who are withdrawn from the study.
Patients will arrive at the clinic in the morning, fasting (nothing by mouth except water for a 
minimum of 8 hours prior to potassium sample collection at the clinic). 
The following assessments will be performed: 
The clinic staff will solicit any AEs, note any changes in concomitant medications on 
the eCRF and source documents. 
Vital signs (pulse rate and blood pressure) will be obtained.
The following tests/procedures will be performed: 

i-STAT blood potassium assessment 

Blood samples for a standard assessment of clinical chemistry including, S-K 

Blood for a standard assessment of hematology parameters 

Urine for standard urinalysis parameters 

A pregnancy test if the patient is a woman of childbearing potential 

An ECG will be performed (Section 5.2.3)

A targeted physical examination will be performed (Section 5.2.2)
Note: If the EOS for the open-label initial phase or the 28-day randomized treatment study phase 
falls on a weekend or a short public holiday, the EOS visit can be performed either on the 
preceding Friday or the following Monday.
If the EOS for the open-label initial phase falls on a prolonged public holidays, the EOS visit 
can be performed from Study Day 4 to Study Day 16. If the EOS for the 28-day randomized 
treatment study phase falls on a prolonged public holidays, the EOS visit can be performed from 
Study Day 32 to Study Day 43. This will only apply during prolonged public holidays. 


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Figure 4
Flow chart based on the Potassium level, which will be measured by i-STAT


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Clinical Study Protocol
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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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1.
The open-label initial phase Day 3 is also the same day as the Randomization Visit (Day 1) of the 28-day 
randomized treatment study phase. Patients achieving normokalemia in the morning of the open-label 
initial phase Day 2 will enter the Study Day 1 of the 28-day randomized treatment study phase directly.
2.
Patient with confirmed i-STAT potassium value <3.0 mmol/L at any time during the study (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 hypokalemia.
3.
Patient with confirmed i-STAT potassium value >6.2 mmol/L during the 28-day randomized treatment 
study phase (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 hyperkalemia.
4.
Patient with confirmed 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 28-day 
randomized treatment study phase, dosing will be reduced from qd to qod for the remainder of the study. 


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Study Code D9480C00001
Version 6.0
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5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the 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
Blood 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 Central Laboratory. All serum 
samples should be examined and any hemolyzed samples MUST be redrawn. In the event that 
hemolysis or other artefacts are suspected based on the reported i-STAT result the sample may 
be re-drawn to confirm the result. Only the confirmatory sample result needs to be reported in 
the eCRF. 
5.2
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 
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.


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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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Table 3
Laboratory Safety Variables
Haematology
Clinical Chemistry (serum)
B-Hemoglobin (Hb)
S-Total Protein
B-Hematocrit
S-Albumin
B-Erythocyte count (RBC)
S-Bicarbonate
B-Total leukocyte count (WBC)
S-Blood Urea Nitrogen
B-Leukocyte differential count (absolute count)
S-Creatinine
B-Platelet count
S-Bilirubin, total
S-Alkaline phosphatise (ALP)
Urinalysis
S-Glucose
U-PH
S-Sodium
U-Specific gravity
S-Potassium1
U-Glucose 
S-Inorganic phosphate
U-Ketones
S-Calcium, total
U-Bilirubin
S-Magnesium
U-Urobilinogen
S-Gamma-glutamyl transferase (GGT)
U-Blood
S-Aspartate transaminase (AST)
S-Alanine transaminase (ALT)
U- Human chorionic gonadotropin (HCG) 
(only for females of childbearing potential) 2
S-Aldosterone3
P-Renin 3
1.
Blood potassium will be measured only by i-STAT at the optional Pre-screening visit. Blood potassium will 
be measured by i-STAT and Serum potassium will be measured by C-lab for Visit 2 to EOS Visit. 
2.
Urine-HCG will be measured at clinic, used the tube provided by Central Laboratory.
3.
Patients need to be either standing or seated upright for at least 2 hours before sample collection for S-
Aldosterone and P-Renin assessment.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at center 
as source data for laboratory variables. For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.3. 
Blood chemistry and hematology parameters will be evaluated fasting, by the Central 
Laboratory, on the open-label initial phase Days 1 for all patients, 3 and 9 (EOS visit) for 


Clinical Study Protocol
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Study Code D9480C00001
Version 6.0
Date 19 August 2020
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patients NOT entering the double-blind 28-day randomized treatment study phase and on the 
28-day randomized treatment study phase Days 1, 15, 29 and 35 (EOS).
S-K will be evaluated as part of the clinical chemistry sample on the open-label initial phase 
Day 1 (60 minute baseline sample), the open-label initial phase Days 3 and 9 (EOS) for patients 
not entering the 28-day randomized treatment study phase, and on the 28-day randomized 
treatment study phase Days 1,15, 29 and 35 (EOS). 
Urine samples will also be collected during the study. The open-label initial phase Day 1 urine 
pregnancy test for women of childbearing potential is performed as part of the screening 
procedure prior to any IP administration and is repeated at the last visit of the study, either on 
the open-label initial phase Day 9, or on the 28-day randomized treatment study phase Day 35.
Urinalysis, will be performed by the Central Laboratory at the open-label initial phase Day 1 
for all patients and on the open-label initial phase Days 3 and 9 for patients NOT entering the 
28-day randomized treatment study phase, and on the 28-day randomized treatment study phase 
Days 1, 15, 29 and the 28-day randomized treatment study phase Day 35 (EOS). 
Note: Whenever possible, all blood draws collected prior to meals should be collected prior to 
insulin/insulin analog treatment. 
5.2.2
Physical assessments
A complete physical examination should be performed within 1 day of administering the first 
dose of study drug on the open-label initial phase Day 1 (Baseline: all patients), and targeted 
physical examination will be conducted on the open-label initial phase Day 3 for all patients 
and on Day 9 for patients not entering the 28-day randomized treatment study phase. During the 
28-day randomized treatment study phase, targeted physical examination will be conducted on 
Days 1, 15, 29, and 35 (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
A 12-lead ECG will be performed after the patients 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 QTc(f) intervals will be recorded from standard lead of the computerized quantitative 12-
lead ECG. 
ECGs will be recorded at the open-label initial phase Day 1, Day 2, the open-label initial phase 
Day 3 and Day 9 (EOS) for patients NOT entering the double-blind 28-day randomized 


Clinical Study Protocol
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treatment study phase, and on the 28-day randomized treatment study phase Days 1, 8, 15, 22, 
29, and 35 (EOS). When applicable ECGs will be performed after the S-Aldo and P-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 but ≥3.5 
mmol/L at the 4 hour post 1st dose time point on the open-label initial phase Day 1, an additional 
ECG will be recorded 1.5 hours post 2nd dose. Patient who develops severe hypokalemia (i-
STAT potassium values <3.0 mmol/L) at any time during the study or > 6.2 mmol/L during the 
28-day randomized treatment study phase, an additional ECG will need to be performed.
Study subjects with pacemakers: 
All ECG variables, including QT/QTc(f), should be read manually and be recorded in the eCRF. 
If not fulfilling the I/E criteria or fulfilling the discontinuation criteria, pacemaker patients 
should be managed as recommended by protocol (without exceptions).
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 visit 3. Subsequent blood 
pressure measurements should be recorded in the arm with the higher pressure. Blood pressure 
should be measured in either supine or sitting position. No shift from one position to another 
should be made during the study. Supine or sitting posture should be adopted for at least 5 
minutes before measurement. The patient should be relaxed and with the arm outstretched and 
supported. Blood pressure should be measured under standardized conditions, as nearly as 
possible at the same time each visit, on the same arm, by the same personnel, and with the same 
apparatus.


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Study Code D9480C00001
Version 6.0
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5.3
Other assessments (Not applicable)
5.4
Pharmacokinetics (Not applicable)
5.5
Pharmacodynamics (Not applicable)
5.6
Genetics (Not applicable)
5.7
Biomarker analysis (Not applicable)
5.8
Storage, re-use and destruction of biological samples
After the analyses are complete the samples will be either completely consumed during the 
analytical process or disposed of after the analysis.
5.9
Labeling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are labeled and shipped in accordance with
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate labeling,
shipment and containment provisions are approved.
5.10
Volume of blood
The total volume of blood that will be drawn from each patient for this study is listed in Table 
4 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: optional pre-
screening and open-label initial phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume
Total (mL)
V1
V 3
(D 17)
V 4
(D 27)
Rand
(D 2/37,8)
EOS
(D 97)
Hematology
2
13
0-15
1
6
Clinical 
Chemistry
8.5
13,6
0-15,6
16
25.5
Potassium 
(Central Lab 
S-K) 
2.5
4-52,6
24
17.5


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Study Code D9480C00001
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Table 4
Volume of blood to be withdrawn from each patient: optional pre-
screening and open-label initial phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume
Total (mL)
V1
V 3
(D 17)
V 4
(D 27)
Rand
(D 2/37,8)
EOS
(D 97)
Potassium 
(i-STAT)
1
11
5-62
24
1
1
11
Maximum 
Blood Volume 
Total (mL)
1
29
7
11.5
11.5
60
V= Visit; D=Day
1.
Blood potassium will be measured only by i-STAT at the optional Pre-screening visit (Visit 1).
2.
Potassium will be measured twice 60 (±10) minutes apart within 1 day of first dose administration on the 
open-label initial phase Day 1(Visit 3) and at 1,2 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.
3.
On the open-label initial phase Day 1(Visit 3), the Central Laboratory clinical chemistry and hematology 
samples will be collected at the same time as the 60 minutes i-STAT screening potassium sample.
4.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) post 1st dose on the open-label initial 
phase Day 2 (Visit 4), for those achieving normokalemia based on the predose i-STAT potassium value, 
they will then enter the randomized phase directly.
5.
Clinical chemistry and hematology samples only for patients with i-STAT potassium values >5.0 mmol/L 
as measured fasting on the open-label initial phase Day 3. 
6.
Central laboratory S-K sample collected as part of the serum clinical chemistry
7.
Study Day in Table 4 is day for the open-label initial phase.
8.
Randomization Visit may occur for patients who achieve normokalemia on open-label initial phase Day 
2 or 3.
Table 5
Volume of blood to be withdrawn from each patient: 28-day randomized 
treatment study phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maxi
mum 
blood 
volu
me
Total 
(mL)
Rand
D12
V6
D22
V7
D52
V8
D82
V9
D122
V10
D152
V11
D192
V12
D222
V13
D262
V14
D292
EOS
D352
Hematology
2
1
1
1
1
8
Clinical 
Chemistry
8.5
11
11
11
11
34


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
71 (101)
Table 5
Volume of blood to be withdrawn from each patient: 28-day randomized 
treatment study phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maxi
mum 
blood 
volu
me
Total 
(mL)
Rand
D12
V6
D22
V7
D52
V8
D82
V9
D122
V10
D152
V11
D192
V12
D222
V13
D262
V14
D292
EOS
D352
Potassium 
(Central Lab 
S-K1)
2.5
1
1
1
1
1
1
1
17.5
Potassium (i-
STAT )
1
1
1
1
1
1
1
1
1
1
1
1
11
Maximum 
Blood 
Volume 
Total (mL)
11.5
3.5
3.5
3.5
3.5
11.5
3.5
3.5
3.5
11.5
11.5
70.5
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 Day 1, 15, 29, and 35.
2.     Study Day in Table 5 is day for the 28-day randomized treatment study phase.
5.11 Guidance related to assessments, and procedures during COVID-19 
pandemic
In view of the ongoing and emerging novel coronavirus (COVID-19) pandemic spreading 
worldwide, the safety and well-being of our study participants is of primary importance.  To 
protect the safety and well-being of study participants, Appendix C will provide guidance on 
the assessments and procedures during this period.
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.


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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/incapacity 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed and 
reported as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfill the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy.
For further guidance on the definition of a SAE, see Appendix A to Clinical Study Protocol


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6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events  will be collected from the time of main study informed consent, throughout 
the treatment period and including the EOS visit. SAEs will be collected from the time of 
optional Pre-screening informed consent, throughout the treatment period and including the 
EOS visit. 
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment (EOS) or other assessment/visit 
as appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the eCRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
6.3.3
Variables 
The following variables will be collect for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity (mild, moderate or severe)

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death


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
Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Description of AE
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may 
be considered severe nausea, but not a SAE unless it meets the criteria shown in Section 6.2. 
On the other hand, a stroke that results in only a limited degree of disability may be considered 
a mild stroke but would be a SAE when it satisfies the criteria shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study personnel: ‘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 protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  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 


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will be considered as additional information.  Wherever possible the reporting Investigator uses 
the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel reports 
a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel 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, during the open-label initial phase, any ZS dose greater 
than 30g within one day, or continuity of the correcting dose (10g TID) for more than 72 hours will 
be considered an overdose; during the randomized treatment phase, a dose higher than 15g/day will 
be considered an overdose. At any time during the study, doses higher than 15g taken at once will 
be considered an overdose.


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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose on ZS occurs in the course of the study, then the Investigator or other site 
personnel inform appropriate AstraZeneca representatives immediately, or no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs.  Elective abortions without complications should not 
be handled as AEs.  The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed up 
and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
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.


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6.6.2
Paternal exposure
Nonclinical data with ZS-9 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 IB for further details). Therefore there is no restriction on fathering children 
or donating sperm during the study.
In case of pregnancy of the patient’s partners, an ICF FOR PREGNANT PARTNERS OF 
STUDY PATIENTS the partner’s pregnancy will be sent to the partner to obtain her consent 
for collection of pregnancy information. Such pregnancy report will follow the same timeframe 
and routing as described for any participant’s pregnancy. These pregnancies will be also 
followed up, and the outcome of the pregnancy (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be obtained and documented 
if possible.
6.7
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
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 subject.
Medication error includes situations where an error: 

occurred

was identified and intercepted before the subject received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as 
a solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 


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
Wrong subject received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to subject (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 

Subject accidentally missed drug dose(s) e.g., forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If an medication error occurs  in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated with 
the medication error (see Section 6.4) and within 30 days for all other medication errors.
7. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product and 
strength
Dosage form 
Manufacturer
Sodium 
Zirconium 
Cyclosilicate (ZS) 5g
Powder for Oral Suspension in 
a sachet
AstraZeneca 
Sodium 
Zirconium 
Cyclosilicate (ZS) 10g
Powder for Oral Suspension in 
a sachet
AstraZeneca
Placebo 
Powder for Oral Suspension in 
a sachet
AstraZeneca


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7.2
Dose and treatment regimens
During the open-label initial phase all patients will receive ZS per os (PO) at a dose of 10g three 
times a day (tid) for a maximum of 6 doses, study drug will be administered orally before 
breakfast on the open-label initial phase Days 1 and 2, but for other dose during the open-label 
initial phase, study drug will be administrated orally with or without food. The individual kit 
will be assigned through IVRS/IWRS. 
For patients with i-STAT potassium values within the normokalemic range (3.5 to 5.0 mmol/L, 
inclusive) in the morning of the open-label initial phase Day 2 or Day 3, the site will contact 
IVRS/IWRS to determine which on-site kit to use for the 28-day randomized treatment study 
phase. Thereafter the 28-day randomized treatment study phase kits will be assigned weekly 
through IVRS/IWRS and be dispensed by designated and trained site pharmacy staff. Study 
drug will be taken orally in the morning during the 28-day randomized treatment study phase, 
with or without food.
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 mmol/L, 
inclusive,  during the open-label initial phase the patient will be directed to not take any more 
ZS during the rest of that day and return the next day to continue the therapy in the study. E.g. 
patients with potassium values between 3.0 mmol/L and 3.4 mmol/L on Day 2 will not take the 
rest of the doses on Day 2, and will return fasting to be assessed for randomization into the 28-
day randomized treatment study phase on Day 3. Patients with potassium values between 3.0 
mmol/L and 3.4mmol/L already on Day 1 will not take the rest of the doses on Day 1, and will 
return fasting to have their potassium tested again on Day 2. If the potassium on Day 2 is 
between 3.5 and 5.0mmol/L then the patient will be randomized into the 28-day randomized 
treatment study phase. If the potassium value is >=5.1mmol/L then the patient will continue 
their therapy as per the study schedule. If the potassium remains low (≤3.4 mmol/L but not <3.0 
mmol/L) on Day 2, the Day 2 doses should not be taken and the patient will return fasting to be 
assessed for randomization into the 28-day randomized treatment study phase on Day 3, and 
only normokalemic patients (potassium between 3.5 - 5.0 mmol/L, inclusive) will be 
randomized.
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 28-day randomized treatment study phase, dosing will be reduced from qd to qod for the 
remainder of the study.
Patients with confirmed potassium <3.0 mmol/L in both study phases should discontinue from 
therapy as per Section 3.9.
Patients with confirmed i-STAT potassium >6.2 mmol/L during the 28-day randomized 
treatment study phase should discontinue from therapy as per Section 3.9.
For doses administered in the clinic during both study phases each dose will be individually 
dispensed by designated, trained site staff. 


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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 study protocol.
The designated individual (e.g., Pharmacist) will account for all study drugs dispensed to and 
returned from the patient.
IP kits will be uniquely coded and assigned through the randomization and subsequent visits 
via the IVRS/IWRS. On receipt of IP supplies the Investigator/designee will check the supplies 
against the shipment manifest and will confirm receipt of IP shipments via the IVRS/IWRS. 
The system will then issue an acknowledgement receipt. Sites are required to place all shipment 
manifests and acknowledgement receipts in the site regulatory binder.
The designated individual (e.g., pharmacist) is also responsible for maintaining accurate records
accounting for the receipt, dispensing and final disposition of all investigational products using 
the appropriate IP logs provided by AstraZeneca.
7.7
Concomitant and other treatments 
All concomitant medications taken by the patient from 7 days prior to the open-label initial 
phase Day 1 until the 28-day randomized treatment study phase Day 35(EOS), or the end of the 
study (7 ± 1 days after the last dose of IP) for patients, will be recorded. 
Whenever possible, all blood draws collected prior to meals should be collected prior to any 
insulin/insulin analog treatment. From the open-label initial phase Day 1 through the 28-day 
randomized treatment study phase Day 28, the time of dosing with insulin/insulin analogs must 
be recorded when IP is administered in the clinic.
During the study, the patient cannot receive alternative treatment for hyperkalemia while taking 
IP. 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.
Any alternative treatment administered after the end of IP administration and prior to the EOS 
visit must be recorded in the concomitant medication eCRF page (and as AE if applicable).


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In addition to therapies for hyperkalemia also other drugs with World Health Organization 
Anatomic Therapeutic Chemical classification code V03AE, i.e., potassium 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.
Changes to RAAS inhibitor and/or diuretics (including adding a new, changing the dose or 
discontinuation or switching of RAAS inhibitor and/or diuretics) during the study are prohibited. 
If clinically indicated to change the RAAS inhibitor and/or diuretics, the patients should 
discontinue study medication.
7.7.1
Other concomitant treatment
When co-administered with ZS, some oral medications with gastric pH-dependent 
bioavailability may exhibit a clinically meaningful increase or decrease in their bioavailability. 
Therefore, these drugs should be administered at least 2 hours before or 2 hours after study drug 
to mitigate the risk of drug interactions. 
Drugs that should be taken 2 hours before or after study drug to avoid a possible raised gastric 
pH drug interaction are listed below:
Class of Drug
Drugs
Azole antifungals
Ketoconazole, 
Itraconazole, 
Posaconazole, 
Voriconazole
Anti-HIV drugs
Atazanavir, Nelfinavir, Indinavir, Ritonavir, 
Saquinavir, Raltegravir, Ledipasvir, Rilpivirine
Tyrosine kinase inhibitors
Erlotinib, Dasatinib, Nilotinib
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
7.8
Post Study Access to Study Treatment (Not Applicable)
8. STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis and conduct of the study will remain blinded until 
protocol violators have been identified, and the study database is locked. Analysis will be 
performed by AstraZeneca or its representatives.
A detailed Statistical Analysis Plan (SAP) will be finalized prior to Database Lock.


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8.2
Sample size estimate
The sample size is determined to detect a clinically meaningful difference in the primary 
endpoint of the mean S-K during the 28-day randomized treatment study phase Study Days 8-
29 between each active dose (high to low) vs. placebo control. Assuming an inter-subject 
standard deviation of 0.50, approximately 250 patients, (100 patients per active dose treatment 
arm and 50 patients for placebo control arm), will provide >90% power to detect a mean 
difference of 0.30 in mean S-K during Study Days 8-29, comparing each active dose (high to 
low) vs. placebo control using a two-sided t-test at a significance level of 5%. Assuming 90% 
of patients will be normokalemic after treatment in the open label initial phase (see Section 7.2), 
approximately 280 patients will be needed to enter the open-label initial phase.  
The power and sample size is determine based on the number of patients required to evaluate 
the primary hypothesis of the study. However, in the testing sequence presented in Table 6, the 
open-label initial phase mean change from baseline of S-K 48 hours after first dose of ZS 10g 
will be evaluated first. A sample size of 280 patients will provide >99% power to detect a more 
than 18% relative reduction (i.e., 1.05 absolute reduction) in mean change from baseline of S-
K 48 hours after the first dose of ZS 10g during the open-label treatment initial phase.   
The assumptions used in the above sample size estimations are taken from the ZS-004 study. 
8.3
Definitions of analysis sets
Unless otherwise specified, all efficacy analyses will be performed using the full analysis set 
(FAS), which is based on the Intent-to-Treat (ITT) principle. That is, patients allocated to a 
treatment group will be followed up, assessed, and analysed as members of that group 
irrespective of their compliance with the planned course of treatment. 
The FAS includes all randomized patients. Patients without any post randomization data will 
not be used in any of the analyses, but will be accounted for in summary statistics tables. Explicit 
definitions are presented in Section 8.3.1 below.
8.3.1
Full analysis sets (FAS)
FAS-OLP: For the open-label initial phase, the full analysis set will include all patients 
registered in the open-label initial phase.
FAS-RTP: For the 28-day randomized treatment study phase, the full analysis set will include 
all patients who are randomized to the 28-day randomized treatment study phase.
Unless otherwise specified, all efficacy analyses will be carried out on the FAS. 
8.3.2
Safety analysis sets (SAF)
SAF-OLP: For the open-label initial phase, the safety analysis set will include all patients as 
treated with at least one dose of IP in the open-label initial phase.


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SAF-RTP: For the 28-day randomized treatment study phase, the safety analysis set will include 
all patients as treated with at least one dose of the 28-day randomized treatment study phase IP 
among those randomized. 
All safety analyses will be based on the SAF sets. 
8.4
Outcome measures for analyses
8.4.1
Primary efficacy variable
The primary efficacy endpoint in this study will be the model-based least squares means 
(LSMEANS) of all S-K values during the 28-day randomized treatment study phase Study Days 
8-29.
8.4.2
Secondary efficacy variables
For the open-label initial phase, the secondary efficacy endpoints will include the following 
parameters:

Exponential rate of change in S-K levels (blood)

Mean change (absolute and percent (%) change) from baseline in S-K levels at all 
measured time intervals post dose (See Table 1)

Proportion of patients who achieve normokalemia during the open-label initial phase 
at 24 hours and at the end of the open-label phase

Time to normalization in S-K levels (normalization defined as S-K levels between 
3.5-5.0 mmol/L, inclusive)
For the subsequent 28-day randomized treatment study phase, the secondary efficacy endpoints 
will include the following parameters:

The proportion of patients who remain normokalemic (as defined by S-K levels 
between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized treatment 
study phase and during the 28-day randomized treatment study phase

The number of days patients remain normokalemic during the 28-day randomized 
treatment study phase

The mean change and mean percent change in S-K levels evaluated relative to both 
the open-label initial phase and the 28-day randomized treatment study phase 
baselines, respectively

The time to hyperkalemia (defined as S-K ≥5.1 mmol/L)

The mean changes in S-Aldo and P-Renin levels


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8.4.3
Safety Variables
In this study, the following safety data will be collected: adverse events (AEs), vital signs, 
physical examinations, ECGs, clinical laboratory evaluations, and other electrolytes 
(specifically, serum calcium [S-Ca], serum magnesium [S-Mg], serum sodium [S-Na], serum 
phosphate [S-PO4], serum bicarbonate [S-HCO3], and blood urea nitrogen [BUN]).
8.5
Methods for statistical analyses
All efficacy analyses will be performed separately for the open-label initial phase and the 28-
day randomized treatment study phase using their respective full analysis sets. Safety data will 
be separately summarized in a descriptive manner on the safety analysis sets for the open-label 
initial phase and the 28-day randomized treatment study phase, respectively.
Analysis of data from the 28-day randomized treatment study phase will be performed after all 
patients have completed, discontinued or withdrawn from  this phase. In addition, all relevant 
queries must be answered and the database must be locked and un-blinded for the 28-day 
randomized treatment study phase prior to the analyses.
Efficacy and safety data will be listed by patient. Descriptive statistics will include of the 
number of non-missing patients (n), mean, standard deviation, median, minimum, and 
maximum for continuous variables and counts and percentage for categorical variables. Where 
applicable, comparisons between each active dose treatment group vs. placebo control group 
will be performed using a 2-sample t-test.
Results of statistical analysis will be presented with a 95% confidence interval (CI) and two-
sided p-value, unless otherwise stated.
Multiple testing strategy
An overall Type I error rate of 5% accounting for efficacy, in both phases of the study, will be 
maintained using a sequential closed testing procedure. 
The analyses for the 28-day randomized treatment study phase will focus on randomized 
withdrawals. Treatment testing will proceed from high dose (ZS 10g) to low dose (ZS 5g) 
relative to placebo, with statistical significance (two-sided p-value ≤ 0.05) required for the high 
dose vs. placebo control in order to proceed to the low dose vs. placebo control. 
Specifically, the following fixed hierarchical sequence will be employed; progression to the 
next test in the sequence will continue till a 2-sided p-value of > 0.05 is encountered, at which 
point further testing will cease. Explicitly, Table 6 will be implemented:


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Table 6
Confirmatory Testing Sequence
Seq
Study Phase 
Efficacy variable
Comparison
1
Initial1
open-label phase mean change from baseline of S-K 
48 hours after first dose of ZS 10g
2
Maintenance2
28-day randomized treatment study phase Days 8-29 
mean S-K
ZS 10g qd vs. 
Placebo
3
Maintenance
28-day randomized treatment study phase Days 8-29 
mean S-K
ZS 5g qd vs. 
Placebo
4
Maintenance
Proportion of patients who remain normokalemic (as 
defined by S-K between 3.5-5.0 mmol/L, inclusive) 
during the 28-day randomized treatment study phase 
at Study Days 29/Exit3
ZS 10g qd vs. 
Placebo
5
Maintenance
Proportion of patients who remain normokalemic (as 
defined by S-K between 3.5-5.0 mmol/L, inclusive) 
during the 28-day randomized treatment study phase 
at Study Days 29/Exit
ZS 5g qd vs. 
Placebo
6
Maintenance
Number of days patients remain normokalemic during 
the 28-day randomized treatment study phase 
ZS 10g qd vs. 
Placebo
7
Maintenance
Number of days patients remain normokalemic during 
the 28-day randomized treatment study phase 
ZS 5g qd vs. 
Placebo
8
Maintenance
Time to hyperkalemia (defined as S-K ≥ 5.1 mmol/L 
during the 28-day randomized treatment study phase)
ZS 10g qd vs. 
Placebo
9
Maintenance
Time to hyperkalemia (defined as S-K ≥ 5.1 mmol/L 
during the 28-day randomized treatment study phase)
ZS 5g qd vs. 
Placebo
1.
Initial Study Phase refers to the Open-Label Initial Phase.
2.
Maintenance Study Phase refers to the 28-day Randomized Treatment Study Phase.
3.
Study Day 29/Exit refer to day of last dose of study treatment.
8.5.1
Analysis of the primary variable
The primary endpoint in this study will be the model-based LSMEANS of all available S-K 
values during the 28-day randomized treatment study phase Study Days 8-29. A log 
transformation will be applied to the S-K level, since historical data shows that S-K 
measurements follows a log-normal distribution, and also to stabilize the variance. A 
longitudinal model (SAS PROC MIXED) will then be used to simultaneously compare each 
active dose (high to low dose) versus placebo control for the 28-day randomized treatment study 
phase to estimate the least squares means Day 8-29 values. The model will include all S-K data 
collected at the schedule visits between Day 8-29 as response variables, and baseline for the 
open-label initial phase eGFR, open-label and double-blind randomized phase baseline S-K 
values as well as age (<55, 55-64, >64 years), country and baseline binary indicators for RAAS 
inhibitors, chronic kidney disease, heart failure, and diabetes mellitus as fixed effects terms and 
subject as the random effect term. In addition, the primary efficacy endpoint will be evaluated 


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in patients with hyperkalemia (defined as S-K ≥5.1 mmol/L) for the subgroups defined in 
Section 8.5.4. More details will be described in the SAP.
The S-K levels used for this analysis will be based on the Central Laboratory measurements. 
Missing Central Laboratory data for a given visit will be replaced by i-STAT values adjusted 
with the mean paired difference between i-STAT and S-K values collect at the same visit. More 
details on how to handle dropouts and missing data will be provided in the SAP.
8.5.2
Analysis of the secondary and additional variables
For the open-label initial phase, the mean and relative reduction in the secondary efficacy 
endpoints will be evaluated for all enrolled patients. The change from baseline will be assessed 
using a paired t-test, and a two-sided p-value ≤0.05 will be considered statistically significant.
The methods used to evaluate the secondary efficacy endpoints, for the 28-day randomized 
treatment study phase; to compare each active dose (high to low) vs. placebo control will be 
describe in the SAP.
Secondary efficacy endpoints will include:

The proportion of patients who remain normokalemic (as defined by S-K between 
3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized treatment study 
phase and during the 28-day randomized treatment study phase

The number of days patients remain normokalemic during the 28-day randomized 
treatment study phase

The mean change and mean percent change in S-K levels evaluated relative to both 
baselines

The time to hyperkalemia (defined as S-K ≥5.1 mmol/L) 

The mean change in S-Aldo and P-Renin levels
In addition, the secondary efficacy endpoint at the end of the 28-day randomized treatment study 
phase will be evaluated in patients with hyperkalemia (defined as S-K ≥5.1 mmol/L) for the 
subgroups defined in Section 8.5.4. More details will be specified in the SAP.
Sensitivity analysis
Sensitivity analyses of the primary efficacy analysis and secondary efficacy analysis of the 
proportion of normokalemic patients at the end of and during the 28-day randomized treatment 
study phase will be performed to assess the robustness of the primary and these key secondary 
results. Details will be provided in the SAP.


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8.5.3
Safety analysis
Separate safety analyses will be performed for the open-label initial phase and the 28-day 
randomized treatment study phase. Safety endpoints will include adverse events (AEs), serious 
AEs (SAEs), vital signs (VS), physical examinations, ECGs, clinical laboratory evaluations, 
and other electrolytes (specifically, serum calcium [S-Ca], serum magnesium [S-Mg], serum 
sodium [S-Na], serum phosphate [S-PO4], serum bicarbonate [S-HCO3], and blood urea 
nitrogen [BUN]).
Hypokalemia will be analyzed based on laboratory values and not by specific MedDRA terms. 
The respective safety analysis will be undertaken on the safety analysis sets, separately for the 
open-label initial phase and for the 28-day randomized treatment study phase. Safety and 
tolerability data will be presented by treatment arm. Where appropriate, the safety analyses will 
include descriptive statistics, counts and percentages. More details will be described in the SAP. 
Only AE with date of onset during the respective observation period will be presented. 
Laboratory data and other investigations will be presented descriptively. More information will 
be provided in the SAP.
Adverse events will be classified according to Medical Dictionary for Regulatory Activities 
(MedDRA [latest version]). The type, timing (onset, duration), relationship, and severity of AEs 
will be reported. Withdrawal due to AEs will also be reported. Narratives will be written for 
every AE classified as serious or leading to withdrawal of IP. Safety results will be displayed 
separately for each of these phases.
8.5.4
Analysis in subsets of patients
The primary efficacy endpoint and the secondary efficacy endpoint of the proportion of patients 
who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/L, inclusive) at the end 
of and during the 28-day randomized treatment study phase will be evaluated for the following 
subgroups:
chronic kidney disease (CKD)
diabetes mellitus (DM)

heart failure (HF)
those on RAAS inhibitors
More details will be described in the SAP.
8.5.5
Interim analysis
No interim analyses are planned.


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9. STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
Provide information and support to the Investigator(s)
Confirm that facilities remain acceptable
Confirm that the investigational team is adhering to the 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.


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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).
9.2.4
Deviation from the clinical study protocol
The Investigator(s) must not deviate from or make any changes to the protocol without 
documented agreement between the Principal Investigator and AstraZeneca or the IRB approval 
based on its deliberations. However, this shall not apply to cases where the deviation or change 
is necessary to avoid an immediate hazard to the subjects or for other compelling medical 
reasons, or where the changes involve only logistical or administrative aspects of the 
clinical study (e.g., changes to the organisation/structure of the AstraZeneca, the 
name/department name of the study site, the address or phone number of the study site or 
AstraZeneca, the job title of the Investigator, and monitors).
The Investigator(s) should document any deviation from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate hazard to the 
subjects or for other medically compelling reason, the Investigator should prepare and submit 
the records explaining the reasons thereof to AstraZeneca and the head of study site.
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 Q1 2021 and to end by Q1 2022.
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study or 
in any other study with ZS.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by AstraZeneca Data Management Center staff or other 
party, according to the Data Management Plan.  


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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 World Health Organization Drug (WHODrug) Dictionary (version 
will be designated in the clinical study report). 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.
The PI is responsible for signing the eCRF and this may be delegated to a trained Investigator.
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.


Clinical Study Protocol
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Study Code D9480C00001
Version 6.0
Date 19 August 2020
91 (101)
10.REGULATORY, 
ETHICAL 
AND 
STUDY 
OVERSIGHT 
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.
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure and use of their 
data must also be explained to the participant in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final 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 Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should submit 
the written approval to AstraZeneca before enrolment of any subject into the study. 
The Ethics Committee 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.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
92 (101)
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.              
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
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


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
93 (101)

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 Ethics Committee
10.5
Changes to the Clinical Study Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principle 
Investigator (PI) and AZ or AZ delegate.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the Clinical Study Protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 
implementation.  Local requirements are to be followed for new versions of Clinical Study 
Protocols.
AstraZeneca will distribute any mew versions of the Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a centre’s Informed Consent Form, 
AstraZeneca and the centre’s Ethics Committee are to approve the revised Informed Consent 
Form before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved by 
each Ethics Committee.
10.6
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct or electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
94 (101)
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.
10.7
Dissemination of Clinical Study Data
A 
description 
of 
this 
clinical 
study 
will 
be 
available 
on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
10.8
Source Data

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
10.9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the [first site to consent patients to the optional pre-screening ICF 
and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any time 


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
95 (101)
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
96 (101)
11.LIST OF REFERENCES
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.
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


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
97 (101)
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 hospitalization

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

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 B
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
98 (101)

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 D9480C00001
Version 6.0
Date 19 August 2020
99 (101)
Appendix B
Handling of Human Biological Samples
Chain of custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each site keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
Withdrawal of Informed Consent for donated biological samples 
If a participant withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed/repatriated, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s’ withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate

Ensures that relevant human biological samples from that participant, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented

Ensures that the participant and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
100 (101)
International Airline Transportation Association (IATA) 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International 
Airline 
Transportation 
Association 
(IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) 
classifies 
infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 2900:
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name.

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 
650 
compliant 
packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00001
Version 6.0
Date 19 August 2020
101 (101)
Appendix C
Guidance related to assessments and procedures during 
COVID-19 pandemic
In view of the ongoing and emerging novel coronavirus (COVID-19) pandemic spreading 
worldwide, the safety and well-being of our study participants is of primary importance.  To 
protect the safety and well-being of study participants, this section will provide guidelines on 
study assessments and procedures during this period.
1
ZS is a potassium binder acting in the gastrointestinal tract and is not absorbed. No 
additional risk from COVID-19 is expected due to ZS. Every effort should be made to 
follow the clinical study protocol (CSP).  Participant safety is paramount, and the 
investigator should continue to reassess the risk/benefit of continued study involvement for 
each study participant.
2
Investigational study sites must comply with local public health rules.
3
If a study participant is suspected or diagnosed with COVID-19, they should follow the 
local guidance for COVID19 diagnosis, quarantine, and treatment procedures.
(a) Please accurately document all diagnoses, procedures, assessments, dosing 
interruptions, and sequelae in the eCRFs.  All AEs/SAEs should be reported in line 
with instructions for safety reporting documented in the CSP.
(b) If a COVID-19 AE/SAE is reported, the investigator should determine whether the 
participant’s investigational product should continue, be interrupted, or stopped in 
accordance with the CSP (section 3.9).
4
If a study participant is unable to attend clinic visits either due to quarantine for being 
infected with or suspected for COVID-19 or due to site closure for COVID-19, the 
investigational product should be discontinued, and every effort should be made to conduct 
safety assessment (e.g., potassium value and ECG measurement), this could be done at an 
alternative healthcare facility or by home visit if possible. Local lab results will not be 
collected or stored in the study database but will help the investigator to assess patient 
safety. The site staff should keep in close contact with the study participant(s), preferably 
through telephone calls, to maintain awareness of their status.
References:
https://www.fda.gov/media/136238/download
https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-aspects-
ongoing-clinical-trials
https://www.ema.europa.eu/en/news/guidance-sponsors-how-manage-clinical-trials-during-covid-19-
pandemic  



SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D9480C00001 – ed. 3.0 
CONFIDENTIAL AND PROPRIETARY 
1 of 60 
STATISTICAL ANALYSIS PLAN 
Study Code 
D9480C00001 
Edition Number 
3.0 
Date 
24-Oct-2022 
A phase 3 multicenter, prospective, randomized, double-blind, 
placebo-controlled study to investigate the safety and efficacy of 
ZS (sodium zirconium cyclosilicate), in patients with 
hyperkalemia (HARMONIZE Asia) 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D9480C00001 – ed. 3.0 
CONFIDENTIAL AND PROPRIETARY 
2 of 60 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
TABLE OF CONTENTS ...................................................................................................... 2 
LIST OF ABBREVIATIONS................................................................................................ 5 
AMENDMENT HISTORY ................................................................................................... 8 
1 
INTRODUCTION ............................................................................................ 11 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .................................... 11 
3 
DATA ANALYSIS CONSIDERATIONS ........................................................ 12 
3.1 
Timing of Analyses ........................................................................................... 12 
3.2 
Analysis Populations ......................................................................................... 12 
3.2.1 
Full analysis set................................................................................................. 12 
3.2.1.1 
Full analysis set in Open-label initial phase (FAS-OLP) .................................... 12 
3.2.1.2 
Full analysis set in Randomized treatment study phase (FAS-RTP) ................... 13 
3.2.2 
Safety analysis set ............................................................................................. 13 
3.2.2.1 
Safety analysis set in Open-label period (SAF-OLP) ......................................... 13 
3.2.2.2 
Safety analysis set in randomized treatment study phase (SAF-RTP) ................ 13 
3.3 
General Considerations ..................................................................................... 14 
3.3.1 
General Study Level Definitions ....................................................................... 15 
3.3.1.1 
Definition of Baseline ....................................................................................... 15 
3.3.1.2 
Definition of On-Treatment ............................................................................... 15 
3.3.1.3 
Definition of Treatment-emergent ..................................................................... 15 
3.3.1.4 
Handling of missing dates ................................................................................. 16 
3.3.2 
Hypotheses ....................................................................................................... 16 
3.3.2.1 
Primary hypotheses ........................................................................................... 16 
3.3.2.2 
Secondary hypotheses ....................................................................................... 17 
3.3.3 
Visit Window .................................................................................................... 19 
3.3.4 
Handling of Unscheduled Visits ........................................................................ 20 
3.3.5 
Handling of Missing Serum Potassium (S-K) Data ............................................ 21 
3.3.6 
Mixed Model: Terms and Estimation ................................................................ 21 
3.3.7 
Multiplicity/Multiple Comparisons ................................................................... 21 
3.3.8 
Handling of Protocol Deviations in Study Analysis ........................................... 24 
3.3.9 
COVID-19 Impact ............................................................................................ 24 
4 
STATISTICAL ANALYSIS ............................................................................. 24 
4.1 
Study Population ............................................................................................... 24 
4.1.1 
Subject Disposition and Completion Status ....................................................... 25 
4.1.1.1 
Definitions and Derivations ............................................................................... 25 
4.1.1.2 
Presentation ...................................................................................................... 25 
4.1.2 
Analysis Sets .................................................................................................... 25 
4.1.2.1 
Definitions and Derivations ............................................................................... 25 
4.1.2.2 
Presentation ...................................................................................................... 26 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D9480C00001 – ed. 3.0 
CONFIDENTIAL AND PROPRIETARY 
3 of 60 
4.1.3 
Protocol Deviations ........................................................................................... 26 
4.1.3.1 
Definitions and Derivations ............................................................................... 26 
4.1.3.2 
Presentation ...................................................................................................... 26 
4.1.4 
Demographics ................................................................................................... 26 
4.1.4.1 
Definitions and Derivations ............................................................................... 26 
4.1.4.2 
Presentation ...................................................................................................... 26 
4.1.5 
Baseline Characteristics .................................................................................... 27 
4.1.5.1 
Definitions and Derivations ............................................................................... 27 
4.1.5.2 
Presentation ...................................................................................................... 27 
4.1.6 
Medical History and Concomitant Disease ........................................................ 27 
4.1.6.1 
Definitions and Derivations ............................................................................... 27 
4.1.6.2 
Presentation ...................................................................................................... 27 
4.1.7 
Prior and Concomitant Medications .................................................................. 28 
4.1.7.1 
Definitions and Derivations ............................................................................... 28 
4.1.7.2 
Presentation ...................................................................................................... 28 
4.1.8 
Study Drug Compliance .................................................................................... 28 
4.1.8.1 
Definitions and Derivations ............................................................................... 28 
4.1.8.2 
Presentation ...................................................................................................... 29 
4.1.9 
COVID-19 Impact ............................................................................................ 29 
4.1.9.1 
Definitions and Derivations ............................................................................... 29 
4.1.9.2 
Presentation ...................................................................................................... 29 
4.2 
Endpoint/Variable Analyses .............................................................................. 29 
4.2.1 
Primary Endpoint .............................................................................................. 34 
4.2.1.1 
Definition.......................................................................................................... 34 
4.2.1.2 
Derivations ....................................................................................................... 34 
4.2.1.3 
Handling of Dropouts and Missing Data ........................................................... 34 
4.2.1.4 
Main Analysis of Primary Endpoint .................................................................. 36 
4.2.1.5 
Supplementary and Sensitivity Analyses of Primary Endpoint .......................... 36 
4.2.1.6 
Subgroup Analysis ............................................................................................ 37 
4.2.2 
Secondary Endpoints for OLP phase ................................................................. 37 
4.2.2.1 
Definition.......................................................................................................... 37 
4.2.2.2 
Derivations ....................................................................................................... 38 
4.2.2.3 
Handling of Dropouts and Missing Data ........................................................... 38 
4.2.2.4 
Primary Analysis of Secondary Endpoints (OLP) .............................................. 38 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint ................................................ 39 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint ......................................... 39 
4.2.2.7 
Subgroup Analyses ........................................................................................... 40 
4.2.3 
Secondary Endpoints for RTP phase ................................................................. 40 
4.2.3.1 
Definition.......................................................................................................... 40 
4.2.3.2 
Derivations ....................................................................................................... 40 
4.2.3.3 
Primary Analysis of Secondary Endpoints for RTP ........................................... 41 
4.2.3.4 
Supplementary Analyses of the Secondary Endpoint ......................................... 42 
4.2.3.5 
Subgroup Analyses ........................................................................................... 42 
4.2.3.6 
Handling of Dropouts and Missing Data ........................................................... 43 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D9480C00001 – ed. 3.0 
CONFIDENTIAL AND PROPRIETARY 
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4.3 
Safety Analyses ................................................................................................ 43 
4.3.1 
Exposure ........................................................................................................... 43 
4.3.1.1 
Definitions and Derivations ............................................................................... 43 
4.3.1.2 
Presentation ...................................................................................................... 44 
4.3.2 
Adverse Events ................................................................................................. 44 
4.3.2.1 
Definitions and Derivations ............................................................................... 44 
4.3.2.2 
Presentation ...................................................................................................... 44 
4.3.3 
Clinical Laboratory, Blood Sample ................................................................... 46 
4.3.3.1 
Definitions and Derivations ............................................................................... 46 
4.3.3.2 
Presentations ..................................................................................................... 46 
4.3.4 
Clinical Laboratory, Urinalysis ......................................................................... 47 
4.3.4.1 
Definitions and Derivations ............................................................................... 47 
4.3.4.2 
Presentations ..................................................................................................... 47 
4.3.5 
Other Laboratory Evaluations ........................................................................... 48 
4.3.5.1 
Definitions and Derivations ............................................................................... 48 
4.3.5.2 
Presentations ..................................................................................................... 48 
4.3.6 
Vital Signs ........................................................................................................ 48 
4.3.6.1 
Definitions and Derivations ............................................................................... 48 
4.3.6.2 
Presentations ..................................................................................................... 48 
4.3.7 
Physical examinations ....................................................................................... 48 
4.3.7.1 
Definitions and Derivations ............................................................................... 48 
4.3.7.2 
Presentations ..................................................................................................... 49 
4.3.8 
Electrocardiogram ............................................................................................. 49 
4.3.8.1 
Definitions and Derivations ............................................................................... 49 
4.3.8.2 
Presentations ..................................................................................................... 49 
4.3.9 
Other Safety Assessments ................................................................................. 50 
5 
INTERIM ANALYSIS ..................................................................................... 50 
6 
REFERENCES ................................................................................................. 51 
7 
APPENDIX ...................................................................................................... 52 
7.1 
Appendix A: IPD Master List ............................................................................ 52 
7.2 
Appendix B: Disallowed Medications ............................................................... 59 
7.3 
Appendix C: Laboratory Safety Variables ......................................................... 60 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AZ 
AstraZeneca 
BMI 
Body Mass Index 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
c-lab 
Central laboratory 
CI 
Confidence Interval 
CKD 
Chronic kidney disease 
CM 
Concomitant medication 
COVID-19 
Coronavirus Disease 2019. 
CRF 
Case Report Form 
CSR 
Clinical Study Report  
CRO 
Clinical Research Organization 
CSP 
Clinical Study Protocol 
DBL 
Database lock 
DM 
Diabetes mellitus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
FAS 
Full Analysis Set 
FAS-OLP 
Full Analysis Set for the Open-Label Initial Phase 
FAS-RTP 
Full Analysis Set for the 28-day Randomized Treatment Study Phase 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyl transferase 
Hb 
Haemoglobin 
HCG 
Human chorionic gonadotropin 


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Abbreviation or 
special term 
Explanation 
HF 
Heart failure 
HL 
Hy’s law 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
IPD 
Important protocol deviations  
ITT 
Intent-to-Treat 
LSMEAN 
Least Square Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
OLP 
Open-label initial phase 
PO 
Per Os 
P-Renin 
Plasma-Renin 
PT 
Preferred Term 
qd 
Once daily 
RAAS 
Renin-Angiotensin-Aldosterone System 
RBC 
Red Blood Cell 
REML 
Restricted maximum likelihood method 
RTP 
28-day randomized treatment study phase 
S-Aldo 
Serum-Aldosterone 
SAE  
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAF-OLP 
Safety Analysis Set for the Open-Label Initial Phase 
SAF-RTP 
Safety Analysis Set for the 28-day Randomized Treatment Study Phase 
SAP 
Statistical Analysis Plan 
S-Ca 
Serum calcium 
S-HCO3 
Serum bicarbonate 
S-K 
Serum potassium 
S-Mg 
Serum magnesium 
S-Na 
Serum sodium 
S-PO4 
Serum phosphate 
SD 
Standard deviation 


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Abbreviation or 
special term 
Explanation 
SOC 
System Organ Class 
TFL 
Tables, Figures and Listings 
TID 
Three times a day 
ULN 
Upper limit of normal 
VS 
Vital Sign 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHODrug 
World health Organization Drug Dictionary 
ZS 
Sodium Zirconium Cyclosilicate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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AMENDMENT HISTORY 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line with 
CSP? 
 
Rationale 
N/A 
27-Sep-2021 
Initial approved SAP 
N/A 
N/A 
Section 3.2.1.1. 
04-Apr-2022 
Definition of FAS-OLP updated to be in line with 
CSP 
Yes 
Update SAP to be in line 
with CSP 
Section 3.3 
04-Apr-2022 
Added convention used for rounding 
NA 
Consistency in outputs.  
Section 3.3.1.1 
04-Apr-2022 
Removed timing for the two pre-dose measurements 
used to derive baseline for OLP. 
Added that baseline values can also be replaced. 
Added a sentence to confirm that measures taken on 
the same day as first IP are assumed to be pre-dose if 
time is missing.  
Yes 
Clarifying the logic for 
imputing missing Clab 
values with i-STAT values.   
Section 3.3.1.2 
04-Apr-2022 
Added definition of ‘on-treatment’ 
Yes 
Clarifying the definition for 
consistency in outputs and 
summaries.  
Section 3.3.2.1 
04-Apr-2022 
Updated/added hypotheses for exponential rate of 
change.  
No 
Defining two time points 
(24/48 hr) as not all 
subjects will have 48h time 
point 
Section 3.3.3 
04-Apr-2022 
Table 2 (Analysis visit windows) updated.  
Yes 
 
Section 3.3.5 
22-Apr-2022 
Section added to summarise how to handle missing 
S-K data 
Yes 
Consistency in how this 
handled for all efficacy 
outcomes. 
Section 4 
04-Apr-2022 
Removed quartiles from summary statistics 
Yes 
Quartiles are not required 
for the summaries. 
Section 4.1.5 
04-Apr-2022 
Serum potassium added as a baseline characteristic 
NA 
To improve assessment of 
baseline characteristics  
Section 4.1.7.1 
04-Apr-2022 
Definition of prior and concomitant added. Updated 
imputation of missing dates to coincide with Section 
3.3.1.3 
Yes 
Clarifying the definition for 
consistency in outputs and 
summaries. 
Section 4.2.1.3 
04-Apr-2022 
Adding a time constraint to imputing missing values 
with i-STAT 
Yes 
Add an additional rule as to 
when it is appropriate to 
impute value. 


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Information added for the seed, number of burn-ins 
and variance structure for the multiple imputation  
 
To provide further details 
on how the multiple 
imputation should be 
carried out.  
Section 4.2.1.5 
04-Apr-2022 
Supplementary analysis of primary endpoint updated 
to be stop date of disallowed medication + 7 days.  
Yes 
To align the supplementary 
analyses for disallowed 
medications. 
Section 4.2.1.6  
04-Apr-2022 
Added a specification of the number of observations 
required to conduct the subgroup analyses 
Yes 
To ensure enough 
observations to generate 
robust estimates.  
Section 4.2.3.6 
04-Apr-2022 
Updated handling of missing data to be in line with 
the primary end point.  
Yes 
Clarifies that all RTP 
endpoint should be based 
on the imputed data.  
Section 4.3.2 
04-Apr-2022 
Removed summary of AEs leading to discontinuation 
and most common AEs. Removed study specific 
AEs. Added summary by decreasing frequency.  
Yes 
To removed summaries of 
AEs that are not required 
and to update the AE table 
to present by decreasing 
frequency rather than 
selecting the most common 
to give a most robust 
overview of AEs.  
Section 4.3.3 
04-Apr-2022 
Removed Hy’s Law definitions and updated the 
elevated liver test summary 
Yes 
To condense the overview 
of elevated liver tests. 
Section 4.3.6 
04-Apr-2022 
Added baseline versus maximum on-treatment 
summary for vital signs.  
Yes 
To provide additional 
analyses of the vital signs.  
Section 3.3.1.3 
12-Aug-2022 
Added definition of ‘treatment-emergent’ 
Yes 
Clarifying the definition for 
consistency in outputs and 
summaries.  
Section 4.2.2.1  
12-Aug-2022 
Updated list of time points at which the proportion of 
subjects who achieve normokalemia are assessed 
during the OLP 
Yes 
End of OLP timepoint was 
missing from list 
Section 4.2.3.2 
12-Aug-2022 
Added derivation for the number of days subjects 
remain normokalemic 
Yes 
To provide further 
clarification on the logic of 
the derivation 
Section 4.2.3.3 
12-Aug-2022 
Added additional description for the summaries 
required for time to hyperkalemia 
Yes 
To align with requirements 
in output To align with 
requirements in output 


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Section 4.2.3.5 
12-Aug-2022 
Updated the minimum number of subjects required 
per subgroup analysis 
Yes 
To allow for a lower 
threshold for the subgroup 
analysis to be performed 
Section 4.3.3.2  
12-Aug-2022 
Updated to use “treatment-emergent” in derivation 
description 
Yes 
To align with the definition 
of treatment-emergent 
added in Section 3.3.1.3 
Section 4.3.6.2  
12-Aug-2022 
Updated to use “treatment-emergent” in derivation 
description 
Yes 
To align with the definition 
of treatment-emergent 
added in Section 3.3.1.3 
Section 4.3.8.2 
12-Aug-2022 
Added that QTcF values above 450 ms at baseline 
should be summarised 
Yes 
To align with requirements 
in output 
Section 3.3.1.4 
18-Oct-2022 
Added sentence to derivation of missing start/end 
dates for concomitant medications and AEs 
Yes 
To provide further logic on 
the imputation of missing 
dates. 
Appendix A 
24-Oct-2022 
Updated IPD master file 
Yes 
To align with the most 
recent version of the IPD 
master file. 
 
 


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1 
INTRODUCTION 
The purpose of this document is to give details for statistical analysis of study D9480C00001 
supporting the clinical study report. The reader is referred to the clinical study protocol (CSP) 
for details of study conduct. 
This statistical analysis plan (SAP) contains a more detailed description of the analyses in the 
CSP for the Harmonize Asia study and is based on version 6.0 of the CSP.  
This SAP applies to the phase 3, multicentre, prospective, randomized, double-blind, placebo-
controlled study to investigate the safety and efficacy of ZS (sodium zirconium cyclosilicate), 
in patients with hyperkalemia (HARMONIZE Asia). 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES 
The text referring to a 2-sample t-test in section 8.5 of the CSP, (“Where applicable, 
comparisons between each active dose treatment group vs. placebo control group will be 
performed using a 2-sample t-test.”) has been removed as needed in the SAP, as this referred 
to the descriptive tabulations of data, and this is no longer part of the planned descriptive 
tabulation of the study. 
The structure of the model used for the main analysis of the primary endpoint has been 
amended to include visit, treatment, as well as visit-by-treatment interaction as fixed effects, 
to reflect the corresponding analysis done in the Harmonize Global study. In addition, rather 
than incorporating a random intercept within subject explicitly in the model, an unstructured 
marginal covariance matrix will be used. This is to provide better potential for achieving good 
model fit (note that a model with a random intercept within subject and an e.g. scaled identity 
as conditional covariance matrix is a special case of this approach). 
The subgroup analysis of the primary endpoint has been amended to assess all subjects, rather 
than those with hyperkalemia (S-K ≥ 5.1mmol/L). This reflects the corresponding analysis in 
the Harmonize Global study and aligns with the primary analysis of the primary outcome. 
Change from baseline in the OLP has been amended to use a one-sample, two-sided, t-test 
instead of a paired, two-sided, t-test. This allows a comparison of the mean change from 
baseline to the null hypothesis of zero (i.e. no change from baseline) rather than assessing the 
difference between the paired observations. This also aligns with the approach taken in the 
Global Harmonize study. 
To better reflect the Intent-to-Treat (ITT) approach defined to the efficacy analyses the 
secondary endpoint reading:  


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- 
 “Proportion of subjects who remain normokalemic (as defined by S-K between 3.5-
5.0 mmol/L, inclusive) during the 28-day randomized treatment study phase at Study 
Days 29/Exit”  
has been changed to:  
- 
“Proportion of subjects who remain normokalemic (as defined by S-K between 3.5-5.0 
mmol/L, inclusive) during the 28-day randomized treatment study phase at Study Days 
29”. 
 
To reflect the flexibility of the duration of the open label phase introduced in the later versions 
of the CSP the endpoint reading: 
- 
“Open-label phase mean change from baseline of S-K 48 hours after first dose of ZS 
10g”  
has been clarified to state: 
- 
 “Open-label phase mean change from baseline of S-K to the end of OLP after first 
dose of ZS 10g”.  
 
To clarify the definition of the full analysis set in the open label initial phase, a subject is 
considered to have been registered into the OLP if they received at least 1 dose of study 
medication in the open label initial phase.  
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
Timing of Analyses 
The primary analysis will be performed after database lock (DBL). No interim analysis is 
planned for this study. 
3.2 
Analysis Populations 
Two main analysis populations are defined for two different periods of this study, the full 
analysis set (FAS) and the safety analysis set (SAF).  
3.2.1 
Full analysis set 
All efficacy analyses, unless otherwise specified, will be performed using the full analysis set 
(FAS), which is based on ITT principle. That is, subjects allocated to a treatment group will be 
followed up, assessed, and analyzed as members of that group irrespective of their compliance 
with the planned course of treatment.  
3.2.1.1 
Full analysis set in Open-label initial phase (FAS-OLP) 
For the open-label initial phase (OLP), the full analysis set will include all subjects who 
received at least 1 dose of study medication in the open-label initial phase.  


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3.2.1.2 
Full analysis set in Randomized treatment study phase (FAS-RTP) 
For the randomized treatment study phase (RTP), the full analysis set will include all subjects 
who are randomized to the 28-day randomized treatment phase, regardless of whether they 
took study medication or not.  
In this set, subjects will be analyzed according to their randomized treatment assignment. 
3.2.2 
Safety analysis set 
All safety analyses will be performed using the SAF. Safety analyses will be performed for 
each study phase, OLP and RTP. 
3.2.2.1 
Safety analysis set in Open-label period (SAF-OLP) 
For the OLP, the safety analysis set will include all subjects who receive at least 1 dose of 
study medication in the initial phase.   
3.2.2.2 
Safety analysis set in randomized treatment study phase (SAF-RTP) 
For the subsequent RTP, the safety analysis set will include all subjects in the FAS-RTP who 
receive at least 1 dose of study medication in the RTP. Subjects with erroneous treatment are 
analyzed according to that treatment only if they only received the erroneous treatment and 
none of the correct treatment. Subjects who receive more than one treatment are analysed 
according to their randomized treatment. 
The analysis sets used for each outcome are provided in Table 1. 
Table 1 Summary of outcome variables and analysis populations 
Outcome variable 
Analysis set 
Efficacy data 
 
Primary endpoint/variables 
FAS-RTP 
Secondary endpoints/variables for open label 
phase 
FAS-OLP  
Secondary endpoints/variables for randomized 
treatment phase 
FAS-RTP 
Study population 
 
Demography characteristics 
FAS-OLP and FAS-RTP 
Baseline and disease characteristics 
FAS-OLP and FAS-RTP 
Important protocol deviations 
FAS-OLP and FAS-RTP 
Medical/surgical history 
FAS-OLP and FAS-RTP 
Concomitant medications 
FAS-OLP and FAS-RTP 
Study drug compliance 
FAS-OLP and FAS-RTP 
Safety data 
 
Exposure 
SAF-OLP and SAF-RTP 


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Outcome variable 
Analysis set 
AEs 
SAF-OLP and SAF-RTP 
Laboratory measurements 
SAF-OLP and SAF-RTP 
Vital signs 
SAF-OLP and SAF-RTP 
ECG 
SAF-OLP and SAF-RTP 
 
3.3 
General Considerations 
All efficacy analyses will be performed separately for the open-label initial phase and the 28-
day randomized treatment study phase using their respective full analysis sets. Safety data will 
be separately summarized in a descriptive manner on the safety analysis sets for the OLP and 
the RTP, respectively. 
All efficacy data will be listed by subject and will include S-K assessments data and efficacy 
response (achieve normokalemia) data. Study population listings will include disposition, 
protocol deviations, subjects excluded from efficacy analysis, demographic and baseline 
characteristics, and safety listings will include treatment compliance, adverse events, 
individual 
laboratory 
measurements, 
vital 
signs, 
physical 
examinations, 
and 
electrocardiograms (ECG).  
Unless otherwise stated, percentages will be calculated out of the population total and for each 
treatment group and will be rounded to 1 decimal place. For continuous data, the mean and 
median will be rounded to one additional place compared to the original data, the standard 
deviation (SD) and standard error (SE) will be rounded to 2 additional places, and the 
minimum and maximum will be displayed to the same accuracy as the original data. If the 
number of decimal places of the original data is > 3, then the minimum and maximum will be 
assigned 3 decimal places, the mean and median 4 decimal places, and the SD and SE 5 
decimal places.   
Results of all statistical analyses will be presented using a 95% confidence interval (CI) and 
two-sided p-value, unless otherwise stated. All p-values will be presented to 3 decimal places. 
All p-values less than 0.001 will be presented as ‘< 0.001’ and p-values greater than 0.999 will 
be presented as ‘> 0.999’.  
SAS® version 9.4 or higher will be used for all analyses. 


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3.3.1 
General Study Level Definitions 
3.3.1.1 
Definition of Baseline 
Efficacy Baseline 
For the OLP: The baseline Serum Potassium (S-K) will be established on the OLP Study 
Visit 3 (pre-dose) by taking the mean of 2 different S-K values.  
For the RTP: The baseline S-K, S-Aldo and P-Renin will be established based on the last pre-
randomization measurement for S-K, S-Aldo and P-Renin, respectively, obtained during the 
OLP.  
If baseline S-K C-lab values are missing, the i-STAT data will be used to replace them as 
described in Section 4.2.1.3. Subjects with missing values at baseline will be excluded from 
the relevant efficacy analysis. 
Safety Baseline 
Safety analyses will be performed separately for OLP and RTP. For change from baseline 
tabulations (laboratory measurements, vital signs, ECG and weight) the baseline will be 
defined as follows: 
For OLP: Baseline will be the last non-missing measurement taken prior to first IP 
administration during OLP. If a measurement was taken on the date of first IP administration 
and no time is recorded, it is assumed that the measurement was taken pre-dose and will be 
considered a candidate for baseline.  
For RTP: Same as OLP baseline, i.e. the last non-missing measurement taken prior to first IP 
administration during OLP. 
3.3.1.2 
Definition of On-Treatment 
For OLP: Any measurements that have an onset day on or after the date of first dose of open-
label study treatment and no later than the date of last dose of open-label study treatment + 1 
day.  
For RTP: Any measurements with an onset date more than one day after the day of last dose 
of open label study medication, and either on or after the day of first dose of randomized study 
medication, and no later than the day of last dose of study medication +1 day.   
3.3.1.3 
Definition of Treatment-emergent 
For OLP: Any measurements reported as ‘abnormal’ whilst on-treatment (defined as per 
Section 3.3.1.2),but were previously reported as ‘normal’ at OLP Baseline (defined as per 
Section 3.3.1.1) 


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For RTP: Any measurements reported as ‘abnormal’ whilst on-treatment (defined as per 
Section 3.3.1.2),but were previously reported as ‘normal’ at RTP Baseline (defined as per 
Section 3.3.1.1) 
3.3.1.4 
Handling of missing dates 
Missing adverse event (AE) and concomitant medication (CM) start and end dates will be 
imputed as follows: 
For partial or missing start dates: 
• Missing day: impute the 1st of the month unless month is same as month of first dose 
of study drug then impute first dose date. 
• Missing day and month: impute 1st January, unless the year is the same as first dose 
date and the end date does not suggest it could have started prior to first dose (i.e. end 
date is before first dose date), then impute first dose date.  
• Completely missing: impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end 
date. 
For partial or missing end dates: 
• Missing day: impute the last day of the month unless month is same as month of first 
dose of study drug then impute last dose date. 
• Missing day and month: impute 31st December unless year is the same as first dose 
date then impute last dose date. 
• Completely missing: need to look at whether the AE or CM is still ongoing before 
imputing a date and also when it started in relation to study drug. If the ongoing flag is 
missing then assume that AE or CM is still present (i.e. do not impute a date). If the 
AE or CM has stopped and start date is prior to first dose date then impute the last 
dose date, if it started on or after first dose date then impute a date that is after the last 
dose date. 
3.3.2 
Hypotheses 
3.3.2.1 
Primary hypotheses 
 
Endpoint: Mean S-K level between placebo and each ZS treatment group (high to low) 
during the 28-day randomized treatment study phase Days 8-29. 
The null hypothesis: No treatment difference in the mean S-K levels during RTP (Days 8-29) 
compared to placebo as follows (two null hypotheses): 


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For this endpoint the null hypothesis is that during RTP (Days 8-29) there is no treatment 
difference in the mean S-K levels; and the alternative is compared to placebo there is a 
difference in the mean S-K levels: 
𝐻0: 𝜇𝑠𝑘(𝑍𝑆10𝑔) = 𝜇𝑠𝑘(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝑠𝑘(𝑍𝑆10𝑔) ≠𝜇𝑠𝑘(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
𝐻0: 𝜇𝑠𝑘(𝑍𝑆5𝑔) = 𝜇𝑠𝑘(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝑠𝑘(𝑍𝑆5𝑔) ≠𝜇𝑠𝑘(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
 
3.3.2.2 
Secondary hypotheses 
For the OLP, the following hypotheses will be tested versus two-sided alternatives: 
Endpoint: Exponential rate of change in S-K levels (blood) at 24 hours and 48 hours during 
OLP. 
The null hypothesis: 
𝐻0: 𝐸𝑥𝑝𝑜𝑛𝑒𝑛𝑡𝑖𝑎𝑙 𝑟𝑎𝑡𝑒 𝛥 𝑆−𝐾 (24 ℎ𝑜𝑢𝑟𝑠) = 0 vs. 𝐻𝐴: 𝐸𝑥𝑝𝑜𝑛𝑒𝑛𝑡𝑖𝑎𝑙 𝑟𝑎𝑡𝑒 𝛥 𝑆−𝐾 (24 ℎ𝑜𝑢𝑟𝑠) ≠0  
𝐻0: 𝐸𝑥𝑝𝑜𝑛𝑒𝑛𝑡𝑖𝑎𝑙 𝑟𝑎𝑡𝑒 𝛥 𝑆−𝐾 (48 ℎ𝑜𝑢𝑟𝑠) = 0 vs. 𝐻𝐴: 𝐸𝑥𝑝𝑜𝑛𝑒𝑛𝑡𝑖𝑎𝑙 𝑟𝑎𝑡𝑒 𝛥 𝑆−𝐾 (48 ℎ𝑜𝑢𝑟𝑠) ≠0  
This is evaluated by the parameter estimate of time (in hours) from a mixed effects model as 
described in Section 4.2.2.4. Note that the exponential rate of change refers to the degree of 
decline in SK values over time, which is assumed to follow an exponential trend. 
 
Endpoint: Mean change (absolute and percent (%) change) from baseline in S-K levels 
The null hypotheses: 
𝐻0: 𝜇Δ S−K (24 ℎ𝑜𝑢𝑟𝑠) = 0 vs. 𝐻𝐴: 𝜇Δ S−K (24 ℎ𝑜𝑢𝑟𝑠) ≠0 
𝐻0: 𝜇Δ S−K (𝐸𝑛𝑑 𝑜𝑓 𝑂𝐿𝑃) = 0 vs. 𝐻𝐴: 𝜇Δ S−K (𝐸𝑛𝑑 𝑜𝑓 𝑂𝐿𝑃)  ≠0 
The end of OLP can be 24 or 48 hours depending on the duration of OLP, as subjects who did 
not achieve normokalemia at 24 hours are evaluated again at 48 hours.   
There will be a similar hypothesis for the mean percent change of S-K at 24 and 48 hours.  
 
 
 
 


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For the RTP, the following hypotheses will be tested:  
 
Endpoint: Proportion of subjects who remain normokalemic at the end of the RTP and during 
the RTP. 
The null hypotheses: 
𝐻0: 𝑂𝑅 (𝑍𝑆10𝑔𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) = 1. vs. 𝐻𝐴: 𝑂𝑅 (𝑍𝑆10𝑔 𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) ≠1 
𝐻0: 𝑂𝑅 (𝑍𝑆5𝑔𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) = 1. vs. 𝐻𝐴: 𝑂𝑅 (𝑍𝑆5𝑔 𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) ≠1 
For each of the treatment arm comparisons, two tests will be done: one aiming at evaluating 
the odds of being normokalemic Day 8-29, performed by means of a generalized random 
effects model as described in Section 4.2.3, and another aiming at evaluating the probability of 
being normokalemic at Day 29 in particular, performed by means of a logistic regression 
model. 
 
Endpoint: Number of days subjects remain normokalemic during the RTP. 
The null hypotheses: 
𝐻0: 𝜇days of normokalemic(𝑍𝑆10𝑔) = 𝜇days of normokalemic(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs.  
 
𝐻𝐴: 𝜇days of normokalemic(𝑍𝑆10𝑔) ≠𝜇days of normokalemic(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
𝐻0: 𝜇days of normokalemic(𝑍𝑆5𝑔) = 𝜇days of normokalemic(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs.  
 
𝐻𝐴: 𝜇days of normokalemic(𝑍𝑆5𝑔) ≠𝜇days of normokalemic(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
 
Endpoint: Time to hyperkalemia.  
The null hypotheses: 
𝐻0: 𝐻𝑅 (𝑍𝑆10𝑔𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) = 1. vs. 𝐻𝐴: 𝐻𝑅 (𝑍𝑆10𝑔 𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) ≠1 
𝐻0: 𝐻𝑅 (𝑍𝑆5𝑔𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) = 1. vs. 𝐻𝐴: 𝐻𝑅 (𝑍𝑆5𝑔 𝑣𝑠 𝑃𝑙𝑎𝑐𝑒𝑏𝑜) ≠1 
 
Endpoint: The mean changes in S-Aldo and P-Renin levels during RTP  
The null hypotheses: 


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𝐻0: 𝜇𝐴𝑙𝑑𝑜(𝑍𝑆10𝑔) = 𝜇𝐴𝑙𝑑𝑜(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝐴𝑙𝑑𝑜(𝑍𝑆10𝑔) ≠𝜇𝐴𝑙𝑑𝑜(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
𝐻0: 𝜇𝐴𝑙𝑑𝑜(𝑍𝑆5𝑔) = 𝜇𝐴𝑙𝑑𝑜(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝐴𝑙𝑑𝑜(𝑍𝑆5𝑔) ≠𝜇𝐴𝑙𝑑𝑜(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
𝐻0: 𝜇𝑅𝑒𝑛𝑖𝑛(𝑍𝑆10𝑔) = 𝜇𝑅𝑒𝑛𝑖𝑛(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝑅𝑒𝑛𝑖𝑛(𝑍𝑆10𝑔) ≠𝜇𝑅𝑒𝑛𝑖𝑛(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
𝐻0: 𝜇𝑅𝑒𝑛𝑖𝑛(𝑍𝑆5𝑔) = 𝜇𝑅𝑒𝑛𝑖𝑛(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) vs. 𝐻𝐴: 𝜇𝑅𝑒𝑛𝑖𝑛(𝑍𝑆5𝑔) ≠𝜇𝑅𝑒𝑛𝑖𝑛(𝑃𝑙𝑎𝑐𝑒𝑏𝑜) 
 
3.3.3 
Visit Window 
In the absence of nominal visits, visits windows will apply. Measurements will be assigned to 
exhaustive visit windows based on study day such that measurements taken at any time point 
can be accounted for and used in summaries and/or analyses. If an unscheduled visit occurred 
in the same window, then the measurement from the scheduled visit will be used in the 
analysis. If there are multiple unscheduled visits in the same visit window, then the visit 
closest to the scheduled visit day will be used. If there are multiple records on the same day 
the last measurement will be used. 
• For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment is used (regardless of where it falls in an interval). 
• Listings display all values contributing to a time point for a subject. 
• For visit-based summaries 
o If there is more than one scheduled value per subject within a time window 
then the closest value to the scheduled visit date is summarized. If the 
scheduled values are equidistant from the nominal visit date, then the earlier 
value is used. Data listings will highlight the values used in the summary table, 
wherever feasible.  
o Note: in summaries of extreme values (i.e. when assessing the 
minimum/maximum on-treatment values), all post baseline values collected are 
used including those collected at unscheduled visits regardless of whether or 
not the value is closest to the scheduled visit date and appears in the 
corresponding visit-based summary. 
Visit windows are described in Table 2. 
 


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Table 2 Time windows for allocation of data to visits for statistical analysis 
 
Study Visit (Target Day)  
Nominal Target Day 
Study Visit Window (Days) 
 
  
Lower 
Upper 
Pre Screening Phase and Screening 
Phase1 
Visit 1 (Pre-screen)  
 
---  
 
---  
 
 
---  
Visit 2 (Screening)  
Open Label Phase 
---  
---  
  11  
OLP-Day 1  
1 
1 
1 
OLP-Day 2 2 
2 
2 
2 
OLP-Day 3 3 
3 
3 
3 
End of OLP (24 hours or 48        
hours) 4                                              
End of Study Visit (OLP-Day 9) 5  
2 or 3 
 
9 
--- 
 
4 
--- 
 
16 
Randomized Treatment Phase 
  
  
  
Randomization (RTP-Day 1) 
1 
1 
1 
Visit 6 (RTP-Day 2)  
2 
2 
2 
Visit 7 (RTP-Day 5)  
5 
3 
6 
Visit 8 (RTP-Day 8)  
8 
7 
9 
Visit 9 (RTP-Day 12)  
12 
10 
13 
Visit 10 (RTP-Day 15)  
15 
14 
17 
Visit 11 (RTP-Day 19)  
19 
18 
20 
Visit 12 (RTP-Day 22)  
22 
21 
24 
Visit 13 (RTP-Day 26)  
26 
25 
27 
Visit 14 (RTP-Day 29)  
29 
28 
31 
End of Study Visit (RTP-Day 35)6  
35 
32 
43 
1. The screening phase lasts up to the date and time when the open label initial phase is initiated, i.e. date and time of 
the first dose. 
2. Potassium is measured predose and 1 hour post dose. The predose measure is considered as the 24-hour 
measurement for all analyses. Patients who achieve normokalemia at 24 hours will proceed to the Randomization 
(RTP-Day 1) visit. 
3. Potassium is measured predose and this measure is considered as the 48-hour measurement for all analyses. 
4. End of OLP (24 hours or 48 hours) the latest treatment day of open label initial phase only for patients who 
complete 24 hours or 48 hours OLP treatment. 
5. End of Study Visit (OLP-Day 9) in open label initial phase only for patients NOT entering the 28-day randomized 
treatment study phase and occurs 7±1 day after the last administration of IP.  
6. End of Study Visit (RTP-Day 35) occurs 7±1 day after last planned administration of IP in RTP.  
 
3.3.4 
Handling of Unscheduled Visits  
Unscheduled visits are included in the method of assigning data to scheduled visits described 
in the rules in Section 3.3.3 above. Unscheduled visits are not included as a separate visit in 
the summary tables, but they will be included in all listings of study data. 


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3.3.5 
Handling of Missing Serum Potassium (S-K) Data 
The S-K levels used for all analyses will be based on the central laboratory (c-lab) 
measurements. If the S-K c-lab data points are missing, the i-STAT data will be used to 
replace missing data by adjusting for the average paired difference between the c-lab and i-
STAT levels collected at the same visit and with the same calibration method for the 
potassium assay. If the time difference between the SK c-lab and i-STAT measurements is 
greater than 15 minutes, the SK measure for that time point will be set as missing.  
3.3.6 
Mixed Model: Terms and Estimation 
The form of the linear mixed effects model employed in the analyses in this study is as 
follows: 
ln (𝑆𝐾 𝑙𝑒𝑣𝑒𝑙)𝑖𝑗= 𝑋𝑖𝑗𝛽+ 𝑍𝑖𝑏𝑖+ 𝜀𝑖𝑗 
where: 
1. ln (𝑆𝐾 𝑙𝑒𝑣𝑒𝑙)𝑖𝑗 is the S-K level in the natural log scale for the 𝑗𝑡ℎ measurement for the 
𝑖𝑡ℎ subject. 
2. 𝑋𝑖𝑗 is the matrix of fixed effects covariates. 
3. 𝛽 is a vector containing the fixed-effects regression coefficients. 
4. 𝑍𝑖 represents the random effects covariates. 
5. 𝑏𝑖 is a normally distributed random effect parameter. 
6. 𝜀𝑖𝑗 is a normally distributed random error term. 
Variance components will be estimated using a restricted maximum likelihood method 
(REML) and an unstructured marginal covariance structure will be assumed. If the specified 
model fails to converge, the final covariance structure will be determined by Akaike’s 
information criteria: Toeplitz, first-order autoregressive and compound symmetry. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
For the analysis of primary endpoint, the model will include S-K data values (natural log 
scale) assigned to the scheduled visits between Days 8-29 as response variables, and the 
following fixed effects: eGFR baseline, OLP and RTP baseline S-K values, visit, treatment, 
visit-by-treatment interaction, as well as age (<55, 55-64, >64 years) and baseline binary 
indicators for renin-angiotensin-aldosterone system (RAAS) inhibitors, chronic kidney 
disease, heart failure, and diabetes mellitus. 
3.3.7 
Multiplicity/Multiple Comparisons 
A sequential closed testing procedure will be used in OLP and RTP to maintain an overall 
Type I error rate of 5%. 


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Treatment testing will proceed from high dose (ZS 10g) to low dose (ZS 5g) relative to 
placebo, with statistical significance (two-sided p-value ≤ 0.05) required for the high dose vs. 
placebo control in order to proceed to the low dose vs. placebo control. 
P-values for tests not included in the sequential closed testing procedure are not adjusted for 
multiplicity and will not be called significant and are considered exploratory. 
Specifically, the following fixed hierarchical sequence will be employed: progression to the 
next test in the sequence will continue until a 2-sided p-value of > 0.05 is encountered, at 
which any point further testing will cease. Explicitly, Table 3 will be implemented. 


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Table 3. Overview of the variables/endpoints and multiplicity testing order 
Endpoints/Variables 
Phase 
Treatment Comparison 
Testing 
Order in 
Hierarchy 
Primary 
Mean serum potassium [S-K] level 
RTP ii 
ZS 10g QD vs. Placebo 
2 
Mean serum potassium [S-K] level 
ZS   5g QD vs. Placebo 
3 
 
 
 
 
 
 
Secondary 
Proportion of subjects who remain normokalemiciv at the end 
of RTPiii 
ZS 10g QD vs. Placebo 
4 
Proportion of subjects who remain normokalemic at the end of 
RTP 
ZS   5g QD vs. Placebo 
5 
Number of days that subjects are normokalemic  
ZS 10g QD vs. Placebo 
6 
Number of days that subjects are normokalemic  
ZS   5g QD vs. Placebo 
7 
Time to hyperkalemiav 
ZS 10g QD vs. Placebo 
8 
Time to hyperkalemia 
ZS   5g QD vs. Placebo 
9 
 
 
 
 
Mean serum potassium [S-K] change from baseline after first 
dose 
OLP i 
NA 
1 
i   OLP refers to the 24 or 48 hours Open Label Phase. 
ii  RTP refers to the 28 days Randomized Treatment Phase, and Days 8-29 is of interest for the endpoints. 
iii End of RTP in the maintenance day refers to the planned day of last dose of study treatment, Day 29. 
iv Normokalemic/Normokalemia is defined as having [S-K] level within the range of 3.5-5.0 mmol/L, inclusive. 
                        v  Hyperkalemia is defined as having [S-K] level greater equal than 5.1 mmol/L. 
 
 
 
 


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3.3.8 
Handling of Protocol Deviations in Study Analysis 
There is no defined Per Protocol population for this study and all efficacy analyses will be 
based on the FAS. Therefore, protocol deviations will not imply exclusion from analyses.  
According to ICH E3 (ICH 1995) guidelines,  
“Protocol deviations consist of any change, divergence or departure from the study 
design or procedures defined in the protocol. Important protocol deviations (IPDs) are 
a subset of protocol deviations that may significantly affect the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s 
rights, safety or well-being.”  
Important protocol deviations relating to subject-level and subject-visit level events are 
defined in the Non-Compliance Handling Plan and presented in Appendix A: IPD Master List. 
They will be reviewed by appropriate medical, clinical, data management, and statistical 
personnel and will be documented prior to database lock.  
A full list of subject inclusion and exclusion criteria is provided in the study protocol. 
3.3.9 
COVID-19 Impact 
If a study participant is unable to attend more than two consecutive clinic visits either due to 
quarantine for being infected with or suspected for COVID-19 or due to site closure for 
COVID-19, the investigational product should be discontinued after discussed with AZ.  
4 
STATISTICAL ANALYSIS 
This section provides information on definitions, derivation, and analysis/data presentation 
per domain. 
For all domains, descriptive statistics presented will depend on the type of variable analyzed 
and will include n (number of subjects included in the analysis), mean, standard deviation 
(SD), median, minimum and maximum. For categorical variables, they will consist of the 
number of observations in the respective category, as well as the corresponding percentages.  
4.1 
Study Population 
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics, medical history, prior and concomitant medications, 
and study drug compliance.  


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The majority of the presentations in this domain, with the exception of the overview of the 
analysis sets and recruitment, will consist of summary statistics provided for each of the 
treatment arms, and for the treatment arms combined.  
4.1.1 
Subject Disposition and Completion Status 
4.1.1.1 
Definitions and Derivations 
Subject accounting will be provided for but not limited to the following: 
• Subjects included in the OLP 
• Subjects included in the RTP  
• Non-randomized subjects 
• Subjects who received treatment in the OLP and in the RTP 
• Subjects who were randomized but did not receive any treatment in RTP 
• Subjects who completed treatment in the OLP  
• Subjects who discontinued treatment in the OLP  
• Randomized subjects who completed treatment in the RTP  
• Randomized subjects who discontinued treatment in the RTP  
• Randomized subjects who completed the study 
• Randomized subjects who withdrew from the study 
• Randomized subjects who discontinued treatment due to global/country situation 
• Randomized subjects who withdrew from the study due to global/country situation 
 
4.1.1.2 
Presentation 
The number and percentage of subjects in the above categories will be presented separately 
for OLP and RTP.   
The subject recruitment will be presented by center for each treatment group. 
Disposition listings will include subject ID, age, gender and race, and will be presented sorted 
by treatment group, subject ID, and date/time of observation.  
4.1.2 
Analysis Sets 
4.1.2.1 
Definitions and Derivations 
Refer to Section 3.2 for definition of analysis sets.  


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4.1.2.2 
Presentation 
The number of subjects included in the FAS and SAF for OLP and RTP, along with the 
reasons for exclusion from either of the analysis sets where relevant, will be summarized. 
A listing of subjects excluded from any analysis set will include subject ID, age, gender and 
race, and will be presented sorted by treatment group, subject ID, and date/time of 
observation. 
4.1.3 
Protocol Deviations 
4.1.3.1 
Definitions and Derivations 
Refer to section 3.3.7 for definition of protocol deviations. 
4.1.3.2 
Presentation 
Important protocol deviations will be listed and summarized separately for the FAS-OLP and 
FAS-RTP. 
The number and percentage of subjects with any IPD will be summarized for each IPD 
category. Subjects with more than one deviation in the same IPD category will be counted 
once for that IPD category. Any subjects who have deviations in more than one IPD category 
will be counted once in the overall summary. 
The number and percentages of subjects within each important protocol deviation type will be 
summarized by study phase, OLP and RTP, respectively. In the RTP, summaries will be 
presented overall and by treatment group. All individual subjects with important protocol 
deviations will be listed as well for OLP and RTP, respectively. 
Similarly, COVID-related IPD will be summarized. 
4.1.4 
Demographics 
4.1.4.1 
Definitions and Derivations 
Demographics are comprised of age, age group, sex, race and ethnicity. 
4.1.4.2 
Presentation 
Demographics will be listed for all subjects enrolled and summarized respectively for the 
FAS-OLP and FAS-RTP. This listing will include subject ID, age, gender, ethnicity and race, 
and will be presented sorted by treatment group and subject ID. 
In addition to being summarized as a continuous variable, age will be summarized as the age 
group categorical variable (<55, 55–64, >64 years). 


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4.1.5 
Baseline Characteristics 
4.1.5.1 
Definitions and Derivations 
Baseline characteristics include height (m), weight (kg) and BMI (kg/m2), baseline serum 
potassium (S-K), baseline eGFR, baseline binary indicators for RAAS, chronic kidney 
disease, heart failure and diabetes mellitus.  
Baseline parameters are measured/collected up to 1 day prior to administration of the 1st dose 
of study drug on the open-label initial phase Day 1 (Visit 3). 
BMI is calculated as: Weight (kg) / [Height (m)]2. 
eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Levey et al 2009) for each time-point where creatinine is measured, 
using central laboratory creatinine: 
𝑒𝐺𝐹𝑅= 141 ∗𝑚𝑖𝑛(𝑆𝐶𝑟𝐾
⁄
, 1)𝛼∗𝑚𝑎𝑥(𝑆𝐶𝑟𝐾
⁄
, 1)−1.209 ∗0.993𝐴𝑔𝑒∗1.018
∗1.159 [𝑖𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑖𝑠 𝑏𝑙𝑎𝑐𝑘] 
Where: 
1. 𝑆𝐶𝑟 is the standardized serum creatinine in mg/dL 
2. 𝐾 = 0.7 (females) or 0.9 (males) 
3. 𝛼 = -0.329 (females) or -0.411 (males) 
4. 𝐴𝑔𝑒 is in years. 
4.1.5.2 
Presentation 
Baseline characteristics will be listed for all subjects enrolled and summarized respectively for 
the FAS-OLP and FAS-RTP. This listing will include subject ID, age, gender and race, and 
will be presented sorted by treatment group and subject ID. 
4.1.6 
Medical History and Concomitant Disease 
4.1.6.1 
Definitions and Derivations 
Medical and surgical history are collected up to one day prior to administration of study drug 
on Day1 (Visit 3) are classified according to the terminology of the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
4.1.6.2 
Presentation 
Medical history and surgical history are grouped by MedDRA system organ class and 
preferred term and are summarized by System Organ Class (SOC) and Preferred Term (PT), 
for all subjects in FAS-OLP and in FAS-RTP.  


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They will be listed for all subjects enrolled and summarized respectively for the FAS-OLP 
and FAS-RTP. This listing will be presented sorted by treatment group, subject ID, and 
date/time of the event. 
4.1.7 
Prior and Concomitant Medications 
4.1.7.1 
Definitions and Derivations 
Medications will be classified according to the latest version of the WHO Drug coding 
dictionary. Prior medication is any medication that started and stopped prior to treatment with 
investigational product. Concomitant medication is any medication that is taken concurrently 
with investigational product regardless of the start date of the medication. Concomitant 
medications include allowed and disallowed medications taken by the subjects during the 
respective phases (i.e. a medication can be concomitant for the OLP but not RTP, or RTP but 
not OLP). Missing medication start and stop dates will be imputed according to Section 
3.3.1.4. 
For the definition of disallowed medications, see Appendix B. 
4.1.7.2 
Presentation 
Prior and concomitant medications (allowed and disallowed) and procedures will be listed 
respectively for all subjects in the SAF-OLP and SAF-RTP, and will be presented sorted by 
treatment group and subject ID. 
Concomitant medications and procedures listed in Section 7.7 of the CSP will be summarized 
by chemical subgroup (ATC 4th level) and preferred WHO name respectively for the SAF-
OLP and SAF-RTP. Subjects with the same concomitant medication/procedure multiple times 
will be counted once per medication/procedure. A medication/procedure that can be classified 
into more than one (chemical and/or therapeutic) subgroup will be presented in each 
subgroup. A medical review may also be done. 
Disallowed medications will be similarly summarized, separately. 
4.1.8 
Study Drug Compliance 
4.1.8.1 
Definitions and Derivations 
Treatment compliance is obtained by summing up the total number of sachets taken and 
dividing it by the expected number of sachets to be taken, multiplied by 100%, where the 
expected number of sachets is calculated over the subject’s actual duration in the trial and not 
the planned duration. Subjects who did not receive IP will have their treatment compliance set 
to missing. 


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4.1.8.2 
Presentation 
Treatment compliance will be summarized separately for the OLP and the RTP, overall and by 
treatment group. 
4.1.9 
COVID-19 Impact 
4.1.9.1 
Definitions and Derivations 
See section 3.3.9 for the definition.  
4.1.9.2 
Presentation 
Depending on the extent of any impact, summaries of data relating to subjects diagnosed with 
COVID-19, and the impact of COVID-19 on study conduct may be generated including 
• 
Disposition (discontinued IP due to COVID-19 and withdrew study due to COVID-19)  
• 
Deviations (overall deviations plus if due to COVID-19 and not due to COVID-19)  
• 
Summary of COVID-19 disruptions (visit impact, drug impacted)  
Listing for subjects affected by the COVID-19 pandemic will also be produced. 
4.2 
Endpoint/Variable Analyses 
This section covers details related to the endpoint analyses such as primary, secondary, other 
endpoints including sensitivity and supportive analyses. 
Efficacy analyses will be undertaken for the open-label initial phase and the 28-day 
randomized treatment study phase on the respective full analysis sets unless otherwise stated.


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Statistical category 
Endpoint 
Analysis set 
Intercurrent event strategy 
Population level summary 
(analysis) 
Details in 
section 
Primary objective:  To evaluate the efficacy of two different doses (5 and 10 g) of ZS orally administered once daily (qd) for 28 days in maintaining 
normokalemia (serum potassium [S-K] between 3.5-5.0 mmol/L, inclusive) in normokalemic subjects, following treatment in the open-label initial phase, 
for hyperkalemic subjects (two consecutive i-STAT potassium values ≥ 5.1 mmol/L, taken 60 minutes apart) at baseline. 
Primary 
Mean S-K level between 
placebo and each ZS 
treatment group (high to 
low) during the 28-day 
randomized treatment 
study phase Days 8-29. 
FAS-RTP 
Treatment policy: intercurrent 
events ignored 
Difference in mean S-K values 
between each of the active 
treatment groups (ZS 10g and 
ZS 5g) and placebo, during 
RTP Days 8-29, estimated using 
a longitudinal mixed model.  
4.2.1.4 
Sensitivity 
Mean i-STAT level 
between placebo and 
each ZS treatment group 
(high to low) during the 
28-day randomized 
treatment study phase 
Days 8-29. 
FAS-RTP 
Treatment policy: intercurrent 
events ignored 
Difference in mean i-STAT 
values between each of the 
active treatment groups (ZS 10g 
and ZS 5g) and placebo, during 
RTP Days 8-29, estimated using 
a longitudinal mixed model. 
4.2.1.5 
Supplementary 
Mean S-K level between 
placebo and each ZS 
treatment group (high to 
low) during the 28-day 
randomized treatment 
study phase Days 8-29. 
FAS-RTP 
Hypothetical strategy for 
disallowed medications: 
measurements obtained while a 
subject was using disallowed 
medication are excluded from the 
analysis. 
 
Difference in mean S-K values 
between each of the active 
treatment groups (ZS 10g and 
ZS 5g) and placebo, during 
RTP Days 8-29, estimated using 
a longitudinal mixed model. 
4.2.1.6 
Secondary objective 1 (OLP):  To evaluate the proportion of subjects who achieve normokalemia after the completion of open-label initial phase treatment 
Secondary 
1- Proportion of subjects 
who achieve 
normokalemia (3.5 – 5.0 
mmol/L) during and at 
the end of OLP 
(classification of each 
screened subject as 
FAS-OLP 
Treatment policy: intercurrent 
events ignored. This policy will be 
used for all four of the endpoints 
in this section. 
 
 
1- Probability of subjects 
achieving normokalemia, at 24 
h and at the end of OLP, 
estimated as proportion of 
responders, with 95% two-sided 
Clopper-Pearson exact CIs. 
2- The time effect derived from 
4.2.2.4 


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Statistical category 
Endpoint 
Analysis set 
Intercurrent event strategy 
Population level summary 
(analysis) 
Details in 
section 
either a “responder” or a 
“non-responder”) 
2- Exponential rate of 
change in S-K levels 
during OLP 24 hours 
post-dose  
3- Mean change 
(absolute and percent 
change) in S-K level at 
all post-dose time 
intervals during OLP 
4- Time to 
normalization in S-K 
levels during OLP 
a longitudinal mixed model 
including all SK measurements 
up to 24 hours post-dose 
3- Mean change (absolute and 
percent change) in S-K level 
from baseline to each of the 
planned measurement occasions 
during OLP, as well as end of 
OLP, analyzed using one 
sample, two-sided t-tests 
4- The CDF of time to S-K 
normalization estimated using 
Kaplan-Meier life table curves  
Supplementary 
Proportion of subjects 
who achieve 
normokalemia without 
use of disallowed 
medications during and 
at the end of OLP 
FAS-OLP 
Composite strategy: Intercurrent 
event (use of disallowed 
medication) is included as part of 
a composite endpoint, where 
subjects can only be counted as a 
"success" (responder) if they did 
not receive any disallowed 
medication before the 
measurement occasion and if they 
are normokalemic (S-K between 
3.5-5.0 mmol/L). 
Probability of subjects 
achieving normokalemia 
without usage of disallowed 
medications, estimated as 
proportion of responders, with 
95% two-sided Clopper-
Pearson exact CIs. 
4.2.2.5 
Supplementary 
Mean change in S-K 
level from baseline to 
24h and end of OLP 
FAS-OLP 
Hypothetical strategy: 
measurements obtained post usage 
of disallowed medications are 
removed from the analysis 
Mean change in S-K level from 
baseline to 24h and end of OLP, 
analyzed using one sample, 
two-sided t-tests 
4.2.2.5 
Supplementary  
Exponential rate of 
change in S-K levels 
during OLP 48 hours 
FAS-OLP 
Treatment policy: intercurrent 
events ignored.  
The time effect derived from a 
longitudinal mixed model 
including all SK measurements 
4.2.2.5 


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Statistical category 
Endpoint 
Analysis set 
Intercurrent event strategy 
Population level summary 
(analysis) 
Details in 
section 
post-dose 
 
up to 48 hours post-dose 
Secondary objective 2 (RTP):  To evaluate the efficacy of ZS in subjects with hyperkalemia for the following subgroups as applicable: 
- 
chronic kidney disease (CKD) 
- 
diabetes mellitus (DM) 
- 
heart failure (HF)  
- 
those on renin-angiotensin-aldosterone system (RAAS) inhibitors. 
Secondary 
1- Proportion of subjects 
who remain 
normokalemic during 
and at the end of RTP 
2- The number of days 
subjects remain 
normokalemic during 
RTP 
3- Time to hyperkalemia  
4- Mean change 
(absolute and percent 
change) in S-K level at 
all post-dose time 
intervals during RTP 
FAS-RTP 
Treatment policy: intercurrent 
events ignored. This policy will be 
used for all four of the endpoints 
in this section. 
 
1- Odds ratio of being 
normokalemic on Day 29, and 
between Day 8 and 29, 
compared between each of the 
active treatment groups (ZS 10g 
and ZS 5g) and placebo using a 
logistic regression model 
(generalized random effect 
model)   
2- The least square mean of 
number of the days will be 
compared between each of the 
active treatment groups (ZS 10g 
and ZS 5g) and placebo using a 
linear regression model 
3- Hazard ratio for median time 
(days) to hyperkalemia between 
each of the active treatment 
groups (ZS 10g and ZS 5g) and 
placebo obtained from Cox 
proportional hazards model  
4- Mean change (absolute and 
percent change) in S-K level 
from baseline to each of the 
planned measurement occasions 
4.2.3.3 


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Statistical category 
Endpoint 
Analysis set 
Intercurrent event strategy 
Population level summary 
(analysis) 
Details in 
section 
during RTP, analyzed using one 
sample, two-sided t-tests 
Supplementary 
Proportion of subjects 
who remain 
normokalemic at the end 
of RTP 
FAS-RTP 
Composite strategy: Intercurrent 
event (use of disallowed 
medication) is included as part of 
a composite endpoint, where 
subjects can only be counted as a 
"success" (responder) if they did 
not receive any disallowed 
medication before the 
measurement occasion and if they 
are normokalemic (S-K between 
3.5-5.0 mmol/L).  
Odds ratio of  being 
normokalemic on Day 29 
compared between each of the 
active treatment groups (ZS 10g 
and ZS 5g) and placebo using a 
logistic regression model  
4.2.3.4 
Secondary objective 3 (RTP):  To evaluate the effect of ZS on serum-Aldosterone (S-Aldo) and Plasma-Renin (P-Renin) levels. 
Secondary 
The mean changes in S-
Aldo and P-Renin levels 
during RTP 
FAS-RTP 
Treatment policy: intercurrent 
events ignored. 
 
Mean difference in values 
between each of the active 
treatment groups (ZS 10g and 
ZS 5g) and placebo estimated 
using a longitudinal mixed 
model.  
4.2.3.3 


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4.2.1 
Primary Endpoint 
The primary efficacy variable is serum potassium [S-K] level during the RTP, Days 8-29, 
using c-lab, or adjusted i-STAT for visits where c-lab is not available.  
4.2.1.1 
Definition 
Several intercurrent events of concern have been identified in this setting, namely the use of 
disallowed medications, changes in treatment, including discontinuations, and death. For the 
main analysis of the primary endpoint a treatment policy approach to all the identified 
intercurrent events will be used (except for death, for which such an approach is not 
applicable).  
However, a supplementary analysis aimed at evaluating the impact of disallowed medication 
use is included. In this analysis, the S-K (or i-STAT, if applicable) measurements obtained 
while a subject was receiving disallowed medication are excluded, reflecting a hypothetical 
scenario where disallowed medication is not available to subjects (i.e. a “hypothetical 
strategy” type of approach, see ICH E9 (R1) 2017 p. 18).  
4.2.1.2 
Derivations 
See section 3.3.1.1 for definition of baseline for the efficacy analyses. 
4.2.1.3 
Handling of Dropouts and Missing Data 
The S-K levels used for the primary analysis will be based on the c-lab measurements 
obtained during the RTP. Missing S-K c-lab values will be replaced as described in Section 
3.3.5.    
For the supplementary analysis aimed at evaluating the impact of usage of disallowed 
medications, if a subject is missing both the central laboratory and i-STAT values they will be 
imputed using multiple imputation (MI). Note that MI will not be used for the main analysis, 
as it is expected that, after i-STAT imputation, the amount of missing data will be minimal, 
and the missing pattern will be MAR, and would be sufficiently explained by the covariates 
included in the model.  
Multiple imputation for the supplementary analysis 
Multiple imputation (MI) will be done where imputation of unavailable c-lab values with i-
STAT values not possible. 
Missing S-K values will be imputed using the Fully Conditional Specification (FCS) method 
(Brand 1999; Van Buuren 2007). The covariates to be included in the imputation model are; 
the available c-lab data obtained post randomization visit (RTP Day 1) with baseline 


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covariates for the open-label initial phase eGFR, the open-label initial phase S-K values, the 
28-day randomized treatment study phase S-K values as well as age (<55, 55-64, >64 years), 
baseline binary indicators for RAAS inhibitors, chronic kidney disease, heart failure, diabetes 
and treatment arm. The imputation will be performed using the log-transformed S-K values. 
M=100 will be chosen as the number of imputed data sets, the seed will be set as 22438 and 
the default 20 burn-ins will be used. An unstructured marginal covariance structure will be 
assumed. If the specified model fails to converge, alternative structures will be used as 
described in Section 3.3.6. 
Analysis: 
Once M complete data sets have been constructed using MI, the statistical analysis will be 
conducted on each of the M complete data sets. Explicitly, a linear mixed models will be 
applied, see Section 4.2.1.4. 
Pooling: 
Rubin’s rules will be implemented for combining estimates and standard errors across the 
imputed data sets and conducting the analysis. Suppose 𝑄̂𝑖 and 𝑊̂𝑖 are the point and variance 
estimates from the ith imputed data set, i = 1, 2, . . . , 100. Then the combined point estimate 
for Q from multiple imputation is the average of the 100 complete-data estimates: 
𝑄̅ =
1
100 ∑𝑄̂𝑖
100
𝑖=1
 
𝑊̅  is the within-imputation variance, which is the average of the m complete-data estimates: 
𝑊̅ = 1
𝑚∑𝑊̂𝑖
100
𝑖=1
 
B is the between-imputation variance: 
𝐵=
1
100 −1 ∑(𝑄̂𝑖−𝑄)
̅̅̅̅2
100
𝑖=1
 
 
Then the variance estimate associated with 𝑄̅ is the total variance is: 
 
 
𝑇= (1 + 𝑥)𝑛= 𝑊̅ + (1 + 1
100)𝐵 
 
The statistic (𝑄̂𝑖−Q̅)𝑇  −(1
2)  is approximately distributed as t with Vm degrees of freedom 
 
𝑉100 = (100 −1) ([1 +
𝑊̅
(1 + 100−1)𝐵])
2
 
No imputation will be done for missing covariates in the models. 


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4.2.1.4 
Main Analysis of Primary Endpoint  
To address the primary objective, a comparison between placebo and each ZS treatment group 
(high to low) with regards to the mean S-K level during the 28-day randomized treatment 
study phase Days 8-29 will be made.  
Descriptive statistics will be presented for S-K values at randomization visit (RTP Day 1) 
through Visit 14 (RTP Day 29), and the EOS visit. Mean change (absolute and percent 
change) from baseline will be summarized by treatment groups (ZS 5g, ZS 10g and placebo). 
In addition, a box plot of S-K values by visit will be presented. 
The primary efficacy endpoint will be analyzed using a longitudinal mixed model (SAS 
PROC MIXED). The model will include all S-K data values (natural log scale) collected at the 
scheduled visits between Days 8-29 as response variables, and treatment, visit, treatment-by-
visit interaction, baseline eGFR, OLP and RTP baseline S-K values as well as age (<55, 55-
64, >64 years) and baseline binary indicators for RAAS inhibitors, chronic kidney disease, 
heart failure, and diabetes mellitus as fixed effects, patients are random effect term. 
The p-value from least square mean (LSMEAN) (two-sided) will be provided to compare the 
overall mean difference in S-K values between each active treatment (ZS 10g and ZS 5g) and 
placebo (the second and third tests in the sequential closed testing procedure). 
The estimated mean difference in log-transformed S-K values between each of the active 
treatment groups (ZS 10g and ZS 5 g) relative to the placebo treatment group will be provided 
along with accompanying 2-sided 95% confidence intervals. The relative difference in back-
transformed S-K, ZS 10g and ZS 5 g vs placebo, will also be presented, along with the 
corresponding 2-sided 95% CI. 
 
4.2.1.5 
Supplementary and Sensitivity Analyses of Primary Endpoint  
A sensitivity analysis will be conducted to assess the potential discrepancy in observed effect 
as assessed through by c-lab potassium, as opposed to i-STAT. This will be performed by 
using the same longitudinal model as was used for the main analysis of the primary endpoint 
on subjects Day 8 to Day 29 i-STAT measurements. 
A supplementary analysis, aimed at evaluating the impact of the usage of disallowed 
medications on the efficacy results, will also be conducted. This will be done by means of 
removing the potassium measurements that occurred while a subject was receiving a 
disallowed medication (between medications start date and stop date, plus 7 days), replacing 
them using a MI approach, and replicating the main analysis on each of the resulting data sets. 
See Section 4.2.1.3 for details on the MI procedure. 


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4.2.1.6 
Subgroup Analysis  
The primary efficacy endpoint will be evaluated in several sub-groups, in order to explore the 
consistency of the treatment effect, as follows:  
• chronic kidney disease status (yes/no) 
• diabetes mellitus status (yes/no) 
• heart failure status (yes/no) 
• those on RAAS inhibitors (yes/no). 
For the subgroup analysis to be conducted, a minimum of 10 subjects per treatment-subgroup 
combination is required, since this is the generally accepted minimum number. A single model 
will be fitted, this model including a treatment by subgroup interaction term in addition to the 
covariates in the original analysis (See section 4.2.1). Estimates of the treatment effect for 
each subgroup will be provided, with corresponding confidence intervals. A p-value for the 
interaction term will also be given. Additionally, LSMEAN for the combinations of treatment 
by subgroup levels will be presented with corresponding confidence intervals. 
4.2.2 
Secondary Endpoints for OLP phase 
4.2.2.1 
Definition 
The secondary efficacy endpoints for OLP phase will include the following: 
1. Proportion of subjects who achieve normokalemia during the OLP at 24 hours (OLP 
Day 2) and at the end of the OLP. Each subject is classified into a responder or a non-
responder category (i.e. a 0-1 type of response for subjects who achieve normokalemia 
or subjects who do not achieve normokalemia), with a subject being a responder if 
they have S-K between 3.5 and 5.0 mmol/L, inclusive. The following 7 time points 
during the OLP phase will be considered: 
o OLP Day 1, at 1, 2 and 4 hours post first dose 
o OLP Day 2, pre-dose and 1 hour post dose 
o OLP Day 3, pre-dose  
o End of OLP 
Note: not all subjects will have OLP Day 2, 1 hour post dose and OLP Day 3 pre-dose 
visit. 
2. Exponential rate of change in S-K levels (blood) at 24 hours during OLP 


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3. Mean change (absolute and percent (%) change) from baseline in S-K levels at all 
measured time intervals post-dose during OLP listed above. 
4. Time to normalization in S-K levels (normalization defined as first time S-K levels 
between 3.5-5.0 mmol/L, inclusive, are achieved) during OLP 
4.2.2.2 
Derivations 
See section 3.3.1.1 for definition of baseline for the efficacy endpoints. 
Time to normalization is defined as the number of hours from the first administration of IP in 
OLP to the date-time of normalization = (date-time of normalization – date-time of first IP 
administration). For analysis of time to normalization, subjects who fail to achieve 
normalization will be censored at the time of last SK measurement in the OLP. 
For analysis of the exponential rate of change, time (in hours) from first dose of IP will be 
derived as (datetime of SK measurement – datetime of first dose of IP)/3600. 
4.2.2.3 
Handling of Dropouts and Missing Data 
Missing S-K c-lab values will be replaced as described in Section 3.3.5.   
4.2.2.4 
Primary Analysis of Secondary Endpoints (OLP) 
Descriptive statistics will be presented for S-K levels at baseline, OLP Day 1 (1, 2 and 4 hours 
post first dose) and OLP Day 2 (pre-dose and 1 hour post the first dose in the day), OLP Day 3 
(pre-dose) and end of OLP, including the mean change (absolute and percent change) from 
baseline. In addition, a box plot of S-K values by timepoint will be presented. 
Similarly, descriptive statistics tabulating the proportion of subjects who achieve 
normokalemia at each of the timepoints specified above will be presented. 
Proportion of subjects who achieve normokalemia 
The observed proportions of subjects achieving normokalemia at  24 hours (OLP Day 2) and 
end of OLP will be provided along with 95% two-sided Clopper-Pearson exact confidence 
intervals. 
Exponential rate of change 
The exponential rate of change in S-K levels will be derived from a longitudinal mixed model 
(SAS PROC MIXED, see Section 3.3.5) of log-transformed S-K levels during the OLP. 
Measurements up to and including 24 hours post-dose will be used as the response variable. 
The model will include OLP baseline eGFR, OLP baseline S-K values as well as age (<55, 
55-64, >64 years), time (in hours) and baseline binary indicators for RAAS inhibitors, chronic 
kidney disease, heart failure, and diabetes mellitus as fixed effects terms. A random intercept 
and slope (for time) will be used in the model. The exponential rate of change will correspond 


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to the estimate of the parameter describing the SK decline over time, i.e. the slope in terms of 
log SK. It will be presented with corresponding standard error, 95% confidence interval and p-
value. 
Mean change (absolute and percent change) from baseline 
For changes and percent changes from baseline in S-K levels at 24 hours (OLP Day 2) (and 
end of OLP, one sample, two-sided t-tests will be applied to test the null hypotheses that the 
means are equal zero. The estimates, corresponding SD, 95% 2-sided CI and p-values will be 
presented.  
Time to normalization in S-K values 
The time to normalization in S-K levels will be summarized using Kaplan-Meier life table 
curves and associated 95% CI points will be provided at 1, 2, 4, 24 and 48 hours post first 
dose of IP.. All S-K assessments during OLP will be used.  
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint 
Not applicable. 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint 
Two supplementary analyses, aiming at evaluating the impact of use of disallowed 
medication, will be performed. The first one will consider the proportion of subjects that 
achieved normokalemia at 24 hours (OLP Day 2) and at the end of OLP without use of rescue 
medication. That is, the analysis of the proportion of normokalemic subjects described above 
will be replicated, with endpoint re-defined so that a subject is considered to be a responder 
only if they achieved normokalemia and did not use disallowed medications prior to the 
relevant timepoint, which would constitute a composite strategy with respect to the 
intercurrent event of disallowed medication usage.  
The second analysis will exclude all SK measurements in the OLP obtained post usage of 
disallowed medications and replicate the analysis of the mean change in SK at 24 hours (OLP 
Day 2)  and at the end of OLP as compared to baseline on the resulting data. This would 
constitute a hypothetical strategy with respect to the intercurrent event of disallowed 
medication usage, with the hypothetical scenario being that disallowed medications are not 
available to subjects.   
Disallowed medications are listed in Appendix B: Disallowed Medications. 
A third supplementary analysis will be performed assessing the exponential rate of change up 
to 48 hours post-dose. The exponential rate of change in S-K levels will be derived from a 
longitudinal mixed model (as described in Section 4.2.2.4) of log-transformed S-K levels 


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during the OLP. Measurements up to and including 48 hours post-dose will be used as the 
response variable.  
4.2.2.7 
Subgroup Analyses 
Not applicable 
4.2.3 
Secondary Endpoints for RTP phase 
4.2.3.1 
Definition 
The secondary efficacy endpoints for RTP phase will include the following: 
1. The proportion of subjects who remain normokalemic (as defined by S-K levels 
between 3.5-5.0 mmol/L, inclusive) at the end of the RTP and during the RTP (Day 8 
to Day 29). 
 
2. The number of days subjects remain normokalemic during the RTP (Day 8 to Day 29). 
3. The time to the first instance of hyperkalemia (defined as S-K ≥5.1 mmol/L). 
4. The mean changes in S-Aldo and P-Renin levels. 
4.2.3.2 
Derivations 
See section 3.3.1.1 for definition of baseline for the efficacy endpoints.  
The number of days subjects remain normokalemic is calculated as the sum of the length of 
each period of normokalemia a subject has. The length of a period of normokalemia is 
calculated as the stop date of normokalemia – start date of normokalemia + 1. For subjects 
who have a period of normokalemia lasting for a single visit, the duration of this period is set 
to 1. For subjects who have a time point missing in between two visits where the subject was 
recorded as being normokalemic, it can be assumed that the subject remained normokalemic 
and extend the period of normokalemia to the next, non-missing time point. For subjects with 
no record of being normokalemic during the RTP, the number of days subjects remain 
normokalemic is set to 0.Time to hyperkalemia is defined as the number of days from 
randomization to the date of hyperkalemia = (date of hyperkalemia -date of randomization) 
+1. 
For analysis of time to hyperkalemia, subjects who discontinue treatment in RTP due to high 
S-K levels (i-STAT potassium levels > 6.2 mmol/l at the 90-minute post dose 2 blood draw) 
will be treated the same as the subjects who developed hyperkalemia (event). Subjects who do 
not become hyperkalemic during RTP will be censored at the time of the last S-K measure 
available for the RTP. 


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4.2.3.3 
Primary Analysis of Secondary Endpoints for RTP 
Descriptive statistics will be presented for S-K levels for all timepoints for each S-K was 
scheduled to be measured, as well as OLP baseline. The statistics will include the mean 
change (absolute and percent change) from baseline. In addition, a plot of S-K values by 
timepoint will be presented. 
Similarly, the proportion of subjects who remain normokalemic will be presented by study 
visit. 
Proportion of subjects normokalemic at Study Day 29 
For the Day 29, the likelihood of being normokalemic will be compared using a logistic 
regression model containing the same baseline covariates as for the primary efficacy endpoint 
with the exception of visit and the visit-by-treatment interaction (see Section 4.2.1.4). The 
estimated odds ratios corresponding to the difference between the treatment arms, 95% 2-
sided CI and p-values will be provided.  
Proportion of subjects normokalemic during the RTP 
The likelihood of being normokalemic during RTP will be analyzed using a generalized mixed 
model (SAS PROC GLIMMIX), which includes a random intercept and logit link. The model 
will include all S-K data values collected at the scheduled visits between Days 8-29, 
dichotomized as normal and abnormal, as response variables, and the same covariates as the 
model used for the main analysis of the primary endpoint (See Section 4.2.1.4).Similarly, to 
the approach used for the primary analysis, the model will attempt to incorporate different 
(unstructured) degree of dependence between the repeated observations and, if issues with 
model fit are observed, switch to simplified dependence structures (see Section 3.3.6). The 
estimated odds ratios corresponding to the difference between the treatment arms, 95% 2-
sided CI and p-values will be provided.  
Number of days subjects remain normokalemic 
The number of normokalemic days during the RTP, inclusive of Days 8-29, 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.  
The number of normokalemic days will be analyzed using a linear regression model with the 
same baseline covariates as for the primary efficacy endpoint, with the exception of visit and 
the visit-by-treatment interaction (see Section 4.2.1.4). The results will be presented per 
treatment arm. The p-value (two-sided) will be provided to compare the LSMEAN of the 
normokalemic days between each active treatment versus placebo. 


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Time to hyperkalemia 
The time to hyperkalemia (days) will be summarized using Kaplan-Meier life table curves and 
associated 95% CI points will be provided at Days 2, 5, 8, 12, 15, 19, 22 and 29 during the 
RTP. Kaplan-Meier curves of the time to hyperkalemia (days) will be displayed for each 
treatment group. 
A Cox proportional hazards model (SAS PROC PHREG) will be used with the same baseline 
covariates as for the primary efficacy endpoint analysis, with the exception of visit and the 
visit-by-treatment interaction (see Section 4.2.1.4). The hazard ratio between each active 
treatment versus placebo will be reported along with a 95% confidence interval and a p-value. 
Mean changes in S-Aldo and P-Renin levels 
Descriptive statistics will be presented for nominal values, change and percent change from 
baseline in S-Aldo and P-Renin levels during the RTP at  Randomization (Day 1),  Day 15, 
Day 29, and EOS for each. 
This endpoint will also be analyzed using a longitudinal mixed model (SAS PROC MIXED) 
respectively for S-Aldo and P-Renin levels. The model will include all S-Aldo and P-Renin 
data values collected at the scheduled visits on Days 15 and 29 as response variables, and RTP 
baseline values for S-Aldo and P-Renin (respectively), baseline OLP eGFR, age (<55, 55-64, 
>64 years) and baseline binary indicators for RAAS inhibitors, chronic kidney disease, heart 
failure and diabetes mellitus as covariates. 
The p-value from LSMEAN (two-sided) will be provided to compare the overall mean 
difference in S-Aldo and P-Renin values between each active treatment (ZS 10g and ZS 5g) 
and placebo. The estimated mean difference in S-Aldo and P-Renin values between each of 
the active treatment groups (ZS 10g and ZS 5 g) relative to the placebo treatment group will 
be provided along with accompanying 95% confidence intervals. 
4.2.3.4 
Supplementary Analyses of the Secondary Endpoint 
One supplementary analysis, aimed at evaluating the impact of disallowed medications use on 
the likelihood of being normokalemic at the end of RTP, will be performed. The intercurrent 
event of disallowed medication is again incorporated through a composite endpoint where 
subjects who receive disallowed medication are classed as “non-responders”. The analysis 
described above will then be replicated using this endpoint. 
4.2.3.5 
Subgroup Analyses 
The secondary efficacy endpoint of the proportion of subjects who remain normokalemic (as 
defined by S-K between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized 
treatment study phase will be evaluated in order to explore the consistency of the treatment 
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• chronic kidney disease status (yes/no) 
• diabetes mellitus status (yes/no) 
• heart failure status (yes/no) 
• those on RAAS inhibitors (yes/no). 
A minimum of 10 responses in total for both arms combined are required for a subgroup 
analysis to be performed. A single model will be fitted, this model including a treatment by 
subgroup interaction term in addition to the covariates in the original analysis. Estimates of 
the treatment effect for each subgroup will be provided, with corresponding confidence 
intervals. A p-value for the interaction term will also be given.  
4.2.3.6 
Handling of Dropouts and Missing Data 
The S-K levels used for all secondary analyses will be based on the c-lab measurements 
obtained during the RTP. Missing S-K c-lab values will be replaced as described in Section 
3.3.5.   
For the number of days subjects remain normokalemic, if an intermediate assessment time 
point is missing, the time interval will be extended until the next non-missing time point. 
4.3 
Safety Analyses  
The respective safety analysis will be undertaken on the safety analysis sets, separately for the 
OLP and for the RTP. Safety and tolerability data will be presented by treatment arm and 
listed, unless otherwise stated.  
Safety endpoints will include adverse events (AEs), vital signs (VS), ECGs, clinical laboratory 
evaluations, and other electrolytes (specifically, serum calcium [S-Ca], serum magnesium [S-
Mg], serum sodium [S-Na], serum phosphate [S-PO4], serum bicarbonate [S-HCO3], and 
blood urea nitrogen [BUN]). 
4.3.1 
Exposure 
4.3.1.1 
Definitions and Derivations 
Duration of exposure is defined as the number of days between the first and the last dose of IP 
+ 1 day, for each treatment period. Duration of exposure for subjects on every other day 
dosing is defined as the number of days between the first and the last dose of IP where 
subjects have a planned dose of IP + 2 days. 
Actual Exposure 
Actual exposure for each subject will be obtained by summing up the days for which at least 
one dose of the drug was taken, excluding dose interruptions, and for each treatment arm and 
overall.  


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4.3.1.2 
Presentation 
Individual subject data for study drug administration will be listed for all subjects respectively 
in the SAF-OLP and SAF-RTP. 
Duration of exposure and actual exposure will be summarized for the OLP and the RTP, 
overall and by treatment group. 
4.3.2 
Adverse Events 
4.3.2.1 
Definitions and Derivations 
On-treatment adverse events are defined as per Section 3.3.1.2.  
The derivations for the following parameters will be the difference between the two dates 
stated below + 1 day (where first dose date is for either the OLP or RTP first dose date as 
applicable). 
• Time from start of treatment to onset of AE (days) 
• Time from last dose to death (days) 
• Time from first dose to death (days) 
• Time from last dose to onset of AE (days) - Calculated for AEs starting after the 
discontinuation of the study treatment. 
• Time from start of treatment to AE becoming serious (days) 
• Time from start of treatment to discontinuation of investigational product (due to 
adverse event) (days). 
MedDRA (using the latest or current version) is used to code AEs apart from hypokalemia. 
The identified risk of hypokalaemia is defined by laboratory values and not by specific 
MedDRA terms. 
Oedema 
Oedema related events will be defined by the following MedDRA PT terms: Hypervolaemia 
Fluid retention, Generalised oedema, Localised oedema, Oedema, Oedema peripheral, 
Peripheral swelling.  
4.3.2.2 
Presentation 
Adverse Events will be presented separately for the OLP and the RTP. The analyses will 
mainly be focused on on-treatment AEs, but some tables will be replicated for all AEs 
occurring during a study period. All adverse events will be summarized by SOC and PT. All 
AEs, including those not considered on-treatment, will be included in safety listings but 
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The onset date of the AE determines the phase in which the AE will be summarized. This is in 
order to have a consistent “worst case” allocation of AEs, because it will not be possible to 
distinguish AEs occurring before or after the actual intake of randomized IP. 
Overall Summary of Adverse Events 
AEs will be summarised by treatment group for the OLP and RTP and will include the 
following:  
• the number and percentage of subjects experiencing an AE 
• the number and percentage of subjects experiencing an AE with an outcome of death 
• the number and percentage of subjects experiencing a SAE 
• the number and percentage of subjects experiencing an AE leading to treatment 
withdrawal  
This table will be done both on-treatment and using all AEs that occurred during RTP.  
 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) 
The number and percentage of subjects with AEs and SAEs will be summarised by SOC and 
PT, by treatment group. A subject with more than one type of AE in a particular SOC will be 
counted only once in the total of subjects experiencing AEs in that particular SOC. Since a 
subject could have more than one type of AE within a particular SOC, the sum of subjects 
experiencing different AEs within the SOC could be larger than the total number of subjects 
experiencing AEs in that SOC. Similarly, a subject who has experienced an AE in more than 
one SOC will be counted only once in the total number of subjects experiencing AEs in all 
SOCs.  
AEs by PT and  frequency 
The number and percentage of subjects with AEs will be summarised by PT and treatment 
group and sorted by descending frequency on PT level.   
Possibly related AEs and SAEs by SOC and PT 
The number and percentage of subjects with possibly related AEs and SAEs will be 
summarised by SOC, PT, and treatment group. 
AEs by SOC, PT, and maximum severity 
The number and percentage of subjects with AEs will be summarised by SOC, PT and 
maximum intensity, and treatment group.  
Deaths 
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summarised by SOC, PT, and treatment group. Subject listings of all deaths and their causes 
will be provided. 
Oedema 
The number and percentage of subjects with oedema related events will be presented by 
treatment group, separately for OLP and RTP.  
4.3.3 
Clinical Laboratory, Blood Sample 
4.3.3.1 
Definitions and Derivations 
A full list of parameters (including other electrolytes) is provided in Appendix C: Laboratory 
Safety Variables.  
These will be evaluated fasting at OLP Day 1, End of OLP and EOS for subjects not entering 
the RTP and at RTP Randomization visit, Visit 10, Visit 14 and EOS for those entering the 
RTP. 
The date, time of collection and results (values, units and reference ranges) will be recorded in 
the appropriate eCRF module.  
The clinical chemistry and hematology will be performed at a central laboratory.  
Elevated liver test results  
• 
ALT >3x, >5x, and >10x ULN during the study.  
• 
AST >3x, >5x, and >10x ULN during the study.  
• 
Total bilirubin  >=2x ULN during the study.  
Hypokalemia 
Hypokalemia is determined as potassium values <3.5 mmol/L. 
4.3.3.2 
Presentations 
Descriptive statistics by time of assessment will be presented for each laboratory parameter 
including other serum electrolytes separately for OLP and RTP. All laboratory values will be 
classified as low, normal, or high based on normal ranges supplied by the central laboratory. 
For purposes of analyses, laboratory results based upon standardized units will be used.  
For each summary of continuous variables, the number of non-missing observations, mean, 
median, standard deviation, minimum, and maximum values will be presented by study phase 
and treatment group for OLP and RTP. 


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Absolute values and change from baseline for all continuous haematology and clinical 
chemistry parameters will be summarized for OLP and RTP by treatment arm and scheduled 
visit. 
Box plots of absolute values by scheduled visit, and box plots of change from baseline by 
visit, may be presented for certain parameters if warranted after data review. 
Any treatment-emergent laboratory data reported as abnormal according to reference values as 
well as individuals with treatment-emergent, abnormal serum laboratory values will be 
summarized and listed for the relevant safety analysis set by treatment group presented 
separately for the OLP and the RTP.  
Additionally, subject listings and summary of all on-treatment hematology and chemistry 
changes will be provided for OLP and RTP by treatment group. 
Elevated liver test results  
Maximum on-treatment ALT and AST versus maximum total bilirubin will be presented. 
Listings of liver biochemistry test results will be provided, separately for OLP and RTP. 
Hypokalemia 
Tabulation of the number and percentage of subjects with hypokalemia (<2.5 mmol/L, <3 
mmol/L, <3.5 mmol/L) at any point during a phase (OLP and RTP), while on treatment, will 
be presented by treatment group.  
4.3.4 
Clinical Laboratory, Urinalysis 
4.3.4.1 
Definitions and Derivations 
A full list of the urinalysis parameters for this study (including other electrolytes) is provided 
in Appendix C: Laboratory Safety Variables 
These will be evaluated fasting at OLP Day 1, End of OLP and EOS for subjects not entering 
the RTP and at RTP Randomization visit, Visit 10, Visit 14 and EOS for those entering the 
RTP. 
The date, time of collection and results (values, units and reference ranges) will be recorded in 
the appropriate eCRF module.  
The urinalysis will be performed at a central laboratory.  
4.3.4.2 
Presentations 
Absolute values and change from baseline for all continuous urinalysis will be summarized for 
OLP and RTP by treatment arm and visit. 


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Urinalysis baseline versus maximum value on treatment shift table will be provided for 
categorical urinalysis parameters.  
If applicable, urinalysis values will be classified as low, normal, or high based on normal 
ranges supplied by the central laboratory and presented in a shift table as described above. For 
purposes of analyses and where applicable, urinalysis results based upon standardized units 
will be used.  
4.3.5 
Other Laboratory Evaluations 
4.3.5.1 
Definitions and Derivations 
In addition to the urinalysis urine-HCG will also be collected during the study. The OLP Day 
1 urine pregnancy test for women of childbearing potential is performed as part of the 
screening procedure prior to any IP administration and is repeated at the last visit of the study, 
either on the OLP EOS visit, or on the RTP EOS visit. 
4.3.5.2 
Presentations 
These data will be listed only, no summary tables will be produced. 
4.3.6 
Vital Signs 
4.3.6.1 
Definitions and Derivations 
Pulse rate and systolic and diastolic blood pressure (BP) will be assessed at OLP Day 1, End 
of OLP and EOS for subjects not entering the RTP and at RTP Randomization visit, Visit 10, 
Visit 14 and EOS for those entering the RTP. 
4.3.6.2 
Presentations 
Summary statistics for vital signs will be calculated for absolute values and change from 
baseline to each subsequent planned visit where applicable. For each summary, the number of 
non-missing observations, mean, median, standard deviation, minimum, and maximum will be 
presented by treatment group for each study phase (OLP and RTP). 
Baseline versus maximum value on treatment shift table will be provided for all vital sign 
parameters.  
Any treatment-emergent, abnormal vital signs will be summarized and listed for the safety 
analysis set by treatment group for each study phase (OLP and RTP). 
4.3.7 
Physical examinations 
4.3.7.1 
Definitions and Derivations 
Any new or aggravated clinically relevant abnormal medical findings at a physical 
examination as compared with the baseline assessment will be reported as an AE. 


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4.3.7.2 
Presentations 
No separate analyses for Physical Examinations will be provided.  
4.3.8 
Electrocardiogram 
4.3.8.1 
Definitions and Derivations 
ECG mean heart rate, P wave duration and QRS durations, PR and QTc intervals aggregate 
will be recorded at OLP Day 1, Day 2, End of OLP and EOS for subjects not entering the 
RTP, and at RTP Randomization Visit (RTP Day 1), Visits 5, 8, 10, 12, 14, and EOS for those 
entering the RTP.  
QTc intervals 
QTc intervals will be calculated using the Fridericia formula: 
𝑄𝑇𝑐𝐹=
𝑄𝑇(𝑚𝑠𝑒𝑐)
(𝑅𝑅(𝑚𝑠𝑒𝑐) 1000
⁄
)1 3
⁄  
Where: 
1. 𝑅𝑅(𝑚𝑠𝑒𝑐) = (60 𝐻𝑅
⁄
) ∗1000 
2. 𝑅𝑅 = RR interval 
3. 𝐻𝑅 = Heart rate. 
4.3.8.2 
Presentations 
Overall ECG evaluations will be presented in a shift table showing baseline classification 
against last on-treatment (OLP and RTP) classification, by treatment group.  
The following ECG variables will be descriptively summarized by treatment group and visit to 
include change from baseline to each subsequent visit: ECG mean heart rate, P wave duration, 
PR interval aggregate, QRS duration aggregate, QT interval aggregate and QTcF interval 
aggregate. The summaries will be presented for OLP and RTP, separately. 
A listing of subjects with overall ECG evaluation reported as abnormal or borderline abnormal 
will also be provided. 
QTc intervals 
Number and percentage of subjects for QTcF for the following categories will be provided for 
OLP and RTP, by treatment group. 
• QTcF value above 450 ms at baseline (>450 ms, 480 ms and > 500 ms): 


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• QTcF value above 450 ms at any time during treatment (>450 ms, 480 ms and > 500 
ms): 
• QTcF increase by more than 30 ms at any time during treatment (>30 ms, >60 ms and 
>90 ms) 
• QTcF value above 450 ms and QTcF increase [a] by more than 30 ms at any time 
during treatment [(value > 450 ms and increase >30 ms and (value > 500 ms and 
increase >60 ms)] 
• QTcF decrease by more than 30 ms at any time during treatment (>30 ms, >60 ms and 
>90 ms). 
4.3.9 
Other Safety Assessments 
Not applicable. 
5 
INTERIM ANALYSIS 
Not applicable.  
 
 


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6 
REFERENCES 
This Statistical Analysis Plan (SAP) is based on ZS-Harmonize Asia Protocol Version 6, 
dated 19 August 2020. 
[1] SAS/STAT® 9.3 User’s Guide. The FREQ Procedure: Odds Ratio and Relative Risks 
for 2 x 2 Tables, viewed Jan 2019, 
https://support.sas.com/documentation/cdl/en/statug/63962/HTML/default/viewer.htm
#statug_freq_a0000000565.htm 
[2] Ann Intern Med. 2009;150(9):604-612. A New Equation to Estimate Glomerular 
Filtration Rate. https://annals.org/aim/article-abstract/744469/new-equation-estimate-
glomerular-filtration-rate 
[3] ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. EMA/CHMP/ICH/436221/2017, 
Committee for Human Medicinal Products 
[4] Brand, J. P. L. (1999). Development, Implementation, and Evaluation of Multiple 
Imputation Strategies for the Statistical Analysis of Incomplete Data Sets. Ph.D. thesis, 
Erasmus University. 
[5] Van Buuren (2007). Multiple imputation of discrete and continuous data by fully 
conditional specification. Statistical Methods in Medical Research, (16), 3, 219–242 
[6] Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John 
Wiley & Sons, Inc 
 
 
 


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7 
APPENDIX  
7.1 
Appendix A: IPD Master List 
IPD Code 
IPD 
CSP Version 
and Date 
Identification method 
Source for 
identification 
1 
Inclusion Criteria Deviations - Subjects who were enrolled or randomized but did not meet critical inclusion criteria.  
1.1  
Provision of informed consent (pre-screening consent - as 
applicable) prior to any study specific procedures.  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Manual CRA review  
 
DM: 
CONSENT1, 
VISIT2  
1.2  
Male and female subjects aged 18 to 90 years, inclusive  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Manual CRA review  
 
DM  
1.3  
Provision of informed consent prior to any study specific 
procedures  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Manual CRA review  
 
DM: CONSENT, 
VISIT1  
1.4  
Two consecutive i-STAT potassium values, measured 60-
minutes (± 10 minutes) apart, both ≥ 5.1 mmol/L and 
measured within 1 day of the first ZS dose on open-label 
initial phase Day 1  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- B&I Programming  
- Source Data review  
 
DM: LB, EX  
1.5  
Ability to have repeated blood draws or effective venous 
catheterization  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
1.6  
Female patients must be 1 year post-menopausal, surgically 
sterile, or using an acceptable method of contraception (an 
acceptable method of contraception is defined as a barrier 
method in conjunction with a spermicide) for the duration of 
the study (from the time they sign consent) and for 3 months 
after the last dose of ZS/matching placebo to prevent 
pregnancy. In addition, oral contraceptives, approved 
contraceptive implant, long-term injectable contraception, 
intrauterine device, or tubal ligation are allowed. Oral 
contraception alone is not acceptable; additional barrier 
methods in conjunction with spermicide must be used  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 


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1.7  
Randomized to the 28-day randomized treatment study phase, 
even though not fulfilling randomization criteria: The i-STAT 
potassium value is within the normal range (3.5 to 5.0 
mmol/L, inclusive).  
Refer to CSP sec. 4.3 for details about randomization criteria  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- B&I Programming  
- Source Data review  
 
DM: LB2  
2 
Exclusion Criteria Deviations - Subjects who were enrolled or randomized even though they fulfilled the critical exclusion criteria. 
2.1  
Participation in another clinical study with an investigational 
product during the last 3 months  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.2  
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  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.3  
Pseudohyperkalemia signs and symptoms, such as hemolyzed 
blood specimen due to excessive fist clenching to make veins 
prominent, difficult or traumatic venepuncture, or history of 
severe leukocytosis or thrombocytosis  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.4  
Patients treated with lactulose, xifaxan (rifaximin) or other 
non-absorbed antibiotics for hyperammonemia within 7 days 
prior to the first dose of study drug  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data review  
 
CM: EX  
2.5  
Patients treated with resins (such as sevelamer acetate or 
sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), 
calcium acetate, calcium carbonate, or lanthanum carbonate, 
within 7 days prior to the first dose of study drug  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data review  
 
CM: EX  
2.6  
Patients with a life expectancy of less than 3 months  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.7  
Patients who are severely physically or mentally incapacitated 
and who in the opinion of investigator are unable to perform 
the subjects’ tasks associated with the protocol  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.8  
Female patients who are pregnant, lactating, or planning to 
become pregnant  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Source Data review  
 
DM: PREG: 
VISIT  
2.9  
Patients with diabetic ketoacidosis  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data review  
MH  
2.10  
Known hypersensitivity or previous anaphylaxis to ZS or to 
components thereof  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
2.11  
Patients with cardiac arrhythmias that require immediate 
CSP v6.0  
- Source Data review  
 


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treatment  
(19-Aug-2020)  
2.12  
History of QT prolongation associated with other medications 
that required discontinuation of that medication  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
- B&I Programming  
 
2.13 
Congenital long QT syndrome 
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
- B&I Programming 
MH 
2.14  
Symptomatic or uncontrolled atrial fibrillation despite 
treatment, or asymptomatic sustained ventricular tachycardia. 
Subjects with atrial fibrillation controlled by medication are 
permitted  
CSP v6.0  
(19-Aug-2020)  
 
- Source Data review  
 
2.15  
QTc(f) > 550 msec  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Source Data review  
DM: 
EG,EG1,EG2,EG
3  
2.16  
Patients on dialysis  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3  
Discontinuation Criteria for study product met but patient not withdrawn from study treatment  
3.1  
Patient Decision to discontinue treatment but patient not 
withdrawn from study treatment  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Source Data review  
DM: EX: EX1: 
DOSDISC  
3.2  
Adverse Event requiring IP discontinuation but patient not 
withdrawn from study treatment  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Source Data review  
DM: EX: EX1: 
DOSDISC  
3.3  
Severe non-compliance with the study protocol (as assessed 
by Investigator and/or AZ)  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3.4  
Patient not discontinued from study medication although Risk 
to subjects was judged by the investigator  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3.5  
Pregnancy is confirmed  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- Source Data review  
DM: PREG: 
DOSDISC  
3.6  
Require treatment with medications prohibited or 
contraindicated for use due to safety concerns with ZS  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3.7  
Start dialysis while in the study  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3.8  
Patient unblinded due to emergency  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
3.9  
Patients who change or switch RAAS inhibitor and/or diuretic 
dose during the study  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
3.10  
Patient develops severe hypokalaemia (i-STAT potassium 
CSP v6.0  
- EDC Automatic Check  
DM: 


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values <3.0 mmol/L) at any time during the study or has i-
STAT level > 6.2 mmol/L during the 28-day randomized 
treatment study phase (confirmed by taking a second 
potassium  
measurement after a 10 ± 2 -minute interval, and both i-STAT 
values meet the study drug discontinuation rule).  
(19-Aug-2020)  
- Source Data review  
LB,LB1,LB2,LB
3: EX: EX1: 
DOSDISC  
3.11 
Patient has a clinically significant cardiac arrhythmia (see 
below) at any time in the 28-day randomized treatment study 
phase, the patient should immediately receive appropriate 
medical treatment and be discontinued from study drug. Any 
of the following cardiac events will result in immediate 
discontinuation from the study drug (independent of whether 
it is in the open-label initial phase or the 28-day randomized 
treatment study phase):  
CSP v6.0 
(19-Aug-2020) 
 
 
 
 
 
 
3.11.1 
- 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])  
- EDC Automatic Check  
- Source Data review  
 
DM: 
AE:DOSIDISC  
3.11.2  
- Acute heart failure  
- B&I Programming - 
Source Data review  
 
DM: EG2, EG3: 
DOSDISC  
3.11.3  
- Significant increase in PR interval (> 250 msec 
in the absence of pre-existing atrioventricular 
block), widening of the QRS complex (>140 msec 
in the absence of pre-existing bundle branch block) 
or new onset peaked T-wave.  
- EDC Automatic Check - 
Source Data review  
 
DM: EG, 
EG2,EG3: 
DOSDISC  
3.11.4 
- 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. 
The QTc(f) algorithm (QT interval corrected by the 
- EDC Automatic Check 
for QTcF only  
- B&I Programming - 
Source Data review  
 
DM: AE: 
DOSDISC  


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Fridericia method) is recommended.  
4  
Discontinuation Criteria for overall study withdrawal met but patient not withdrawn from study  
4.1  
Voluntary discontinuation by the patient  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
4.2  
Severe non-compliance to protocol as judged by the 
Investigator and/or Sponsor  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
5  
Investigational Product (IP) Deviation  
5.1  
Participant received incorrect IP (corporate IPD):Subject 
received incorrect IP to that to which they were randomised.  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
5.2  
Subjects who were randomised but did not receive IP  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data review  
DS: DS1: IE1; 
EX1: DOSDISC 
5.3  
Incorrect Dose Adjustment during Open Label Phase:  
If a patient develops confirmed i-STAT potassium values 
between 3.0 mmol/L and 3.4 mmol/L, inclusive, during the 
open-label initial phase, but patient takes more ZS during the 
rest of that day. (refer to CSP sec. 7.2)  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data review  
 
LB: LB1: EX  
5.4  
Incorrect dose adjustment during 28-Day Randomized 
Treatment Phase: 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 28 -day randomized 
treatment study phase, dosing is not reduced from qd to qod 
for the remainder of the study.  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
- 
 
5.5  
Incorrect dose adjustment during 28-Day Randomized 
Treatment Phase:  
After dosing reduced from qd to qod, if a patient i-STAT 
potassium value is back to normal (3.5 – 6.2 mmol/L 
inclusive), during the 28-day randomized treatment study 
phase, dosing is increased back from qod to qd for the 
remainder of the study.  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
 
5.6  
Use of expired IP  
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
6 
Excluded Medications taken 


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6.1  
Subject received concomitant medication defined as 
prohibited in the CSP (corporate IPD).  
Administration of prohibited concomitant medication or non-
drug therapy as outlined in CSP sec 7.7)  
CSP v6.0  
(19-Aug-2020)  
- Manual Physician Review 
based on CMR/GPR reports  
- B&I Programming  
- Source Data Review  
CM  
7. 
Deviations to study procedure 
7.1  
Two or more successive visits missed or not performed 
according to the protocol  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data Review  
VISIT, VISIT1  
7.2  
Any of the following visits missed:  
For those patients randomized (with patient randomization 
number) on Day 2 and get randomized same day, they should 
complete:  
- Enrolment/screening visit  
- Open label initial phase Day 1  
- Randomization visit  
 
For those patients randomized (with patient randomization 
number) on Day 3, they should complete:  
- Enrolment/screening visit  
- Open label initial phase Day 1  
- Open label initial phase Day 2  
- Randomization visit  
 
For those patients who failed OLP, they should complete:  
- Enrolment/screening visit  
- Open label initial phase Day 1  
- Open label initial phase Day 2  
- Open label initial phase Day 3  
CSP v6.0  
(19-Aug-2020)  
- B&I Programming  
- Source Data Review  
 
VISIT, VISIT1  
7.3  
Patient is not fasting for any of the following visits as per 
protocol for K sample for i-STAT or central lab for open-label 
initial phase:  
- Day 1 – 0min (1st potassium sample for assessment, pre-
dose)  
- Day 1 – 60 min (2nd potassium sample for assessment, pre-
dose)  
- Day 2 or Day 3 or Randomization – 0 min (pre-dose)  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check 
for Local Labs only  
- Source Data Review  
 
DM: LB, 
LB1,LB2  


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7.4  
Missing ALL of the following i-STAT and central lab 
potassium samples (as applicable) for Open-label initial 
phase:  
- Day 1 – 0min (1st potassium sample for assessment, pre-
dose)  
- Day 1 – 60 min (2nd potassium sample for assessment, pre-
dose)  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check 
for Local Labs only  
- Source Data Review  
 
DM: LB  
7.5  
Missing the i-STAT and central lab potassium samples for 
Randomization Visit (open-label initial phase Day 2 or Day 3) 
– 0 min (pre-dose)  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check 
for Local Labs only  
- Source Data Review  
DM: LB1, LB2  
7.6  
Patient is not fasting for any of the following visits as per 
protocol for S-K sample for i-STAT or central lab for 
Randomized Treatment Phase – Day 1, 15, 29, 35  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check 
for Local Labs only  
- Source Data Review  
DM: LB2  
7.7  
For subjects randomized and not withdrawn before Day 8 of 
the 28-day randomized treatment study phase, missing BOTH 
the i-STAT and central lab potassium samples from Day 8 to 
Day 28  
CSP v6.0  
(19-Aug-2020)  
- EDC Automatic Check  
- B&I Programming  
- Source Data review  
DM: LB2, 
ASMPERF: DS1: 
DS: VISIT  
7.8 
Missing any of two consecutive i-STAT potassium values, 
measured ± 10 minutes apart during study drug adjustment or 
patient discontinuation 
CSP v6.0  
(19-Aug-2020) 
- Source Data review  
 
 
8 
Other Important Protocol Deviations (including missing PI eCRF signature [corporate IPD], others to be agreed by Study 
Team) 
8.1  
Any deviation considered important that was not predicted or 
prespecified.  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
8.2  
Add study specific IPDs that are not covered by any category 
above.  
CSP v6.0  
(19-Aug-2020)  
- Source Data review  
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code D9480C00001 
Edition Number 1.0 
Date  
59 
 
7.2 
Appendix B: Disallowed Medications 
Disallowed medications in the study broadly consist of two classes: potassium binders and 
RAASi / diuretics. For the former, any use of while on IP is to be considered as an instance 
of disallowed medication usage. For the latter, as per the CSP, the addition of a new RAAS 
inhibitor and/or diuretic, or change of the dose, discontinuation, or switch of these drugs, is 
to be considered as an instance of usage of disallowed mediation. 
The exact method by which such instances of usage can be identified in the database will be 
documented separately. 
 
 


Statistical Analysis Plan  
Study Code D9480C00001 
Edition Number 1.0 
Date  
60 
7.3 
 Appendix C: Laboratory Safety Variables 
Haematology  
Clinical Chemistry (serum) 
B-Hemoglobin (Hb)  
S-Total Protein 
B-Hematocrit  
S-Albumin 
B-Erythocyte count (RBC)  
S-Bicarbonate 
B-Total leukocyte count (WBC)  
S-Blood Urea Nitrogen 
B-Leukocyte differential count (absolute count)  
S-Creatinine 
B-Platelet count  
S-Bilirubin, total 
S-Alkaline phosphatise (ALP) 
Urinalysis  
S-Glucose 
U-PH  
S-Sodium 
U-Specific gravity  
S-Potassium1 
U-Glucose  
S-Inorganic phosphate 
U-Ketones  
S-Calcium, total 
U-Bilirubin  
S-Magnesium 
U-Urobilinogen  
S-Gamma-glutamyl transferase (GGT) 
U-Blood  
S-Aspartate transaminase (AST) 
 
S-Alanine transaminase (ALT) 
U- Human chorionic gonadotropin (HCG)  
(only for females of childbearing potential) 2 
S-Aldosterone3 
P-Renin 3 
1. Blood potassium will be measured only by i-STAT at the optional Pre-screening visit. Blood potassium will be 
measured by i-STAT and Serum potassium will be measured by C-lab for Visit 2 to EOS Visit.  
2. Urine-HCG will be measured at clinic, used the tube provided by Central Laboratory.  
3. Subjects need to be either standing or seated upright for at least 2 hours before sample collection for S-Aldosterone and 
P-Renin assessment.